DOCSLIB.ORG

Responses During Sepsis Interactions Exacerbate Innate Immune CCR1

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Responses During Sepsis Interactions Exacerbate Innate Immune CCR1 The Journal of Immunology CCR1 and CC Chemokine Ligand 5 Interactions Exacerbate Innate Immune Responses during Sepsis1 Traci L. Ness,* Kristin J. Carpenter,* Jillian L. Ewing,* Craig J. Gerard,† Cory M. Hogaboam,2* and Steven L. Kunkel* CCR1 has previously been shown to play important roles in leukocyte trafficking, pathogen clearance, and the type 1/type 2 cytokine balance, although very little is known about its role in the host response during sepsis. In a cecal ligation and puncture model of septic peritonitis, CCR1-deficient (CCR1؊/؊) mice were significantly protected from the lethal effects of sepsis when compared with wild-type (WT) controls. The peritoneal and systemic cytokine profile in CCR1؊/؊ mice was characterized by a robust, but short-lived and regulated antibacterial response. CCR1 expression was not required for leu- -kocyte recruitment, suggesting critical differences extant in the activation of WT and CCR1؊/؊ resident or recruited peri toneal cells during sepsis. Peritoneal macrophages isolated from naive CCR1؊/؊ mice clearly demonstrated enhanced cytokine/chemokine generation and antibacterial responses compared with similarly treated WT macrophages. CCR1 and CCL5 interactions markedly altered the inflammatory response in vivo and in vitro. Administration of CCL5 increased sepsis-induced lethality in WT mice, whereas neutralization of CCL5 improved survival. CCL5 acted in a CCR1-dependent manner to augment production of IFN-␥ and MIP-2 to damaging levels. These data illustrate that the interaction between CCR1 and CCL5 modulates the innate immune response during sepsis, and both represent potential targets for therapeutic intervention. The Journal of Immunology, 2004, 173: 6938–6948. epsis is the most common cause of death in noncoronary mune response to sepsis (7, 8). Although differences in critical care units in the U.S. with Ͼ751,000 cases per year chemokine receptor expression in septic patients have been re- S at an estimated overall cost of $16.7 billion (increasing by ported (9), the significance of these differences is not under- 1.5% per year) (1). Due to the paucity of effective therapeutic stood. Almost nothing is known about the role these receptors treatments (2), the care of septic patients is predominantly sup- play in the septic response (10, 11). portive and mortality rates remain high. Although recombinant ac- CCR1 is expressed by a broad spectrum of leukocytes, including tivated protein C has shown some promise (3), investigators con- neutrophils, monocytes, eosinophils, and lymphocytes (12). Stud- tinue to search for novel therapies. ies of CCR1-deficient (CCR1Ϫ/Ϫ) mice have implicated CCR1 in During a normal infection, the immune system of an immuno- the modulation of leukocyte trafficking (13), parasite and viral competent host works to contain and destroy the pathogen. A sep- clearance (14, 15), and the balance of type 1 and type 2 cytokines tic response occurs when a pathogen circumvents the innate and (16); however, little is known about its role in the innate immune acquired immune defenses, resulting in systemic spread of the in- response during sepsis and multiorgan failure. In vitro, CCR1 has fection. In a continued attempt to eliminate the infection, the host been shown to bind several ligands, including CCL3, CCL5–9, enhances production of several proinflammatory cytokines and CCL14–16, and CCL23, although CCL3, CCL5, and CCL6 are the chemokines that act to increase the infiltration and activation of major agonists identified in vivo (17, 18). Serum levels of CCL3 inflammatory leukocytes. These factors have been shown to play a and CCL5 are elevated in septic patients (19), and peritoneal CCL3 significant role in the resulting tissue damage preceding sepsis- (20) and CCL6 (7) concentrations are increased in the cecal