Enhanced Β Integrin Adhesion Underlies Thrombosis Risk in JAK2

This Month

CD40-targeting HIV vaccine attacks the latent reservoir 2 Neonatal Fc receptor antagonist safely reduces IgGs in healthy adults 3 Reversing B cell impairment in chronic hepatitis B infection 4 Intratumor NK cells respond to PD-1/PD-L1 blockade 5

October 2018 JCI This Month is a summary of the most recent articles in The Journal of Clinical Investigation and JCI Insight jci.org/this-month Enhanced β integrin adhesion underlies thrombosis risk in JAK2-

Scan for the digital version V617F–driven neoplasms p. 2 of JCI This Month. Journal of Clinical Investigation Consulting Editors

Soman N. Abraham Richard T. D'Aquila Katherine A. High Terri Laufer Sallie R. Permar Roy L. Silverstein John S. Adams Alan Daugherty Helen H. Hobbs Mitchell A. Lazar David J. Pinsky M. Celeste Simon Qais Al-Awqati Sudhansu Dey Ronald Hoffman Brendan Lee Edward Plow Mihaela Skobe Kari Alitalo Anna Mae Diehl V. Michael Holers William M.F. Lee Catherine Postic Donald Small Dario C. Altieri Harry C. Dietz III Steven Holland Rudolph L. Leibel Alice S. Prince Lois Smith Masayuki Amagai Gianpietro Dotti David Holtzman Wayne I. Lencer Louis J. Ptacek Akrit Sodhi Brian H. Annex Michael Dustin Michael J. Holtzman Jon D. Levine Luigi Puglielli Weihong Song M. Amin Arnaout Connie J. Eaves Lawrence B. Holzman Ross L. Levine Pere Puigserver Ashley L. St. John Alan Attie Dominique Eladari Maureen Horton Klaus Ley Bali Pulendran Jonathan Stamler Jane E. Aubin Joel K. Elmquist Tamas L. Horvath Rodger A. Liddle Ellen Puré Colin L. Stewart Michael F. Beers Stephen G. Emerson Gokhan S. Hotamisligil Richard Locksley Susan E. Quaggin Doris Stoffers Vann Bennett Jonathan A. Epstein Steven R. Houser Fanxin Long Marlene Rabinovitch Warren Strober Gregory K. Bergey Adrian Erlebacher Ralph H. Hruban Gary Lopaschuk Daniel J. Rader Maureen A. Su Nina Bhardwaj Joel D. Ernst Christopher A. Hunter Nigel Mackman Shahin Rafii D. James Surmeier Morris J. Birnbaum James M. Ervasti David James Richard B. Mailman Gwendalyn J. Randolph Katalin Susztak Joyce Bischoff Robert V. Farese Jr. Richard J. Jones Rama K. Mallampalli Jeffrey C. Rathmell Catharina Svanborg Craig Blackstone Eric R. Fearon William G. Kaelin Jr. Kieren A. Marr W. Kimryn Rathmell Ira Tabas Bruce R. Blazar Anthony W. Ferrante Jr. Klaus Kaestner Jack Martin Barbara Rehermann Alan R. Tall Gerard C. Blobe Edward A. Fisher Mark L. Kahn Steven O. Marx Muredach P. Reilly Sakae Tanaka William A. Boisvert Richard A. Flavell Raghu Kalluri Rodger P. McEver Linda Resar Victor J. Thannickal Nancy Bonini Alessia Fornoni S. Ananth Karumanchi Elizabeth McNally Ryan Riddle Andrei Thomas-Tikhonenko Brendan Boyce Tatiana Foroud David A. Kass Cornelis J. Melief Sarah A. Robertson Georgia D. Tomaras Jonathan Bromberg Martin Friedlander Robert S. Kass Shlomo Melmed Howard A. Rockman Peter Tontonoz Frank C. Brosius Stephen J. Galli Masato Kasuga George Michalopoulos Paul B. Rosenberg Laurence A. Turka Hal E. Broxmeyer J. Victor Garcia-Martinez Daniel P. Kelly Jeffrey H. Miner Theodora S. Ross Marcel R.M. van den Brink Michael J. Caplan Alfred L. George Jr. Dontscho Kerjaschki Peter J. Mohler Marc E. Rothenberg Luc Van Kaer Diego H. Castrillon Sharon Gerecht Sundeep Khosla Jeffrey D. Molkentin Anil Rustgi David M. Virshup Harold Chapman Stanton L. Gerson Richard N. Kitsis David D. Moore Scheherazade Sadegh-Nasseri Matthias von Herrath Ajay Chawla Robert E. Gerszten Peter S. Klein Edward E. Morrisey J. Evan Sadler Kathryn R. Wagner Benjamin K. Chen Todd Golde Steven Kliewer James H. Morrissey Junichi Sadoshima Yisong Y. Wan Benny J. Chen Sherita Golden Björn C. Knollmann Deborah M. Muoio Jose-Alain Sahel Bart O. Williams Ju Chen Stanley Goldfarb Walter J. Koch Anthony J. Muslin Jean E. Schaffer Allan W. Wolkoff Jun Chen Larry B. Goldstein Jay K. Kolls Martin G. Myers Jr. Philipp E. Scherer Joseph C. Wu Marie-Françoise Chesselet Fred Sanford Gorelick Issei Komuro Benjamin G. Neel Michael D. Schneider Thomas A. Wynn Vivian G. Cheung Kathleen J. Green Christopher D. Kontos Paul W. Noble Detlef Schuppan Ramnik J. Xavier Raymond Chung Steven K. Grinspoon Murray Korc Guillermo Oliver Amita Sehgal Yiping Yang Jeanne M. Clark David Hafler Gary Koretzky Eric N. Olson Clay Semenkovich Srinivasan Yegnasubramanian Sheila Collins Jonathan J. Hansen Stavroula Kousteni Harry T. Orr Jonathan S. Serody Mone Zaidi Ronald G. Collman Raymond Clement Harris John W. Krakauer Leo E. Otterbein John Seykora Kang Zhang Marco Colonna Stanley L. Hazen Rohit N. Kulkarni Roberto Pacifici Theresa A. Shapiro Len Zon Shaun R. Coughlin Peter Heeringa Chulan Kwon Akhilesh Pandey Mari Shinohara Weiping Zou Tyler J. Curiel Meenhard Herlyn Antonio La Cava William C. Parks Steven E. Shoelson R. Suzanne Zukin David D'Alessio Joachim Herz Fadi G. Lakkis Warren S. Pear Gerald I. Shulman Featured Editor The JCI’s Editorial Board is composed of peer scientists at Johns Hopkins University School of Medicine, the This Month University of Maryland School of Medicine, and the National Institutes of Health. Editorial Board members October 2018 review and oversee peer review of each manuscript that is submitted to the JCI, and the Board meets weekly to discuss manuscripts undergoing review.

Ted M. Dawson, MD, PhD, Associate Editor, is the For the JCI Leonard and Madlyn Abramson Professor in Neuro- Editor degenerative Diseases and Director of the Institute for Rexford S. Ahima Cell Engineering at Johns Hopkins University School Deputy Editors of Medicine. He also serves as director of the Morris K. Arturo Casadevall, Gregg L. Semenza, Gordon F. Tomaselli Udall Parkinson’s Disease Research Center of Excel- Associate Editors lence. His laboratory is interested in identifying the Richard F. Ambinder, Mark E. Anderson, molecular mechanisms underlying neuronal survival and death in neurologic and Mary Y. Armanios, William R. Bishai, neurodegenerative diseases. Dr. Dawson is a member of the Association of American Robert A. Brodsky, Peter A. Calabresi, Thomas L. Clemens, Franco R. D’Alessio, Physicians and a fellow of the American Association for the Advancement of Science. Ted M. Dawson, Angelo M. DeMarzo, Publication highlights Stephen Desiderio, Mark Donowitz, Andrew P. Feinberg, Paul M. Hassoun, Yun SP, Kam TI, Panicker N, Kim S, Oh Y, Park JS, Kwon SH, Park YJ, Elizabeth M. Jaffee, Mariana J. Kaplan, Karuppagounder SS, Park H, Kim S, Oh N, Kim NA, Lee S, Brahmachari S, Mao X, Marikki Laiho, Leo Luznik, Marcela V. Maus, Timothy H. Moran, Laszlo Nagy, William Nelson, Lee JH, Kumar M, An D, Kang SU, Lee Y, Lee KC, Na DH, Kim D, Lee SH, Brian O’Rourke, Ben Ho Park, Jonathan D. Powell, Roschke VV, Liddelow SA, Mari Z, Barres BA, Dawson VL, Lee S, Dawson TM, Thomas C. Quinn, Hamid Rabb, Jean-Pierre Ko HS. Block of A1 astrocyte conversion by microglia is neuroprotective in models Raufman, Stuart C. Ray, Jeffrey D. Rothstein, Jonathan Schneck, Akrit S. Sodhi, of Parkinson’s disease. Nat Med. 2018;24(7):931–938. Charlotte J. Sumner, Simeon I. Taylor, Mao X, Ou MT, Karuppagounder SS, Kam TI, Yin X, Xiong Y, Ge P, Umanah GE, David L. Thomas, Robert G. Weiss, Sarah J. Wheelan, Marsha Wills-Karp Brahmachari S, Shin JH, Kang HC, Zhang J, Xu J, Chen R, Park H, Andrabi SA, Editorial Advisory Group Kang SU, Gonçalves RA, Liang Y, Zhang S, Qi C, Lam S, Keiler JA, Tyson J, Kim D, Peter Agre, Carol W. Grieder, Paul B. Rothman, Panicker N, Yun SP, Workman CJ, Vignali DA, Dawson VL, Ko HS, Dawson TM. Diane E. Griffin, and David Valle Pathological α-synuclein transmission initiated by binding lymphocyte-activation Biostatistician gene 3. Science. 2016;353(6307):aah3374. Eliseo Guallar Computational Biologist Wang Y, An R, Umanah GK, Park H, Nambiar K, Eacker SM, Kim B, Bao L, Patrick Cahan Harraz MM, Chang C, Chen R, Wang JE, Kam TI, Jeong JS, Xie Z, Neifert S, JCI Scholars Qian J, Andrabi SA, Blackshaw S, Zhu H, Song H, Ming GL, Dawson VL, Justin Lowenthal, Austin K. Mattox Dawson TM. A nuclease that mediates cell death induced by DNA damage and Staff Editors poly(ADP-ribose) polymerase-1. Science. 2016;354(6308):aad6872. Executive Editor Sarah C. Jackson Brahmachari S, Ge P, Lee SH, Kim D, Karuppagounder SS, Kumar M, Mao X, Science Editors Shin JH, Lee Y, Pletnikova O, Troncoso JC, Dawson VL, Dawson TM, Ko HS. Activa- Elyse Dankoski, Monika Deshpande, tion of tyrosine kinase c-Abl contributes to α-synuclein–induced neurodegeneration. Corinne Williams J Clin Invest. 2016;126(8):2970–2988. Editor at Large Ushma S. Neill JCI This Month ISSN 2324-7703 (print); (ASCI) indicates corresponding (online) ISSN 2325-4556 authors who are ASCI members. For the full JCI online: jci.me/128/10 Contact the JCI and JCI Insight 2015 Manchester Road The American Society for Clinical Investigation holds the rights Ann Arbor, Michigan 48104, USA to and publishes the Journal of Clinical Investigation and Phone: 734.222.6050 JCI Insight. The opinions expressed herein are solely those of Email: [email protected] (JCI); the authors and are not necessarily endorsed by the ASCI. [email protected] (JCI Insight)

jci.org/this-month october 2018 1 research Editor’s picks

on the jci cover hematology JAK2-V617F mutation boosts pathological thrombosis by enhancing β integrin adhesion Activating mutations in the non-tyrosine-kinase expressing the JAK2-V617F mutation. Stephen Oh

