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Lupus Erythematosus Immunostimulatory Molecules In Downloaded from http://www.jimmunol.org/ by guest on September 25, 2021 is online at: average * The Journal of Immunology , 21 of which you can access for free at: 2011; 187:538-552; Prepublished online 25 May from submission to initial decision 4 weeks from acceptance to publication Eneida Villanueva, Srilakshmi Yalavarthi, Celine C. Berthier, Jeffrey B. Hodgin, Ritika Khandpur, Andrew M. Lin, Cory J. Rubin, Wenpu Zhao, Stephen H. Olsen, Matthew Klinker, David Shealy, Michael F. Denny, Joel Plumas, Laurence Chaperot, Matthias Kretzler, Allen T. Bruce and Mariana J. Kaplan 2011; doi: 10.4049/jimmunol.1100450 http://www.jimmunol.org/content/187/1/538 Netting Neutrophils Induce Endothelial Damage, Infiltrate Tissues, and Expose Immunostimulatory Molecules in Systemic Lupus Erythematosus J Immunol cites 65 articles Submit online. Every submission reviewed by practicing scientists ? is published twice each month by http://jimmunol.org/subscription Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts http://www.jimmunol.org/content/187/1/538.full#ref-list-1 http://www.jimmunol.org/content/suppl/2011/05/25/jimmunol.110045 0.DC1 This article Information about subscribing to The JI No Triage! Fast Publication! Rapid Reviews! 30 days* Why • • • Material References Permissions Email Alerts Subscription Supplementary The Journal of Immunology The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2011 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. This information is current as of September 25, 2021. The Journal of Immunology Netting Neutrophils Induce Endothelial Damage, Infiltrate Tissues, and Expose Immunostimulatory Molecules in Systemic Lupus Erythematosus Eneida Villanueva,*,1 Srilakshmi Yalavarthi,*,1 Celine C. Berthier,† Jeffrey B. Hodgin,‡ Ritika Khandpur,x Andrew M. Lin,x Cory J. Rubin,x Wenpu Zhao,* Stephen H. Olsen,‡ Matthew Klinker,* David Shealy,{ Michael F. Denny,*,2 Joel Plumas,‖,#,** Laurence Chaperot,‖,#,** Matthias Kretzler,† Allen T. Bruce,x and Mariana J. Kaplan* An abnormal neutrophil subset has been identified in the PBMC fractions from lupus patients. We have proposed that these low- density granulocytes (LDGs) play an important role in lupus pathogenesis by damaging endothelial cells and synthesizing increased Downloaded from levels of proinflammatory cytokines and type I IFNs. To directly establish LDGs as a distinct neutrophil subset, their gene array profiles were compared with those of autologous normal-density neutrophils and control neutrophils. LDGs significantly overex- press mRNA of various immunostimulatory bactericidal proteins and alarmins, relative to lupus and control neutrophils. In con- trast, gene profiles of lupus normal-density neutrophils do not differ from those of controls. LDGs have heightened capacity to synthesize neutrophils extracellular traps (NETs), which display increased externalization of bactericidal, immunostimulatory pro- teins, and autoantigens, including LL-37, IL-17, and dsDNA. Through NETosis, LDGs have increased capacity to kill endothelial http://www.jimmunol.org/ cells and to stimulate IFN-a synthesis by plasmacytoid dendritic cells. Affected skin and kidneys from lupus patients are infiltrated by netting neutrophils, which expose LL-37 and dsDNA. Tissue NETosis is associated with increased anti-dsDNA in sera. These results expand the potential pathogenic roles of aberrant lupus neutrophils and suggest that dysregulation of NET formation and its subsequent responses may play a prominent deleterious role. The Journal of Immunology, 2011, 187: 538–552. ecent evidence from our group and others indicates that more, lupus patients with higher circulating LDG numbers have neutrophils may play an important role in the induction of increased prevalence of skin involvement and/or vasculitis (1). R autoimmune responses and organ damage in systemic Although currently no specific LDG surface markers have been by guest on September 25, 2021 lupus erythematosus (SLE) (1–3). Furthermore, microarray data identified that would allow them to be distinguished from normal- indicate that neutrophil-specific genes are highly expressed in density granulocytes, their nuclear morphology suggests that these PBMCs from lupus patients because of the cosegregation of low- cells present a more immature phenotype (1, 3). However, it is still density granulocytes (LDGs) in mononuclear cell fractions (3, 4). unknown whether lupus LDGs play prominent roles, when com- These LDGs represent a distinct neutrophil subset that is present pared with normal-density lupus neutrophils, in other aspects of in the peripheral blood of