JAK2 are associated with the development of discusses β1 and β2 integrin targeting as a potential chronic myeloproliferative neoplasias (CMNs) strategy to mitigate risk in CMN patients in an characterized by myeloid overproliferation and accompanying Commentary. This issue’s cover abnormal homing of leukocytes to the spleen. The shows the expression of endothelial VCAM1 (white) V617F point mutation in JAK2 occurs in 95% of and ICAM1 (purple) together with myeloid-derived patients with the CMN polycythemia vera or cells (yellow) and other immune cell populations in essential thrombocytosis, and these patients are at a mouse spleen. Image credit: Lars Philipsen. an elevated risk developing life-threatening thrombosis. Recent work identified an interaction JAK2-V617F promotes venous between JAK2-V617F and the β1 and β2 integrins thrombosis through β1/β2 integrin that regulate leukocyte trafficking within the activation bloodstream, but the mechanisms underlying Bärbel Edelmann, Nibedita Gupta, increased thrombotic risk remained unclear. In this Tina M. Schnoeder, Anja M. Oelschlegel, issue of the JCI, Bärbel Edelmann et al. reveal that Khurrum Shahzad, Jürgen Goldschmidt, the JAK2-V617F mutation produces constitutive Lars Philipsen, Soenke Weinert, Aniket Ghosh, Related Commentary activity in the integrin signaling molecule Rap1, Felix C. Saalfeld, Subbaiah Chary Nimmagadda, Neutralize the neutrophils! leading to enhanced affinity ofβ 1 and β2 integrins Peter Müller, Rüdiger Braun-Dullaeus, Juliane Mohr, Neutrophil β1/β2 integrin for the endothelial adhesion molecules VCAM1 and Denise Wolleschak, Stefanie Kliche, Holger Amthauer, activation contributes to ICAM2. Neutralizing the overactive β integrins Florian H. Heidel, Burkhart Schraven, JAK2-V617F–driven thrombosis suppressed venous thrombosis and aberrant Berend Isermann, Andreas J. Müller, Stephen T. Oh leukocyte trafficking to the spleen in mice and Thomas Fischer https://jci.me/90312 https://jci.me/123388

aids/hiv

CD40-targeting HIV-1 vaccine enhances mice. These results support further development of the CD40-targeting vaccine to enhance viral control immunity against latent reservoir in mice in HIV-1–positive individuals. HIV-1–infected individuals require lifelong a vaccine against 5 highly conserved HIV-1 antigens TLR3 agonist and CD40-targeting treatment to suppress viral replication because of that targets CD40-expressing DCs to enhance vaccination induces immune the virus’s persistence in a latent reservoir. A subset immunity in CD4+ and CD8+ T cell subsets. In the responses and reduces HIV-1 reservoirs of HIV-1–infected individuals, termed elite present study, Liang Cheng and colleagues report Liang Cheng, Qi Wang, Guangming Li, controllers, maintain robust T cell responses in spite that the CD40-targeted vaccine profoundly delayed Riddhima Banga, Jianping Ma, Haisheng Yu, of long-term infection, leading to combined viral rebound following cART discontinuation in Fumihiko Yasui, Zheng Zhang, antiretroviral therapy–free (cART-free) viral control. HIV-1–positive humanized mice. When combined Giuseppe Pantaleo, Matthieu Perreau, A team led by Lishan Su and Yves Levy used with a TLR3-activating adjuvant, the vaccine Sandra Zurawski, Gerard Zurawski, Yves Levy, insights from studies of elite controllers to develop partially depleted latent HIV-1 reservoirs in the and Lishan Su https://jci.me/99005

2 jci.org/this-month october 2018 JCI | Research: Editor’s picks

clinical medicine Targeting neonatal Fc receptor safely reduces IgGs in healthy adults Pathogenic autoantibodies are central to the colleagues conducted a first-in-human study to Neonatal Fc receptor antagonist pathology of multiple sclerosis, myasthenia evaluate the FcRn antagonist efgartigimod in 62 efgartigimod safely and sustainably gravis, and other severe autoimmune disorders. healthy adults. Single and repeated dosing reduces IgGs in humans While IgG-modulating therapies exist, they can produced both robust and lasting reductions in Peter Ulrichts, Antonio Guglietta, Torsten Dreier, cause severe adverse reactions. Recently, the IgG levels in the human volunteers, with no Tonke van Bragt, Valérie Hanssens, Erik Hofman, neonatal Fc receptor (FcRn) was identified as part reports of serious adverse events. These results Bernhardt Vankerckhoven, Peter Verheesen, of an IgG-recycling pathway that maintains high support further study of efgartigimod as an Nicolas Ongenae, Valentina Lykhopiy, F. Javier IgG levels in circulation. FcRn blockade is alternative to approved strategies for treating Enriquez, JunHaeng Cho, Raimund J. Ober, presently being investigated as a potentially safer autoreactive IgG diseases. E. Sally Ward, Hans de Haard, and Nicolas Leupin approach to reducing IgG levels. Peter Ulrichts and http://jci.me/97911

Impairment of the cervicovaginal mucosa in women using Depo-Provera contraceptive Injectable medroxyprogesterone acetate, commercially known as infection. These findings add to increasing concerns about progesterone-only Depo-Provera, is a progesterone-only hormonal birth control. A growing contraceptive use in areas with high HIV prevalence and provide insights into number of epidemiological analyses associate use of Depo-Provera with an the pathways that maintain vaginal mucosal integrity. The accompanying increased risk of HIV-1 infection, leading to speculation that the regimen may image compares keratin 10 expression in the vaginal epithelium of women increase vaginal transmission of the disease. Irina Zalenskaya and colleagues using either Depo-Provera or an oral contraceptive. compared whole-genome transcriptome profiles from the ectocervical mucosa Use of contraceptive depot medroxyprogesterone acetate is of healthy women who had selected either Depo-Provera (n = 31) or a associated with impaired cervicovaginal mucosal integrity combined estrogen-progesterone oral contraceptive (n = 32) to ascertain Irina A. Zalenskaya, Neelima Chandra, Nazita Yousefieh, Xi Fang, whether the contraceptives induce differential gene expression in the Oluwatosin E. Adedipe, Suzanne S. Jackson, Sharon M. Anderson, protective mucosal barrier. In Depo-Provera–treated women, multiple mucosal Christine K. Mauck, Jill L. Schwartz, Andrea R. Thurman, and Gustavo F. Doncel maintenance genes were downregulated, which pathway analysis predicted http://jci.me/120583 would impair cervicovaginal immunity, increasing vulnerability to HIV-1

jci.org/this-month october 2018 3 JCI | Research: Editor’s picks

infectious disease

Related Research Antigen-specific B cell function is PD-1 blockade partially recovers dysfunctional virus–specific B cells in chronic hepatitis B infection impaired in chronic hepatitis B infection Loghman Salimzadeh, Nina Le Bert, Charles-A. Dutertre, Emerging evidence indicates that humoral immune responses are critical to Upkar S. Gill, Evan W. Newell, Christian Frey, Magdeleine Hung, controlling hepatitis B virus and may be defective in patients with chronic HBV (CHB) Nikolai Novikov, Simon Fletcher, Patrick T.F. Kennedy, infection. In this issue, complementary studies used fluorochrome-labeled HBV and Antonio Bertoletti http://jci.me/121957 surface antigens (HBsAgs) to reveal that antigen-specific B cells persist in CHB, but Circulating and intrahepatic antiviral B cells have altered phenotype and function. These cells expressed PD-1, a marker of are defective in hepatitis B exhaustion, and phenotypically resembled atypical memory B cells. Loghman Alice R. Burton, Laura J. Pallett, Laura E. McCoy, Kornelija Suveizdyte, Salimzadeh, Nina Le Bert, et al. showed that HBsAg-specific B cells had defective Oliver E. Amin, Leo Swadling, Elena Alberts, Brian R. Davidson, antibody production in chronic versus resolved infection. Alice Burton et al. observed Patrick T.F. Kennedy, Upkar S. Gill, Claudia Mauri, Paul A. Blair, that HBsAg-specific B cells displayed exhaustion-like defects in signaling, antiviral Nadege Pelletier, and Mala K. Maini http://jci.me/121960 cytokine production, and survival and could home to the liver, suggestive of the hepatic milieu in addition to chronic antigenic stimulation. Both studies discovered Related Commentary that PD-1 blockade combined with CD40L can partially restore defective function in Entering the spotlight: hepatitis B surface HBsAg-specific B cells. In the accompanying Commentary, Christoph Neumann- antigen–specific B cells Haefelin and Robert Thimme discuss targeting HBsAg-specific B cells as a potential Christoph Neumann-Haefelin and Robert Thimme strategy for enhancing viral control in CHB patients. http://jci.me/124098

transplantation

Disrupting vimentin at the The vimentin intermediate filament network restrains regulatory distal pole complex T cell suppression of graft-versus-host disease enhances Treg function Cameron McDonald-Hyman, James T. Muller, Strategies that manipulate the immunomodulatory functions of Tregs have the potential to improve Michael Loschi, Govindarajan Thangavelu, transplantation outcomes, but unique properties of this distinct cell population pose challenges for the clinical Asim Saha, Sudha Kumari, Dawn K. Reichenbach, development of safe and effective therapies. Unlike conventional T cells, which concentrate PKC-θ at the Michelle J. Smith, Guoan Zhang, Brent H. Koehn, immunological synapse, Tregs accumulate PKC-θ at the opposite-facing distal pole complex (DPC), a protein Jiqiang Lin, Jason S. Mitchell, Brian T. Fife, structure that regulates T cell polarity and activation. Cameron McDonald-Hyman and colleagues identified the Angela Panoskaltsis-Mortari, Colby J. Feser, intermediate filament protein vimentin as an essential binding partner for PKC-θ at the DPC (see the Andrew Kemal Kirchmeier, Mark J. Osborn, accompanying image). Disruption of the vimentin superstructure of the DPC enhanced Treg function. Moreover, Keli L. Hippen, Ameeta Kelekar, Jonathan S. Serody, in a mouse model of graft-versus-host disease, adoptive transfer of vimentin-disrupted Tregs suppressed Laurence A. Turka, David H. Munn, lethality more effectively than did transfer of control Tregs. These findings support the translational potential Hongbo Chi, Thomas A. Neubert, Michael L. Dustin, and of vimentin disruption to enhance Treg-targeting cellular therapies. Bruce R. Blazar (ASCI) http://jci.me/95713

4 jci.org/this-month october 2018 JCI | Research: Editor’s picks Memory T cell responses correspond to efficacy of herpes zoster vaccines Aging compromises antiviral immunity, leaving gE-specific T cell responses, the elevations were Th1 memory differentiates elderly individuals especially vulnerable to viral larger and T cell memory response was more recombinant from live infections and reactivations, including increased sustained in individuals treated with the adjuvanted herpes zoster vaccines incidence of herpes zoster that results from varicella vaccine. There were also important differences Myron J. Levin, Miranda E. Kroehl, Michael J. Johnson, zoster virus (VZV) reactivations. A live-attenuated between regulatory and immunologic checkpoint Andrew Hammes, Dominik Reinhold, Nancy Lang, VZV vaccine has low efficacy in protecting against phenotypes that distinguished the two vaccines. and Adriana Weinberg http://jci.me/121484 herpes zoster, but a newly approved adjuvanted Anne Gershon’s accompanying Commentary Related Commentary vaccine incorporating the VZV glycoprotein E (gE) suggests that the identification of immune Tale of two vaccines: differences in subunit confers robust protection. Myron Levin and correlates that parallel the vaccines’ clinical response to herpes zoster vaccines colleagues examined differential immune responses outcomes provides insight into mechanisms of both Anne A. Gershon http://jci.me/123217 to the two vaccines in older adults. While both vaccine performance and the pathogenesis of vaccines evoked acute increases in VZV- and herpes zoster.

oncology Inhibition of the aryl hydrocarbon receptor suppresses polyamine- PD-1–expressing NK cell subset dependent tumor growth contributes to efficacy of Polyamine metabolism plays an essential role in DNA translation, protein synthesis, and cellular proliferation. Observations of elevated polyamine levels checkpoint blockade in tumors support the potential of targeting its metabolism in anticancer Tumors with a low MHC I burden are typically unresponsive to checkpoint-targeting treatments. Anna Bianchi-Smiraglia, Archis Bagati, and coworkers identified a therapies, which depend on MHC-mediated activation of cytotoxic T cells. However, role for the aryl hydrocarbon receptor (AHR) in regulating polyamine biosynthe- some cancers are sensitive to PD-1/PD-L1 blockade in spite of low MHC I expression, sis through its effects on two protumorigenic proteins, ornithine decarboxylase suggesting that the therapy may be capable of stimulating antitumor activity in other and the antizyme inhibitor AZIN1. They discovered that a clinically approved immune cell types. Joy Hsu, Jonathan Hodgkins, and colleagues describe an integral role anti-leprosy agent, clofazimine, is an AHR antagonist. Noting that AHR levels for NK cells in mediating antitumor immunity elicited by PD-1/PD-L1 blockade. In inversely correlate with survival in patients with multiple myeloma (MM), the multiple mouse models, they identified a subpopulation of PD-1–expressing NK cells group evaluated clofazimine in mouse models of MM. Clofazimine reduced that reside exclusively within tumors. In tumor models in which NK cells, but not T cells, disease burden in MM mice with an efficacy comparable to that of bortezomib, mediated tumor rejection or in which T cells were depleted, PD-1 blockade was effective the preferred treatment for MM. In an accompanying Commentary, Robert as long as NK cells remained. These results suggest that intratumoral NK cells can Casero Jr. speculates that this polyamine-regulating axis identifies intriguing contribute to checkpoint blockade therapies. In the accompanying Commentary, Cordelia targets for treating polyamine-dependent malignancies. Dunai and William Murphy indicate that further study of this NK subset could produce strategies that exploit its role in checkpoint inhibition. Inhibition of the aryl hydrocarbon receptor/polyamine biosynthesis axis suppresses multiple myeloma Contribution of NK cells to immunotherapy mediated Anna Bianchi-Smiraglia, Archis Bagati, Emily E. Fink, Hayley C. Affronti, by PD-1/PD-L1 blockade Brittany C. Lipchick, Sudha Moparthy, Mark D. Long, Spencer R. Rosario, Joy Hsu, Jonathan J. Hodgins, Malvika Marathe, Chris J. Nicolai, Shivana M. Lightman, Kalyana Moparthy, David W. Wolff, Dong Hyun Yun, Marie-Claude Bourgeois-Daigneault, Troy N. Trevino, Camillia S. Azimi, Amit K. Scheer, Zhannan Han, Anthony Polechetti, Matthew V. Roll, Ilya I. Gitlin, Haley E. Randolph, Thornton W. Thompson, Lily Zhang, Alexandre Iannello, Katerina I. Leonova, Aryn M. Rowsam,Eugene S. Kandel, Andrei V. Gudkov, Nikhita Mathur, Karen E. Jardine, Georgia A. Kirn, John C. Bell, Michael W. McBurney, P. Leif Bergsagel, Kelvin P. Lee, Dominic J. Smiraglia, and Mikhail A. Nikiforov David H. Raulet, and Michele Ardolino http://jci.me/99317 http://jci.me/70712 Related Commentary Related Commentary NK cells for PD-1/PD-L1 blockade immunotherapy: Targeting the aryl hydrocarbon receptor/polyamine pinning down the NK cell biosynthesis axis of evil for cancer therapy Cordelia Dunai and William J. Murphy http://jci.me/123121 Robert A. Casero Jr. http://jci.me/123266

jci.org/this-month october 2018 5 JCI | Features

viewpoint review Safeguarding the integrity of DNA repair defects betray cancer’s the scientific literature vulnerability to immunotherapy In recent years, scientists have voiced concerns over the reliability Defective DNA repair exposes the genome to damage and exacerbates the of scientific literature, noting an increasing incidence of retractions, accumulation of somatic mutations. Mutations in DNA repair pathways are common duplications, and failures to replicate findings. While questionable in cancer and may offer clues to selecting more effective treatments. In this issue of publications represent a small fraction of all published studies, each the JCI, a review by Katherine Bever and Dung Le describes evidence that DNA repair threatens the credibility of the scientific community. A Viewpoint defects can increase a tumor’s vulnerability to immunotherapy. Recent reports authored by JCI Deputy Editor Arturo Casadevall and Ferric Fang confirm that DNA mismatch repair defects promote increased tumor immunogenicity, outlines seven suggested approaches for improving scientific a positive predictor of clinical immunotherapy response. Ongoing studies suggest that literature from the ground up, starting with more rigorous training in mutations in other DNA repair pathways may also predict sensitivity to immuno- scientific practices and ethics at the level of graduate and postdoc- therapy. Although more research is needed, defects in the DNA repair pathways and toral trainees. Arguing in favor of a culture of intellectual honesty and other sources of genome instability have the potential to serve as powerful experimental rigor, the authors present a roadmap for the scientific biomarkers for identifying immunotherapy-responsive cancers. community to embark on a self-correcting course toward a more reliable body of literature. DNA repair defects and implications for immunotherapy Katherine M. Bever and Dung T. Le Making the scientific literature fail-safe http://jci.me/122010 Arturo Casadevall (ASCI) and Ferric C. Fang http://jci.me/123884

North Carolina—Highly Regarded School of Medicine Seeking Immunologist

Merritt Hawkins, the nation’s leading academic search firm, invites In addition to working with a world-class program and team you to consider an opportunity to join the division of Department of of physicians, you will be working in one of the most desirable Microbiology and Immunology at a highly ranked medical school. locations in the United States. North Carolina has all that a We are seeking an Immunologist for a full-time, tenure-track, faculty physician and their family could want. The area offers the role. This is an opportunity to join a growing faculty with updated following benefits: research and laboratory facilities located on a beautiful campus. • Short drive to the mountains or the coast This institution will provide for significant research time as well as teaching opportunities to Masters and Ph.D. level students. This • Four seasons with a generally temperate climate opportunity features: • Affordable housing options • A faculty that has a history of hosting nationally funded research • Access to an international airport programs which provide the students with relevant training in • University town that is experiencing 400% growth in its uptown important problems in biomedical sciences. population in the next year • The use a wide array of molecular and genetic approaches to • An abundance of outdoor activities, unique shops, dining, probe the underlying mechanisms of microbial pathogenesis, and nightlife. antibiotic resistance, cancer cell signaling, autoimmunity, and • This prominent University center has made the area culturally macrophage biology. diverse, economically resilient, and nationally recognized as a • The program is multi-disciplinary by nature and offers great place to live. students research opportunities in a broad range of disciplines, including bacterial and viral pathogenesis, cancer biology, and For immediate consideration please inquire with an updated copy cellular immunology. of your CV so we can discuss the position by phone. Also, inform me of your best available times to speak. I look forward to your reply • Full-time research techs and personnel support and thank you for your review. Please do not delay as we anticipate • Newly renovated lab space a significant response. • The ability to have everything that an Immunologist would need and desire within the laboratory Please contact Donald Howell at • 100% hard salary that can be augmented with research dollars [email protected] or at (866) 406-0269 and reference IMM-86181.