all adult SLE patients analyzed. Lupus disease pathogenesis, including providing a supply of potential LDGs are likely to be pathogenic, given their heightened capa- autoantigens or inducing or perpetuating autoimmune responses city to induce vascular damage and synthesize type I IFNs upon and tissue damage. exposure to specific stimulants, such as G-CSF and polyinosinic: Neutrophils immobilize and kill invading microbes extracellu- polycytidylic acid, when compared with autologous lupus normal- larly through the formation of neutrophil extracellular traps (NETs). density neutrophils and healthy control neutrophils (1). Further- As a unique type of neutrophil cell death, recently described as *Division of Rheumatology, Department of Internal Medicine, University of Mich- (Grant P30 CA46592), the Rheumatic Disease Core Center (Grant P30 AR48310), igan Medical School, Ann Arbor, MI 48109; †Division of Nephrology, Department of and the Applied Systems Biology Core in the O’Brien Renal Center (Grant P30 Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48109; DK081943). ‡Department of Pathology, University of Michigan Medical School, Ann Arbor, MI x The sequences presented in this article have been submitted to the Gene Expression 48109; Department of Dermatology, University of Michigan Medical School, Ann { ‖ Omnibus under accession number GSE26975. Arbor, MI 48109; Centocor Research and Development, Radnor, PA 19355; Uni- versite´ Joseph Fourier, Grenoble 38041, France; #INSERM U823, Immunobiologie et Address correspondence and reprint requests to Dr. Mariana J. Kaplan, Division of Immunotherapie des Cancers, La Tronche 38706, France; and **Etablissement Fran- Rheumatology, Department of Internal Medicine, University of Michigan Medical cais du Sang Rhone-Alpes, Laboratoire R&D, La Tronche 38701, France School, 5520 MSRBI, 1150 West Medical Center Drive, Ann Arbor, MI 48109-5680. E-mail address: [email protected] 1E.V. and S.Y. contributed equally to the manuscript and share first authorship. The online version of this article contains supplemental material. 2Current address: Division of Rheumatology and Autoimmunity Center, Temple University, Philadelphia, PA. Abbreviations used in this article: ANCA, anti-neutrophilic cytoplasmic Ab; CTSG, cathepsin-G; DEFA4, defensin a-4; EC, endothelial cell; ELANE, elastase-2; IPA, Received for publication February 11, 2011. Accepted for publication April 24, 2011. Ingenuity Pathway Analysis; LCN2, lipocalin-2; LDG, low-density granulocyte; LTF, This work was supported by the National Institutes of Health through Public Health lactotransferrin; MMP-8, matrix metalloproteinase-8; MNase, micrococcal nuclease; Service Grant HL088419 (to M.J.K.), the Arthritis Foundation (to M.J.K.), the Uni- MPO, myeloperoxidase; NET, neutrophil extracellular trap; pDC, plasmacytoid den- versity of Michigan/Centocor Postdoctoral Research Program (to M.J.K. and E.V.), dritic cell; RNP, ribonucleoprotein; SLE, systemic lupus erythematosus; SLEDAI, the Anthony Gramer Fund in Inflammation Research (to M.J.K.), the Babcock Re- systemic lupus erythematosus disease activity index. search Endowment (to A.T.B.), and Training Grant in Cell and Molecular Dermatol- ogy 5T32AR007197 (to C.J.R.). This work was supported in part by the National Copyright Ó 2011 by The American Association of Immunologists, Inc. 0022-1767/11/$16.00 Institutes of Health through the University of Michigan’s Cancer Center Support www.jimmunol.org/cgi/doi/10.4049/jimmunol.1100450 The Journal of Immunology 539 NETosis, this response is distinct from apoptosis and necrosis recognizing human neutrophil elastase (Abcam, Cambridge, MA), human and characterized by the active release of nuclear chromatin fi- Ro/SSA and human La/SSB (Santa Cruz Biotechnology, Santa Cruz, CA), bers (5, 6). NETosis is triggered by a variety of stimuli including mouse Abs recognizing human Smith (Abcam), human Cathelicidin/ OSX12 (Abcam), and human dsDNA (Millipore, Temecula, CA), and microorganisms, proinflammatory cytokines, activated platelets, goat anti-human IL-17 (R&D Systems, Minneapolis, MN) were used. and endothelial cells (ECs) (6, 7). A variety of putative auto- Secondary detection was performed using goat anti-rabbit–FITC (Southern antigens are present within and attached to NET chromatin fibers, Biotechnology Associates, Birmingham, AL), donkey anti-goat Alexa 568 including citrullinated histones (8) and various bactericidal pro- (Invitrogen, Carlsbad, CA), and/or anti-mouse Cy3 (Sigma-Aldrich, St. Louis, MO). Prolong Gold Antifade and Hoechst 33342 were from In- teins and/or enzymes such as the cathelicidin LL-37, neutrophil vitrogen.
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