6 jci.org/this-month october 2018 Current research articles aids/hiv No recovery of replication-competent HIV-1 from human liver macrophages Abraham J. Kandathil, Sho Sugawara, Ashish Goyal, Christine M. Durand, Jeffrey Quinn, Jaiprasath Sachithanandham, Andrew M. Cameron, Justin R. Bailey, Alan S. Perelson, and Ashwin Balagopal http://jci.me/121678 TLR3 agonist and CD40-targeting vaccination induces immune responses and reduces HIV-1 reservoirs p. 2 Liang Cheng, Qi Wang, Guangming Li, Riddhima Banga, Jianping Ma, Haisheng Yu, Fumihiko Yasui, Zheng Zhang, Giuseppe Pantaleo, Matthieu Perreau, Sandra Zurawski, Gerard Zurawsk, Yves Levy, and Lishan Su http://jci.me/99005 clinical medicine Use of contraceptive depot medroxyprogesterone acetate is associated with impaired cervicovaginal mucosal integrity p. 3 Irina A. Zalenskaya, Neelima Chandra, Nazita Yousefieh, Xi Fang, Oluwatosin E. Adedipe, Suzanne S. Jackson, Sharon M. Anderson, Christine K. Mauck, Jill L. Schwartz, Andrea R. Thurman, and Gustavo F. Doncel http://jci.me/120583 Immunogenomic analyses associate immunological alterations with mismatch repair defects in prostate cancer Daniel Nava Rodrigues, Pasquale Rescigno, David Liu, Wei Yuan, Suzanne Carreira, Maryou B. Lambros, George Seed, Joaquin Mateo, Ruth Riisnaes, Stephanie Mullane, Claire Margolis, Diana Miao, Susana Miranda, David Dolling, Matthew Clarke, Claudia Bertan, Mateus Crespo, Gunther Boysen, Ana Ferreira, Adam Sharp, Ines Figueiredo, Daniel Keliher, Saud Aldubayan, Kelly P. Burke, Semini Sumanasuriya, Mariane Sousa Fontes, Diletta Bianchini, Zafeiris Zafeiriou, Larissa Sena Teixeira Mendes, Kent Mouw, Michael T. Schweizer, Colin C. Pritchard, Stephen Salipante, Mary-Ellen Taplin, Himisha Beltran, Mark A. Rubin, Marcin Cieslik, Dan Robinson, Elizabeth Heath, Nikolaus Schultz, Joshua Armenia, Wassim Abida, Howard Scher, Christopher Lord, Alan D’Andrea, Charles L. Sawyers, Arul M. Chinnaiyan, Andrea Alimonti, Peter S. Nelson, Charles G. Drake, Eliezer M. Van Allen, and Johann S. de Bono http://jci.me/121924 Neonatal Fc receptor antagonist efgartigimod safely and sustainably reduces IgGs in humans p. 3 Peter Ulrichts, Antonio Guglietta, Torsten Dreier, Tonke van Bragt, Valérie Hanssens, Erik Hofman, Bernhardt Vankerckhoven, Peter Verheesen, Nicolas Ongenae, Valentina Lykhopiy, F. Javier Enriquez, JunHaeng Cho, Raimund J. Ober, E. Sally Ward, Hans de Haard, and Nicolas Leupin http://jci.me/97911 endocrinology REVERBa couples the circadian clock to hepatic glucocorticoid action Giorgio Caratti, Mudassar Iqbal, Louise Hunter, Donghwan Kim, Ping Wang, Ryan M. Vonslow, Nicola Begley, Abigail J. Tetley, Joanna L. Woodburn, Marie Pariollaud, Robert Maidstone, Ian J. Donaldson, Zhenguang Zhang, Louise M. Ince, Gareth Kitchen, Matthew Baxter, Toryn M. Poolman, Dion A. Daniels, David R. Stirling, Chad Brocker, Frank Gonzalez, Andrew S.I. Loudon, David A. Bechtold, Magnus Rattray, Laura C. Matthews, and David W. Ray http://jci.me/96138 Endothelial cell CD36 optimizes tissue fatty acid uptake Ni-Huiping Son, Debapriya Basu, Dmitri Samovski, Terri A. Pietka, Vivek S. Peche, Florian Willecke, Xiang Fang, Shui-Qing Yu, Diego Scerbo, Hye Rim Chang, Fei Sun, Svetlana Bagdasarov, Konstantinos Drosatos, Steve T. Yeh, Adam E. Mullick, Kooresh I. Shoghi, Namrata Gumaste, KyeongJin Kim, Lesley-Ann Huggins, Tenzin Lhakhang, Nada A. Abumrad, and Ira J. Goldberg (ASCI) http://jci.me/99315 hematology

JAK2-V617F promotes venous thrombosis through β1/β2 integrin activation p. 2 Bärbel Edelmann, Nibedita Gupta, Tina M. Schnoeder, Anja M. Oelschlegel, Khurrum Shahzad, Jürgen Goldschmidt, Lars Philipsen, Soenke Weinert, Aniket Ghosh, Felix C. Saalfeld, Subbaiah Chary Nimmagadda, Peter Müller, Rüdiger Braun-Dullaeus, Juliane Mohr, Denise Wolleschak, Stefanie Kliche, Holger Amthauer, Florian H. Heidel, Burkhart Schraven, Berend Isermann, Andreas J. Müller, and Thomas Fischer http://jci.me/90312 Leukemogenic nucleophosmin mutation disrupts the transcription factor hub that regulates granulomonocytic fates Xiaorong Gu, Quteba Ebrahem, Reda Z. Mahfouz, Metis Hasipek, Francis Enane, Tomas Radivoyevitch, Nicolas Rapin, Bartlomiej Przychodzen, Zhenbo Hu, Ramesh Balusu, Claudiu V. Cotta, David Wald, Christian Argueta, Yosef Landesman, Maria Paola Martelli, Brunangelo Falini, Hetty Carraway, Bo T. Porse, Jaroslaw Maciejewski, Babal K. Jha, and Yogen Saunthararajah http://jci.me/97117

jci.org/this-month october 2018 7 Current research articles immunology PD-1+CD8+ T cells are clonally expanding effectors in human chronic inflammation Alessandra Petrelli, Gerdien Mijnheer, David P. Hoytema van Konijnenburg, Maria M. van der Wal, Barbara Giovannone, Enric Mocholi, Nadia Vazirpanah, Jasper C. Broen, Dirkjan Hijnen, Bas Oldenburg, Paul J. Coffer, Sebastian J. Vastert, Berent J. Prakken, Eric Spierings, Aridaman Pandit, Michal Mokry, and Femke van Wijk http://jci.me/96107 Inhibition of neogenin fosters resolution of inflammation and tissue regeneration Martin Schlegel, Andreas Körner, Torsten Kaussen, Urs Knausberg, Carmen Gerber, Georg Hansmann, Hulda Soffia Jónasdóttir, Martin Giera, and Valbona Mirakaj http://jci.me/96259 Long noncoding RNA LERFS negatively regulates rheumatoid synovial aggression and proliferation Yaoyao Zou, Siqi Xu, Youjun Xiao, Qian Qiu, Maohua Shi, Jingnan Wang, Liuqin Liang, Zhongping Zhan, Xiuyan Yang, Nancy Olsen, Song Guo Zheng, and Hanshi Xu http://jci.me/97965 infectious disease Th1 memory differentiates recombinant from live herpes zoster vaccines p. 4 Myron J. Levin, Miranda E. Kroehl, Michael J. Johnson, Andrew Hammes, Dominik Reinhold, Nancy Lang, and Adriana Weinberg http://jci.me/121484 Zika virus infects human testicular tissue and germ cells Giulia Matusali, Laurent Houzet, Anne-Pascale Satie, Dominique Mahé, Florence Aubry, Thérèse Couderc, Julie Frouard, Salomé Bourgeau, Karim Bensalah, Sylvain Lavoué, Guillaume Joguet, Louis Bujan, André Cabié, Gleide Avelar, Marc Lecuit, Anna Le Tortorec, and Nathalie Dejucq-Rainsford http://jci.me/121735 PD-1 blockade partially recovers dysfunctional virus–specific B cells in chronic hepatitis B infection p. 4 Loghman Salimzadeh, Nina Le Bert, Charles-A. Dutertre, Upkar S. Gill, Evan W. Newell, Christian Frey, Magdeleine Hung, Nikolai Novikov, Simon Fletcher, Patrick T.F. Kennedy, and Antonio Bertoletti http://jci.me/121957 Circulating and intrahepatic antiviral B cells are defective in hepatitis B p. 4 Alice R. Burton, Laura J. Pallett, Laura E. McCoy, Kornelija Suveizdyte, Oliver E. Amin, Leo Swadling, Elena Alberts, Brian R. Davidson, Patrick T.F. Kennedy, Upkar S. Gill, Claudia Mauri, Paul A. Blair, Nadege Pelletier, and Mala K. Maini http://jci.me/121960 Pseudomonas aeruginosa utilizes host polyunsaturated phosphatidylethanolamines to trigger theft-ferroptosis in bronchial epithelium Haider H. Dar, Yulia Y. Tyurina, Karolina Mikulska-Raminska, Indira Shrivastava, Hsiu-Chi Ting, Vladimir A. Tyurin, James Krieger, Claudette M. St. Croix, Simon Watkins, Erkan Bayir, Gaowei Mao, Catherine R. Armbruster, Alexandr Kapralov, Hong Wang, Mathew R. Parsek, Tamil S. Anthonymuthu, Abiola F. Ogunsola, Becca A. Flitter, Cody J. Freedman, Jordan R. Gaston, Ted R. Holman, Joseph M. Pilewski, Joel S. Greenberger, Rama K. Mallampalli, Yohei Doi, Janet S. Lee, Ivet Bahar, Jennifer M. Bomberger, Hülya Bayır (ASCI), and Valerian E. Kagan http://jci.me/99490 nephrology Mutations in multiple components of the nuclear pore complex cause nephrotic syndrome Daniela A. Braun, Svjetlana Lovric, David Schapiro, Ronen Schneider, Jonathan Marquez, Maria Asif, Muhammad Sajid Hussain, Ankana Daga, Eugen Widmeier, Jia Rao, Shazia Ashraf, Weizhen Tan, C. Patrick Lusk, Amy Kolb, Tilman Jobst-Schwan, Johanna Magdalena Schmidt, Charlotte A. Hoogstraten, Kaitlyn Eddy, Thomas M. Kitzler, Shirlee Shril, Abubakar Moawia, Kathrin Schrage, Arwa Ishaq A. Khayyat, Jennifer A. Lawson, Heon Yung Gee, Jillian K. Warejko, Tobias Hermle, Amar J. Majmundar, Hannah Hugo, Birgit Budde, Susanne Motameny, Janine Altmüller, Angelika Anna Noegel, Hanan M. Fathy, Daniel P. Gale, Syeda Seema Waseem, Ayaz Khan, Larissa Kerecuk, Seema Hashmi, Nilufar Mohebbi, Robert Ettenger, Erkin Serdaroğlu, Khalid A. Alhasan, Mais Hashem, Sara Goncalves, Gema Ariceta, Mercedes Ubetagoyena, Wolfram Antonin, Shahid Mahmood Baig, Fowzan S. Alkuraya, Qian Shen, Hong Xu, Corinne Antignac, Richard P. Lifton, Shrikant Mane, Peter Nürnberg, Mustafa K. Khokha, and Friedhelm Hildebrandt http://jci.me/98688 ASK1 contributes to fibrosis and dysfunction in models of kidney disease John T. Liles, Britton K. Corkey, Gregory T. Notte, Grant R. Budas, Eric B. Lansdon, Ford Hinojosa-Kirschenbaum, Shawn S. Badal, Michael Lee, Brian E. Schultz, Sarah Wise, Swetha Pendem, Michael Graupe, Laurie Castonguay, Keith A. Koch, Melanie H. Wong, Giuseppe A. Papalia, Dorothy M. French, Theodore Sullivan, Erik G. Huntzicker, Frank Y. Ma, David J. Nikolic-Paterson, Tareq Altuhaifi, Haichun Yang, Agnes B. Fogo, and David G. Breckenridge http://jci.me/99768 neuroscience Selective disruption of TLR2-MyD88 interaction inhibits inflammation and attenuates Alzheimer’s pathology Suresh B. Rangasamy, Malabendu Jana, Avik Roy, Grant T. Corbett, Madhuchhanda Kundu, Sujyoti Chandra, Susanta Mondal, Sridevi Dasarathi, Elliott J. Mufson, Rama K. Mishra, Chi-Hao Luan, David A. Bennett, and Kalipada Pahan http://jci.me/96209 Schwann cell–derived periostin promotes autoimmune peripheral polyneuropathy via macrophage recruitment Denise E. Allard, Yan Wang, Jian Joel Li, Bridget Conley, Erin W. Xu, David Sailer, Caellaigh Kimpston, Rebecca Notini, Collin-Jamal Smith, Emel Koseoglu, Joshua Starmer, Xiaopei L. Zeng, James F. Howard Jr., Ahmet Hoke, Steven S. Scherer, and Maureen A. Su http://jci.me/99308

8 jci.org/this-month october 2018 oncology Ubiquitin ligase RNF8 suppresses Notch signaling to regulate mammary development and tumorigenesis Li Li, Kiran Kumar Naidu Guturi, Brandon Gautreau, Parasvi S. Patel, Amine Saad, Mayako Morii, Francesca Mateo, Luis Palomero, Haithem Barbour, Antonio Gomez, Deborah Ng, Max Kotlyar, Chiara Pastrello, Hartland W. Jackson, Rama Khokha, Igor Jurisica, El Bachir Affar, Brian Raught, Otto Sanchez, Moulay Alaoui-Jamali, Miguel A. Pujana, Anne Hakem, and Razq Hakem http://jci.me/120401 Ubiquitin-specific protease 7 sustains DNA damage response and promotes cervical carcinogenesis Dongxue Su, Shuai Ma, Lin Shan, Yue Wang, Yuejiao Wang, Cheng Cao, Beibei Liu, Chao Yang, Liyong Wang, Shanshan Tian, Xiang Ding, Xinhua Liu, Na Yu, Nan Song, Ling Liu, Shangda Yang, Qi Zhang, Fuquan Yang, Kai Zhang, and Lei Shi http://jci.me/120518 Inhibition of the aryl hydrocarbon receptor/polyamine biosynthesis axis suppresses multiple myeloma p. 5 Anna Bianchi-Smiraglia, Archis Bagati, Emily E. Fink, Hayley C. Affronti, Brittany C. Lipchick, Sudha Moparthy, Mark D. Long, Spencer R. Rosario, Shivana M. Lightman, Kalyana Moparthy, David W. Wolff, Dong Hyun Yun, Zhannan Han, Anthony Polechetti, Matthew V. Roll, Ilya I. Gitlin, Katerina I. Leonova, Aryn M. Rowsam, Eugene S. Kandel, Andrei V. Gudkov, P. Leif Bergsagel, Kelvin P. Lee, Dominic J. Smiraglia, and Mikhail A. Nikiforov http://jci.me/70712 Contribution of NK cells to immunotherapy mediated by PD-1/PD-L1 blockade p. 5 Joy Hsu, Jonathan J. Hodgins, Malvika Marathe, Chris J. Nicolai, Marie-Claude Bourgeois-Daigneault, Troy N. Trevino, Camillia S. Azimi, Amit K. Scheer, Haley E. Randolph, Thornton W. Thompson, Lily Zhang, Alexandre Iannello, Nikhita Mathur, Karen E. Jardine, Georgia A. Kirn, John C. Bell, Michael W. McBurney, David H. Raulet, and Michele Ardolino http://jci.me/99317 Stromal epigenetic alterations drive metabolic and neuroendocrine prostate cancer reprogramming Rajeev Mishra, Subhash Haldar, Veronica Placencio, Anisha Madhav, Krizia Rohena-Rivera, Priyanka Agarwal, Frank Duong, Bryan Angara, Manisha Tripathi, Zhenqiu Liu, Roberta A. Gottlieb, Shawn Wagner, Edwin M. Posadas, and Neil A. Bhowmick http://jci.me/99397 Specific covalent inhibition of MALT1 paracaspase suppresses B cell lymphoma growth Lorena Fontán, Qi Qiao, John M. Hatcher, Gabriella Casalena, Ilkay Us, Matt Teater, Matt Durant, Guangyan Du, Min Xia, Natalia Bilchuk, Spandan Chennamadhavuni, Giuseppe Palladino, Giorgio Inghirami, Ulrike Philippar, Hao Wu, David A. Scott, Nathanael S. Gray, and Ari Melnick (ASCI) http://jci.me/99436 Epigenetic silencing of tumor suppressor Par-4 promotes chemoresistance in recurrent breast cancer Nathaniel W. Mabe, Douglas B. Fox, Ryan Lupo, Amy E. Decker, Stephanie N. Phelps, J. Will Thompson, and James V. Alvarez http://jci.me/99481 pulmonology Expansion of hedgehog disrupts mesenchymal identity and induces emphysema phenotype Chaoqun Wang, Nabora S. Reyes de Mochel, Stephanie A. Christenson, Monica Cassandras, Rebecca Moon, Alexis N. Brumwell, Lauren E. Byrnes, Alfred Li, Yasuyuki Yokosaki, Peiying Shan, Julie B. Sneddon, David Jablons, Patty J. Lee, Michael A. Matthay, Harold A. Chapman, and Tien Peng http://jci.me/99435 transplantation The vimentin intermediate filament network restrains regulatory T cell suppression of graft-versus-host disease p. 5 Cameron McDonald-Hyman, James T. Muller, Michael Loschi, Govindarajan Thangavelu, Asim Saha, Sudha Kumari, Dawn K. Reichenbach, Michelle J. Smith, Guoan Zhang, Brent H. Koehn, Jiqiang Lin, Jason S. Mitchell, Brian T. Fife, Angela Panoskaltsis-Mortari, Colby J. Feser, Andrew Kemal Kirchmeier, Mark J. Osborn, Keli L. Hippen, Ameeta Kelekar, Jonathan S. Serody, Laurence A. Turka, David H. Munn, Hongbo Chi, Thomas A. Neubert, Michael L. Dustin, and Bruce R. Blazar (ASCI) http://jci.me/95713 CD122 signaling in CD8+ memory T cells drives costimulation-independent rejection David V. Mathews, Ying Dong, Laura B. Higginbotham, Steven C. Kim, Cynthia P. Breeden, Elizabeth A. Stobert, Joseph Jenkins, J. Yun Tso, Christian P. Larsen, and Andrew B. Adams http://jci.me/95914 vascular biology Endothelial pyruvate kinase M2 maintains vascular integrity Boa Kim, Cholsoon Jang, Harita Dharaneeswaran, Jian Li, Mohit Bhide, Steven Yang, Kristina Li, and Zolt Arany (ASCI) http://jci.me/120912

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jci.org/this-month october 2018 9 This Month

A murine model of prosthetic joint infection p. 10

October 2018 JCI This Month is a summary of the NETs promote thrombus formation in HIT 11 most recent articles in Visualizing T cell dynamics in glioma 12 The Journal of Clinical Investigation and JCI Insight Plasma lipids predict cardiac event risk 13 Identification of HIV-associated microglia-like cells 13 jci.org/this-month JCI Insight Consulting Editors

Christopher M. Adams Peter Crawford Thomas W.H. Kay Daniel Ory Maria-Luisa Alegre Lisa L. Cunningham Barbara I. Kazmierczak Sophie Paczesny Ravi K. Amaravadi Ronald P. DeMatteo Hans-Peter Kiem Stephanie T. Page John K. Amory Elia J. Duh William Y. Kim Mary-Elizabeth Patti Jennifer H. Anolik Sarah K. England David G. Kirsch Janos Peti-Peterdi Cristian Apetrei Mark W. Feinberg Claire E. Lewis Fernando P. Polack Rajendra S. Apte John H. Fingert Mathias Lichterfeld Matthew D. Ringel Zoltan Arany Robert Flaumenhaft André Lieber Steven M. Rowe Hossein Ardehali Edward A. Fon Michail S. Lionakis Svati H. Shah Kenneth I. Ataga Lawrence Fong Carey N. Lumeng Vijay H. Shah Joseph Bass Nikolaos G. Frangogiannis Ivan Maillard Alice T. Shaw Alexander G. Bassuk Anthony R. French Ziad Mallat Rhonda F. Souza Antonio C. Bianco Terrence L. Geiger Peter Mannon Fayyaz S. Sutterwala Jonathan S. Bogan Noyan Gokce Franck Mauvais-Jarvis Shu Takeda Laura M. Bohn Raphaela Goldbach-Mansky Dermot P.B. McGovern Natalie J. Torok Nunzio Bottini Daniel R. Goldstein Borna Mehrad Stephen H. Tsang Sebastien G. Bouret Douglas K. Graham Ingo K. Mellinghoff Ellie Tzima Jason Brenchley Khalid A. Hanafy David K. Meyerholz Fumihiko Urano Renier J. Brentjens Eric B. Haura Jason C. Mills Deborah J. Veis G.R. Scott Budinger John Cijiang He Joshua D. Milner Charles P. Venditti George A. Calin Robert O. Heuckeroth Satdarshan (Paul) Singh Monga Joseph M. Vinetz Stephen Chan Cory M. Hogaboam Hidayatullah G. Munshi Sing Sing Way Timothy Chan Young-Kwon Hong Matthias Nahrendorf Bernd Wollnik Yuan Chang Benjamin D. Humphreys Mary Nakamura Minna Woo Zhou-Feng Chen Ken Inoki Lisa F.P. Ng Prescott G. Woodruff Keith A. Choate Shingo Kajimura Mark Nicolls Lori M. Zeltser Wendy Chung Pawel Kalinski Laura J. Niedernhofer Yutong Zhao Craig M. Coopersmith John Y. Kao S. Tiong Ong Binhua P. Zhou George Cotsarelis Michael G. Kaplitt Puneet Opal On the JCI Insight cover This Month October 2018 Modeling Gram-negative infection of prosthetic joints For JCI Insight Prosthetic joints restore mobility Editor and have improved the lives of mil- Howard A. Rockman lions of patients. Unfortunately, infec- Associate Editors tion occurs in approximately 1%–2% of Rodger A. Liddle, Yiping Yang primary and 3%–6% of revision joint Executive Editor replacement surgeries and is particu- Sarah C. Jackson larly challenging to treat due to the Science Editor Corinne Williams formation of biofilms on the prosthetic surface. Gram-negative pathogens, ASCI Staff such as Pseudomonas aeruginosa and Executive Director Escherichia coli, are becoming preva- John B. Hawley Managing Director lent causes of prosthetic joint infec- Karen D. Guth tions (15%–36%); however, the etiology of Gram-negative prosthetic infection is Associate Director relatively understudied compared with Gram-positive infections. In this issue, Maya Hoptman John Thompson and colleagues developed a murine model of Gram-negative Associate Director, Technology prosthetic joint infection in which an orthopedic-grade titanium implant was Shawn Pyle placed in the femur, followed by infection with P. aeruginosa or E. coli. Bacterial Production Editors Catherine Ahmann, Ken Beauchamp, strains demonstrated in vitro biofilm-forming activity associated with in vivo Molly Jean, Lara L. McCarron biofilm formation on the implant, reactive alterations of bone, and infiltration Scientific Illustrator of inflammatory cells. Moreover, bacterial burden of mice with P. aeruginosa– Bruce Worden infected implants could be reduced by treatment with a bispecific antibody that Copy Editors targets the virulence factors PcrV and Psl. Collectively, this study provides a Clare Cross, Meredith Dimick, Barbara Fabyan, Rachel Nelson, model to study Gram-negative prosthetic joint infections and shows the utility Chet Provoda of the model for evaluating therapeutic strategies. The cover image is a scan- Associate Copy Editor ning electron micrograph of a P. aeruginosa–infected implant that shows sub- Megan O'Reilly stantial biofilm formation on day 21. Associate Editor, Copy and Production Rachel Bullen Mouse model of Gram-negative prosthetic joint infection Publications Coordinator reveals therapeutic targets Megan Jenkins John M. Thompson, Robert J. Miller, Alyssa G. Ashbaugh, Carly A. Dillen, Julie E. Pickett, Yu Wang, System Administrator and Developer Roger V. Ortines, Robert S. Sterling, Kevin P. Francis, Nicholas M. Bernthal, Taylor S. Cohen, Christine Tkaczyk, Bryan English Li Yu, C. Kendall Stover, Antonio DiGiandomenico, Bret R. Sellman, Daniel L.J. Thorek, and Lloyd S. Miller (ASCI) Software Developers http://jci.me/121737 Austin Brewer, Jose L. Jardon Science Communications Specialist Neha Aggarwal (ASCI) indicates corresponding authors who are ASCI members. Accounts Manager Paula Kremidas Administrative Assistant Make your 18-hour days count. Theresa Kaiser Figures Coordinator Keith Kalinowski Submit your work to JCI Insight today.

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jci.org/this-month october 2018 10 Editor’s picks

hematology NETs entrap patients with HIT The immune-mediated disorder heparin-induced thrombocytopenia (HIT) is characterized by arterial and venous thromboembolism. Early detection and anticoagula- tion do not fully prevent recurrent life-threatening thromboses. Plasma myeloperoxidase is elevated in affected patients, suggesting neutrophil activation. Using murine models and an endothelialized microfluidics system, Kandace Gollomp and colleagues demonstrate that induction of HIT promotes neutrophil adhesion to venous endothelium. Following injury to venules, neutrophils accumulated downstream of nascent thrombi, underwent retrograde migration, and elaborated neutrophil extracellular traps (NETs) that promote thrombus growth. Platelet factor 4 (PF4), which is released in high concentrations in HIT, bound to NETs, physically compacting them and enhancing DNase resistance. Binding of HIT antibodies to PF4-NETs further enhanced resistance to digestion. In HIT mice, interventions that promote degradation or inhibit release of NETs limited Neutrophil accumulation and NET release contribute to thrombosis in HIT thrombus size, supporting involvement of neutrophils in Kandace Gollomp, Minna Kim, Ian Johnston, Vincent Hayes, John Welsh, HIT-associated venous thrombosis. The accompanying Gowthami M. Arepally, Mark Kahn, Michele P. Lambert, Adam Cuker, Douglas B. Cines, images show reduced thrombus formation in NET-deficient Lubica Rauova, M. Anna Kowalska, and Mortimer Poncz (ASCI) HIT mice (Padi4–/–) versus control animals. http://jci.me/99445

endocrinology Gestational diabetes associates with specific methylation changes in offspring Children born to mothers who had gestational CpGs. While the methylation status of the CpGs did Gestational diabetes diabetes mellitus (GDM) are at increased risk of not associate with offspring BMI, many changes in and maternal obesity are metabolic disease later in life. The predisposition to methylation could be linked to prepregnancy BMI associated with epigenome-wide metabolic disease may be due to genetic variation of the mothers. In a validation cohort, 3 of the methylation changes in children or could be the result of environment and prepregnancy BMI-associated CpG alterations and 1 Line Hjort, David Martino, epigenetic alteration. Line Hjort and colleagues GDM-associated CpG alteration was replicated. Louise Groth Grunnet, Haroon Naeem, measured DNA methylation profiles in peripheral Together, these results indicate that methylation Jovana Maksimovic, Anders Henrik Olsson, blood collected from children aged 9–16 years changes may underlie metabolic disease in Cuilin Zhang, Charlotte Ling, whose mothers either had GDM or uncomplicated offspring of mothers with GDM, and these Sjurdur Frodi Olsen, Richard Saffery, pregnancies. Compared with controls, maternal methylation alterations may be predictive and Allan Arthur Vaag GDM associated with 76 differentially methylated biomarkers for metabolic disease risk. http://jci.me/122572

11 jci.org/this-month october 2018 JCI Insight | Editor’s picks

immunology T cell dynamics in glioma indicate immunoevasive tumor environment Proper T cell activation within a tumor is essential for eliminating cancer cells. Dynamic interactions between T cells and other cells within the tumor microenviron- ment dictate T cell responses; therefore, a better understanding of T cell dynamics in tumors and normal tissue could improve therapeutic approaches. Laura Díaz, Elena Saavedra-López, Leire Romarate, and colleagues evaluated T cell dynamics within human glioma tissue samples and found that T cells establish synapses with glioma cells, as well as myeloid cells (see the accompanying image). T cells preferentially Imbalance of immunological synapse-kinapse states formed immunologic synapses with stromal cells, as opposed to malignant cells. reflects tumor escape to immunity in glioblastoma Moreover, T cells within a malignant area had morphological features that were Laura R. Díaz, Elena Saavedra-López, Leire Romarate, Izaskun Mitxitorena, distinct from T cells in surrounding nonmalignant tissue. High-resolution imaging of T Paola V. Casanova, George P. Cribaro, José M. Gallego, Ana Pérez-Vallés, cells within malignant tissue revealed a prevalence of immune kinapses, a state Jerónimo Forteza-Vila, Clara Alfaro-Cervello, José M. García-Verdugo, associated with low antigenic sensing. The imbalance of immune synapses and Carlos Barcia Sr, and Carlos Barcia Jr. kinapses within the tumor is indicative of an immunoevasive environment. http://jci.me/120757 NF-κB and TRAFs enhance 4-1BB–expressing CAR T cell function Adoptively transferred T cells expressing phenotype. However, the mechanisms underlying cell viability, proliferation, and persistence. These chimeric antigen receptors (CARs) have these differences have not been fully explored. results provide important information that should demonstrated clinical benefits for B cell Gongbo Li and colleagues compared murine be taken into consideration for optimizing CAR T malignancies; however, response rates are closely CD19-targeted CARs with different costimulatory cell design. tied to CAR T cell persistence, which requires domains in murine models. Compared with 4-1BB enhancement of CAR T costimulation. CARs currently approved for clinical CD28-containing CAR T cells, 4-1BB–containing function requires NF-κB and TRAFs use include one of two costimulatory domains, CAR T cells required enhanced persistence for Gongbo Li, Justin C. Boucher, Hiroshi Kotani, CD28 or 4-1BB, both of which produce similar maximal function. This increase in persistence was Kyungho Park, Yongliang Zhang, clinical outcomes. However, there are differences in mediated by enhanced NF-κB signaling and Bishwas Shrestha, Xuefeng Wang, Lawrence Guan, the clinical activities of CARs containing these expression of antiapoptotic proteins. TNF Nolan Beatty, Daniel Abate-Daga, molecules, with CD28 driving an effector receptor–associated factors (TRAFs) were also and Marco L. Davila http://jci.me/121322 phenotype and 4-1BB driving a memory required for 4-1BB costimulation and impacted C T

review Teasing apart cartilage-protective and -destructive microRNAs in osteoarthritis

Osteoarthritis (OA) is a debilitating disease that is OA patients compared with healthy subjects; The complex landscape of characterized by progressive degeneration of articular therefore, these regulatory molecules represent microRNAs in articular cartilage: cartilage. The development of effective therapeutic potential targets for therapeutic intervention. Helal biology, pathology, and interventions will require more complete understand- Endisha, Jason Rockel, Igor Jurisica, and Mohit Kapoor therapeutic targets ing of the factors that help maintain cartilage review known cartilage-protective and -destructive Helal Endisha, Jason Rockel, Igor Jurisica, homeostasis. Alterations in expression of several miRs and discuss how the gene targets of these miRs and Mohit Kapoor microRNAs (miRs) have been reported in the joints of may contribute to OA pathogenesis. http://jci.me/121630

jci.org/this-month october 2018 12 JCI Insight | Editor’s picks

aids/hiv cardiology Microglia-like cell population identified Plasma lipid in HIV patient cerebrospinal fluid profiles are Neurological impairment occurs in a subset of HIV-infected individuals and dramatically decreases quality of life. Immune cell activation in the CNS associates with this impairment and occurs even in patients predictive of with long-term viral suppression; however, the cells that drive CNS damage in HIV infection are poorly under- stood. Shelli Farhadian and colleagues collected cerebrospinal fluid (CSF) and blood from 2 HIV-positive cardiac event risk patients and performed single-cell RNA sequencing to evaluate differences in cell populations between Patients with a history of myocardial blood and CSF. The authors identified a rare population of myeloid cells in the CSF of HIV-infected patients infarction (MI) are at high risk of additional who had a transcription profile similar to that found in neurodegenerative disease–associated microglia. adverse cardiac events. It remains a challenge Moreover, this population was present in a third HIV-infected patient and was present at higher frequencies to accurately identify and aggressively target + in HIV patients than in an HIV-uninfected control subject. The results of this study highlight the utility of those individuals with stable disease that are single-cell sequencing to identify rare cell populations that have potential as drivers of disease phenotypes. most likely to suffer fatal and not-fatal cardiac Single-cell RNA sequencing reveals microglia-like cells events. Alterations in plasma lipids have in cerebrospinal fluid during virologically suppressed HIV previously been linked to cardiac disease; Shelli F. Farhadian, Sameet S. Mehta, Chrysoula Zografou, Kevin Robertson, therefore, Piyushkumar Mundra and Richard W. Price, Jenna Pappalardo, Jennifer Chiarella, David A. Hafler, Serena S. Spudich colleagues retrospectively evaluated plasma http://jci.me/121718 lipidomics in a subcohort of LIPID study participants and identified lipid species associated with future cardiovascular events and cardiovascular death. The addition of seven autoimmunity lipid species to current conventional risk factors significantly increased predictability of cardiovascular events and death. Moreover, Characterization of B cell–specific effects these lipid species were also predictive of future cardiovascular events in a diabetic case of chronic belimumab in SLE patients cohort from the ADVANCE study. These results One hallmark of systemic lupus erythematosus (SLE) is the development of autoantibodies. The indicate that plasma lipid profiles have strong anti-BAFF antibody belimumab depletes B cells and can be beneficial for patients with SLE; however, it is potential as biomarkers to predict secondary not clear how belimumab alters the B cell repertoire. Weiqing Huang, Tam Quach, and colleagues analyzed B cardiac event risk. cell populations in long-term belimumab-treated SLE patients, a small cohort of SLE patients before and Large-scale plasma lipidomic after belimumab treatment, and control subjects. Chronic belimumab treatment resulted in the loss of profiling identifies lipids that transitional 3 (T3) and naive B cells as well as a reduction of class-switched memory B cells, B1 cells, and predict cardiovascular events in plasmablasts; however, treatment did not affect levels of T1 B cells. Sequencing analysis indicated that secondary prevention belimumab had a minimal effect on the naive B cell repertoire but appears to promote negative selection of Piyushkumar A. Mundra, autoreactive B cells. These results support future studies to evaluate how belimumab affects function of the Christopher K. Barlow, Paul J. Nestel, surviving B cells. Elizabeth H. Barnes, Adrienne Kirby, Belimumab promotes negative selection of activated autoreactive Peter Thompson, David R. Sullivan, B cells in systemic lupus erythematosus patients Zahir H. Alshehry, Natalie A. Mellett, Weiqing Huang, Tam D. Quach, Cosmin Dascalu, Zheng Liu, Tungming Leung, Kevin Huynh, Kaushala S. Jayawardana, Miranda Byrne-Steele, Wenjing Pan, Qunying Yang, Jian Han, Martin Lesser, Corey Giles, Malcolm J. McConville, Thomas L. Rothstein, Richard Furie, Meggan Mackay, Cynthia Aranow, and Anne Davidson Sophia Zoungas, Graham S. Hillis, http://jci.me/122525 John Chalmers, Mark Woodward, Gerard Wong, Bronwyn A. Kingwell, John Simes, Andrew M. Tonkin, Peter J. Meikle, and LIPID Study Investigators http://jci.me/121326

13 jci.org/this-month october 2018 Current articles

Induction of antiinflammatory purinergic signaling in activated human iNKT cells Jennifer C. Yu, Gene Lin, Joshua J. Field, and Joel Linden http://jci.me/91954 1,25-Dihydroxyvitamin D suppresses M1 macrophages and promotes M2 differentiation at bone injury sites Samiksha Wasnik, Charles H. Rundle, David J. Baylink, Mohammad Safaie Yazdi, Edmundo E. Carreon, Yi Xu, Xuezhong Qin, Kin-Hing William Lau, and Xiaolei Tang http://jci.me/98773 Guaiacol as a drug candidate for treating adult polyglucosan body disease Or Kakhlon, Igor Ferreira, Leonardo J. Solmesky, Netaly Khazanov, Alexander Lossos, Rafael Alvarez, Deniz Yetil, Sergey Pampou, Miguel Weil, Hanoch Senderowitz, Pablo Escriba, Wyatt W. Yue, and H. Orhan Akman http://jci.me/99694 Nicotinamide mononucleotide preserves mitochondrial function and increases survival in hemorrhagic shock Carrie A. Sims, Yuxia Guan, Sarmistha Mukherjee, Khushboo Singh, Paul Botolin, Antonio Davila Jr., and Joseph A. Baur http://jci.me/120182 Lipocalin-2 derived from adipose tissue mediates aldosterone-induced renal injury Wai Yan Sun, Bo Bai, Cuiting Luo, Kangmin Yang, Dahui Li, Donghai Wu, Michel Félétou, Nicole Villeneuve, Yang Zhou, Junwei Yang, Aimin Xu, Paul M. Vanhoutte, and Yu Wang http://jci.me/120196

Excessive localized leukotriene B4 levels dictate poor skin host defense in diabetic mice Stephanie L. Brandt, Sue Wang, Naiara N. Dejani, Nathan Klopfenstein, Seth Winfree, Luciano Filgueiras, Brian P. McCarthy, Paul R. Territo, and C. Henrique Serezani http://jci.me/120220 Ruxolitinib inhibits cyclosporine-induced proliferation of cutaneous squamous cell carcinoma Melody Abikhair Burgo, Nazanin Roudiani, Jie Chen, Alexis L. Santana, Nicole Doudican, Charlotte Proby, Diane Felsen, and John A. Carucci http://jci.me/120750 Impaired monocyte cholesterol clearance initiates age-related retinal degeneration and vision loss Norimitsu Ban, Tae Jun Lee, Abdoulaye Sene, Mayur Choudhary, Michael Lekwuwa, Zhenyu Dong, Andrea Santeford, Jonathan B. Lin, Goldis Malek, Daniel S. Ory, and Rajendra S. Apte (ASCI) http://jci.me/120824 Attached stratified mucus separates bacteria from the epithelial cells in COPD lungs Joan Antoni Fernández-Blanco, Dalia Fakih, Liisa Arike, Ana M. Rodríguez-Piñeiro, Beatriz Martínez-Abad, Elin Skansebo, Sonya Jackson, James Root, Dave Singh, Christopher McCrae, Christopher M. Evans, Annika Åstrand, Anna Ermund, and Gunnar C. Hansson http://jci.me/120994 Calpain-6 controls the fate of sarcoma stem cells by promoting autophagy and preventing senescence Caroline Andrique, Laetitia Morardet, Laetitia K. Linares, Madi Y. Cissé, Candice Merle, Frédéric Chibon, Sylvain Provot, Eric Haÿ, Hang-Korng Ea, Martine Cohen-Solal, and Dominique Modrowski http://jci.me/121225 Large-scale plasma lipidomic profiling identifies lipids that predict cardiovascular events in secondary prevention p. 13 Piyushkumar A. Mundra, Christopher K. Barlow, Paul J. Nestel, Elizabeth H. Barnes, Adrienne Kirby, Peter Thompson, David R. Sullivan, Zahir H. Alshehry, Natalie A. Mellett, Kevin Huynh, Kaushala S. Jayawardana, Corey Giles, Malcolm J. McConville, Sophia Zoungas, Graham S. Hillis, John Chalmers, Mark Woodward, Gerard Wong, Bronwyn A. Kingwell, John Simes, Andrew M. Tonkin, Peter J. Meikle, and LIPID Study Investigators http://jci.me/121326 Targeting CD46 for both adenocarcinoma and neuroendocrine prostate cancer Yang Su, Yue Liu, Christopher R. Behrens, Scott Bidlingmaier, Nam-Kyung Lee, Rahul Aggarwal, Daniel W. Sherbenou, Alma L. Burlingame, Byron C. Hann, Jeffry P. Simko, Gayatri Premasekharan, Pamela L. Paris, Marc A. Shuman, Youngho Seo, Eric J. Small, and Bin Liu http://jci.me/121497 Two-photon imaging of the mammalian retina with ultrafast pulsing laser Grazyna Palczewska, Patrycjusz Stremplewski, Susie Suh, Nathan Alexander, David Salom, Zhiqian Dong, Daniel Ruminski, Elliot H. Choi, Avery E. Sears, Timothy S. Kern, Maciej Wojtkowski, and Krzysztof Palczewski http://jci.me/121555 Mouse model of Gram-negative prosthetic joint infection reveals therapeutic targets p. 10 John M. Thompson, Robert J. Miller, Alyssa G. Ashbaugh, Carly A. Dillen, Julie E. Pickett, Yu Wang, Roger V. Ortines, Robert S. Sterling, Kevin P. Francis, Nicholas M. Bernthal, Taylor S. Cohen, Christine Tkaczyk, Li Yu, C. Kendall Stover, Antonio DiGiandomenico, Bret R. Sellman, Daniel L.J. Thorek, and Lloyd S. Miller (ASCI) http://jci.me/121737 Polygenic risk score for predicting weight loss after bariatric surgery Juan de Toro-Martín, Frédéric Guénard, André Tchernof, Louis Pérusse, Simon Marceau, and Marie-Claude Vohl http://jci.me/122011 Human defects in STAT3 promote oral mucosal fungal and bacterial dysbiosis Loreto Abusleme, Patricia I. Diaz, Alexandra F. Freeman, Teresa Greenwell-Wild, Laurie Brenchley, Jigar V. Desai, Weng-Ian Ng, Steven M. Holland, Michail S. Lionakis, Julia A. Segre, Heidi H. Kong, and Niki M. Moutsopoulos http://jci.me/122061

jci.org/this-month october 2018 14 Current articles

MEG3 is increased in idiopathic pulmonary fibrosis and regulates epithelial cell differentiation Jason J. Gokey, John Snowball, Anusha Sridharan, Joseph P. Speth, Katharine E. Black, Lida P. Hariri, Anne-Karina T. Perl, Yan Xu, and Jeffrey A. Whitsett (ASCI) http://jci.me/122490 Belimumab promotes negative selection of activated autoreactive B cells in systemic lupus erythematosus patients p. 13 Weiqing Huang, Tam D. Quach, Cosmin Dascalu, Zheng Liu, Tungming Leung, Miranda Byrne-Steele, Wenjing Pan, Qunying Yang, Jian Han, Martin Lesser, Thomas L. Rothstein, Richard Furie, Meggan Mackay, Cynthia Aranow, and Anne Davidson http://jci.me/122525 Gestational diabetes and maternal obesity are associated with epigenome-wide methylation changes in children p. 11 Line Hjort, David Martino, Louise Groth Grunnet, Haroon Naeem, Jovana Maksimovic, Anders Henrik Olsson, Cuilin Zhang, Charlotte Ling, Sjurdur Frodi Olsen, Richard Saffery, and Allan Arthur Vaag http://jci.me/122572 Improved outcomes in PI3K-pathway-altered metastatic HPV oropharyngeal cancer Glenn J. Hanna, Alec Kacew, Nicole G. Chau, Priyanka Shivdasani, Jochen H. Lorch, Ravindra Uppaluri, Robert I. Haddad, and Laura E. MacConaill http://jci.me/122799 Cyclin-dependent kinase 4 is a preclinical target for diet-induced obesity Niloy Jafar Iqbal, Zhonglei Lu, Shun Mei Liu, Gary J. Schwartz, Streamson Chua Jr., and Liang Zhu http://jci.me/123000 Multidimensional assessment of alveolar T cells in critically ill patients James M. Walter, Kathryn A. Helmin, Hiam Abdala-Valencia, Richard G. Wunderink, and Benjamin D. Singer http://jci.me/123287 Brugada syndrome trafficking–defective Nav1.5 channels can trap cardiac Kir2.1/2.2 channels Marta Pérez-Hernández, Marcos Matamoros, Silvia Alfayate, Paloma Nieto-Marín, Raquel G. Utrilla, David Tinaquero, Raquel de Andrés, Teresa Crespo, Daniela Ponce-Balbuena, B. Cicero Willis, Eric N. Jiménez-Vazquez, Guadalupe Guerrero-Serna, Andre M. da Rocha, Katherine Campbell, Todd J. Herron, F. Javier Díez-Guerra, Juan Tamargo, José Jalife, Ricardo Caballero, and Eva Delpón http://jci.me/96291

Leukotriene B4 promotes neovascularization and macrophage recruitment in murine wet-type AMD models Fumiyuki Sasaki, Tomoaki Koga, Mai Ohba, Kazuko Saeki, Toshiaki Okuno, Keijiro Ishikawa, Takahito Nakama, Shintaro Nakao, Shigeo Yoshida, Tatsuro Ishibashi, Hamid Ahmadieh, Mozhgan Rezaei Kanavi, Ali Hafezi-Moghadam, Josef M. Penninger, Koh-Hei Sonoda, and Takehiko Yokomizo http://jci.me/96902 The phosphatidic acid phosphatase lipin-1 facilitates inflammation-driven colon carcinogenesis Clara Meana, Ginesa García-Rostán, Lucía Peña, Gema Lordén, África Cubero, Antonio Orduña, Balázs Győrffy, Jesús Balsinde, and María A. Balboa http://jci.me/97506 Neutrophil accumulation and NET release contribute to thrombosis in HIT p. 11 Kandace Gollomp, Minna Kim, Ian Johnston, Vincent Hayes, John Welsh, Gowthami M. Arepally, Mark Kahn, Michele P. Lambert, Adam Cuker, Douglas B. Cines, Lubica Rauova, M. Anna Kowalska, and Mortimer Poncz (ASCI) http://jci.me/99445 Laminin α1 is a genetic modifier of TGF-β1–stimulated pulmonary fibrosis Chang-Min Lee, Soo Jung Cho, Won-Kyung Cho, Jin Wook Park, Jae-Hyun Lee, Augustine M. Choi, Ivan O. Rosas, Ming Zheng, Gary Peltz, Chun Geun Lee, and Jack A. Elias (ASCI) http://jci.me/99574 Beclin-1 regulates cigarette smoke–induced kidney injury in a murine model of chronic obstructive pulmonary disease Maria A. Pabón, Edwin Patino, Divya Bhatia, Jocelyn Quintero, Kevin C. Ma, Eli J. Finkelsztein, Juan C. Osorio, Faryal Malick, Francesca Polverino, Caroline A. Owen, Stefan W. Ryter, Augustine M.K. Choi, Suzanne M. Cloonan, and Mary E. Choi http://jci.me/99592 IFI16 filament formation in salivary epithelial cells shapes the anti-IFI16 immune response in Sjögren’s syndrome Brendan Antiochos, Mariusz Matyszewski, Jungsan Sohn, Livia Casciola-Rosen, and Antony Rosen (ASCI) http://jci.me/120179 Human immunodeficiency virus infection induces lymphoid fibrosis in the BM-liver-thymus-spleen humanized mouse model Jasmine Samal, Samantha Kelly, Ali Na-Shatal, Abdallah Elhakiem, Antu Das, Ming Ding, Anwesha Sanyal, Phalguni Gupta, Kevin Melody, Brad Roland, Watfa Ahmed, Aala Zakir, and Moses Bility http://jci.me/120430 A limb-girdle muscular dystrophy 2I model of muscular dystrophy identifies corrective drug compounds for dystroglycanopathies Peter R. Serafini, Michael J. Feyder, Rylie M. Hightower, Daniela Garcia-Perez, Natássia M. Vieira, Angela Lek, Devin E. Gibbs, Omar Moukha-Chafiq, Corinne E. Augeli-Szafran, Genri Kawahara, Jeffrey J. Widrick, Louis M. Kunkel, and Matthew S. Alexander http://jci.me/120493

15 jci.org/this-month october 2018 Imbalance of immunological synapse-kinapse states reflects tumor escape to immunity in glioblastoma p. 12 Laura R. Díaz, Elena Saavedra-López, Leire Romarate, Izaskun Mitxitorena, Paola V. Casanova, George P. Cribaro, José M. Gallego, Ana Pérez-Vallés, Jerónimo Forteza-Vila, Clara Alfaro-Cervello, José M. García-Verdugo, Carlos Barcia Sr., and Carlos Barcia Jr. http://jci.me/120757 4-1BB enhancement of CAR T function requires NF-κB and TRAFs p. 12 Gongbo Li, Justin C. Boucher, Hiroshi Kotani, Kyungho Park, Yongliang Zhang, Bishwas Shrestha, Xuefeng Wang, Lawrence Guan, Nolan Beatty, Daniel Abate-Daga, and Marco L. Davila http://jci.me/121322 Gluconeogenesis and risk for fasting hyperglycemia in Black and White women Stephanie T. Chung, Amber B. Courville, Anthony U. Onuzuruike, Mirella Galvan-De La Cruz, Lilian S. Mabundo, Christopher W. DuBose, Kannan Kasturi, Hongyi Cai, Ahmed M. Gharib, Peter J. Walter, H. Martin Garraffo, Shaji Chacko, Morey W. Haymond, and Anne E. Sumner http://jci.me/121495 Chronic infection stunts macrophage heterogeneity and disrupts immune-mediated myogenesis Richard M. Jin, Jordan Warunek, and Elizabeth A. Wohlfert http://jci.me/121549 IL-33 modulates inflammatory brain injury but exacerbates systemic immunosuppression following ischemic stroke Shenpeng R. Zhang, Marius Piepke, Hannah X. Chu, Brad R.S. Broughton, Raymond Shim, Connie H.Y. Wong, Seyoung Lee, Megan A. Evans, Antony Vinh, Samy Sakkal, Thiruma V. Arumugam, Tim Magnus, Samuel Huber, Mathias Gelderblom, Grant R. Drummond, Christopher G. Sobey, and Hyun Ah Kim http://jci.me/121560 Single-cell RNA sequencing reveals microglia-like cells in cerebrospinal fluid during virologically suppressed HIV p. 13 Shelli F. Farhadian, Sameet S. Mehta, Chrysoula Zografou, Kevin Robertson, Richard W. Price, Jenna Pappalardo, Jennifer Chiarella, David A. Hafler, and Serena S. Spudich http://jci.me/121718 Essential role of IFN-γ in T cell–associated intestinal inflammation Yoshihiro Eriguchi, Kiminori Nakamura, Yuki Yokoi, Rina Sugimoto, Shuichiro Takahashi, Daigo Hashimoto, Takanori Teshima, Tokiyoshi Ayabe, Michael E. Selsted, and André J. Ouellette http://jci.me/121886 Microbiota-sensitive epigenetic signature predicts inflammation in Crohn’s disease Daniel Kelly, Michael Kotliar, Vivienne Woo, Sajjeev Jagannathan, Jordan Whitt, Jessica Moncivaiz, Bruce J. Aronow, Marla C. Dubinsky, Jeffrey S. Hyams, James F. Markowitz, Robert N. Baldassano, Michael C. Stephens, Thomas D. Walters, Subra Kugathasan, Yael Haberman, Nambirajan Sundaram, Michael J. Rosen, Michael Helmrath, Rebekah Karns, Artem Barski, Lee A. Denson, and Theresa Alenghat http://jci.me/122104 Abnormal neutrophil signature in the blood and pancreas of presymptomatic and symptomatic type 1 diabetes Federica Vecchio, Nicola Lo Buono, Angela Stabilini, Laura Nigi, Matthew J. Dufort, Susan Geyer, Paola Maria Rancoita, Federica Cugnata, Alessandra Mandelli, Andrea Valle, Pia Leete, Francesca Mancarella, Peter S. Linsley, Lars Krogvold, Kevan C. Herold, Helena Elding Larsson, Sarah J. Richardson, Noel G. Morgan, Knut Dahl-Jørgensen, Guido Sebastiani, Francesco Dotta, Emanuele Bosi, the DRI_Biorepository Group, the Type 1 Diabetes TrialNet Study Group, and Manuela Battaglia http://jci.me/122146 Necroptosis of infiltrated macrophages drives Yersinia pestis dispersal within buboes Mohammad Arifuzzaman, W.X. Gladys Ang, Hae Woong Choi, Matthew L. Nilles, Ashley L. St. John, and Soman N. Abraham http://jci.me/122188 Antioxidant metabolism regulates CD8+ T memory stem cell formation and antitumor immunity Karolina Pilipow, Eloise Scamardella, Simone Puccio, Sanjivan Gautam, Federica De Paoli, Emilia M.C. Mazza, Gabriele De Simone, Sara Polletti, Marta Buccilli, Veronica Zanon, Pietro Di Lucia, Matteo Iannacone, Luca Gattinoni, and Enrico Lugli http://jci.me/122299 Long-term remission despite clonal expansion of replication-competent HIV-1 isolates Rebecca T. Veenhuis, Abena K. Kwaa, Caroline C. Garliss, Rachel Latanich, Maria Salgado, Christopher W. Pohlmeyer, Christopher L. Nobles, John Gregg, Eileen P. Scully, Justin R. Bailey, Frederic D. Bushman, and Joel N. Blankson (ASCI) http://jci.me/122795 Combination anti–PD-1 and antiretroviral therapy provides therapeutic benefit against SIV Geetha H. Mylvaganam, Lynette S. Chea, Gregory K. Tharp, Sakeenah Hicks, Vijayakumar Velu, Smita S. Iyer, Claire Deleage, Jacob D. Estes, Steven E. Bosinger, Gordon J. Freeman, Rafi Ahmed, and Rama R. Amara http://jci.me/122940 Haptoglobin improves shock, lung injury, and survival in canine pneumonia Kenneth E. Remy, Irene Cortés-Puch, Steven B. Solomon, Junfeng Sun, Benjamin M. Pockros, Jing Feng, Juan J. Lertora, Roy R. Hantgan, Xiaohua Liu, Andreas Perlegas, H. Shaw Warren, Mark T. Gladwin, Daniel B. Kim-Shapiro, Harvey G. Klein, and Charles Natanson (ASCI) http://jci.me/123013 reviews The complex landscape of microRNAs in articular cartilage: biology, pathology, and therapeutic targets p. 12 Helal Endisha, Jason Rockel, Igor Jurisica, and Mohit Kapoor http://jci.me/121630 The evolving relationship of wound healing and tumor stroma Flip issue to read JCI content. Deshka S. Foster, R. Ellen Jones, Ryan C. Ransom, Michael T. Longaker (ASCI), and Jeffrey A. Norton http://jci.me/99911

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