liga- associated multiple organ failure (4, 5) and may serve as potential tion and puncture (CLP) mouse model of sepsis. Both CCL3 (21) targets for immunotherapy. and CCL6 (7) have been demonstrated to play protective roles Chemokines are a family of small, primarily secreted proteins against sepsis-induced lethality and injury in a murine CLP model, that are responsible for modulating multiple aspects of inflam- while the role of CCL5 has yet to be explored. matory responses and host defense (6). Many studies have dem- The purpose of this study was to investigate the role of CCR1 in the onstrated several of these to be key mediators in the host im- innate immune response to experimental sepsis. CCR1Ϫ/Ϫ mice were significantly protected against CLP-induced lethality. Although CCR1 deficiency had no effect on the inflammatory cell recruitment *Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109; and †Children’s Hospital, Harvard Medical School, Boston, MA 02115 to the peritoneal cavity, loss of the receptor promoted accelerated cytokine expression and enhanced macrophage activity, both of Received for publication June 15, 2004. Accepted for publication September 22, 2004. which contributed to a more efficient and regulated antibacterial The costs of publication of this article were defrayed in part by the payment of page response. CCL5 was identified as a key modulator of the host charges. This article must therefore be hereby marked advertisement in accordance response that acted in a CCR1-dependent manner to trigger the with 18 U.S.C. Section 1734 solely to indicate this fact. unregulated, exaggerated expression of proinflammatory cyto- 1 This work was supported by Grants HL031237 and P50HL074024 from the Na- kines, resulting in increased injury and mortality following sepsis. tional Institutes of Health to S.L.K. 2 Address correspondence and reprint requests to Dr. Cory M. Hogaboam, Depart- ment of Pathology, University of Michigan Medical School, 1301 Catherine Road, Room 5214, Medical Sciences I, Ann Arbor, MI 48109-0602. E-mail address: 3 Abbreviations used in this paper: CLP, cecal ligation and puncture; TSA, thymic- [email protected] shared Ag; WT, wild type. Copyright © 2004 by The American Association of Immunologists, Inc. 0022-1767/04/$02.00 The Journal of Immunology 6939 Materials and Methods of 300 cells from multiple high-powered fields, was multiplied by the total Mice peritoneal cell count to determine the number for each cell type. Three independent experiments (three to five mice per group) showed similar Specific pathogen-free wild-type (WT) BALB/c mice (6–8 wk of age) results, and data were pooled. were purchased from The Jackson Laboratory (Bar Harbor, ME). CCR1- deficient (CCR1Ϫ/Ϫ) mice were generated, as previously described, and Measurement of cytokines and chemokines by ELISA were backcrossed onto a BALB/c genetic background (22). Mice were bred Concentrations of murine TNF-␣, IFN-␥, IL-12 (p70), IL-10, MIP-2, KC, and housed in the animal care facility (University Laboratory of Animal CCL2, CCL3, CCL5, CCL6, CCL17, CXCL9, and CXCL10 were mea- Medicine) at the University of Michigan. The Animal Use Committee at sured in cell-free peritoneal lavage fluid, serum, and cell culture superna- the University of Michigan approved all experimental procedures tants using a standardized sandwich ELISA previously described in detail involving mice. (25). Briefly, flat-bottom 96-well microtiter plates (Nunc, Roskilde, Den- Cecal ligation and puncture mark) were coated overnight at 4°C with mAb (for IL-10) or affinity- purified polyclonal Abs for the specific cytokine of interest (R&D Systems, CLP was used to induce acute septic peritonitis, as previously described Rochester, MN). Specific Ab for capture and detection of KC was obtained (23). Mice were anesthetized with a combination of 2.25 mg of ketamine from PeproTech. Plates were coated with 0.4 ␮g/ml (KC), 0.5 ␮g/ml HCl (Abbott Laboratories, Chicago, IL) and 150 ␮g of xylazine (Lloyd (IFN-␥, IL-12, CCL2, and CCL5), or 1.0 ␮g/ml (TNF-␣, IL-10, MIP-2, Laboratories, Shenandoah, IA) administered i.p. A 1-cm incision was made CCL3, CCL6, CCL17, CXCL9, and CXCL10) appropriate capture Abs. to the lower left abdomen of the mouse, and the cecum was exposed. The Plates were washed with PBS-Tween 20 (0.05%) and blocked with 2% cecum was ligated distally with 3.0 silk suture and punctured through and BSA in PBS for 90 min at 37°C. Plates were rinsed four times, and samples through with a 21- or 26-gauge needle. The cecum was returned to the were loaded and incubated at 37°C for 1 h. After washing, a biotinylated peritoneal cavity, and surgical staples were used to close the incision. Mice secondary polyclonal Ab specific for the cytokine being measured (R&D immediately received 1 ml of saline s.c. for fluid resuscitation and were Systems; PeproTech for KC) was added at 0.5 ␮g/ml (or 0.25 ␮g/ml for warmed on a heating pad to facilitate their revival from the anesthetic. CCL5) for 30 min at 37°C. The plate was washed, and streptavidin-per- oxidase conjugate (Bio-Rad, Richmond, CA) was added to the wells for 30 Experimental protocols min at 37°C. This was followed by another set of washes before the ad- dition of a chromogenic substrate (Bio-Rad). After full development oc- The first set of survival studies was performed to determine the effect of the curred, the reaction was stopped and the plate was read in an ELISA plate presence of CCR1 on survival following induction of acute septic perito- reader at 490 nm. Recombinant murine cytokines/chemokines (R&D Sys- nitis in female and male mice. Due to differential susceptibility, female tems) were used to generate standard curves, and concentrations were ex- mice were subjected to 21-gauge CLP, while 26-gauge CLP was performed pressed as ng or pg/ml. Limits of detection were ϳ50 pg/ml. ELISA spec- on male mice. Survival of CLP groups (n ϭ 8–10 mice per group) was ificity was confirmed for each assay.
Load more

Recommended publications
  • C-X-C Motif Chemokine Ligand 10 Produced by Mouse Sertoli Cells in Response to Mumps Virus Infection Induces Male Germ Cell Apoptosis
    Citation: Cell Death and Disease (2017) 8, e3146; doi:10.1038/cddis.2017.560 OPEN Macmillan Publishers Limited, part of Springer Nature. www.nature.com/cddis Corrected: Correction C-X-C motif chemokine ligand 10 produced by mouse Sertoli cells in response to mumps virus infection induces male germ cell apoptosis Qian Jiang1, Fei Wang1, Lili Shi1, Xiang Zhao1, Maolei Gong1, Weihua Liu1, Chengyi Song2, Qihan Li3, Yongmei Chen1, Han Wu*,1,2 and Daishu Han*,1 Mumps virus (MuV) infection usually results in germ cell degeneration in the testis, which is an etiological factor for male infertility. However, the mechanisms by which MuV infection damages male germ cells remain unclear. The present study showed that C-X-C motif chemokine ligand 10 (CXCL10) is produced by mouse Sertoli cells in response to MuV infection, which induces germ cell apoptosis through the activation of caspase-3. CXC chemokine receptor 3 (CXCR3), a functional receptor of CXCL10, is constitutively expressed in male germ cells. Neutralizing antibodies against CXCR3 and an inhibitor of caspase-3 activation significantly inhibited CXCL10-induced male germ cell apoptosis. Furthermore, the tumor necrosis factor-α (TNF-α) upregulated CXCL10 production in Sertoli cells after MuV infection. The knockout of either CXCL10 or TNF-α reduced germ cell apoptosis in the co-cultures of germ cells and Sertoli cells in response to MuV infection. Local injection of MuV into the testes of mice confirmed the involvement of CXCL10 in germ cell apoptosis in vivo. These results provide novel insights into MuV-induced germ cell apoptosis in the testis.
    [Show full text]
  • Enhanced Monocyte Migration to CXCR3 and CCR5 Chemokines in COPD
    ERJ Express. Published on March 10, 2016 as doi: 10.1183/13993003.01642-2015 ORIGINAL ARTICLE IN PRESS | CORRECTED PROOF Enhanced monocyte migration to CXCR3 and CCR5 chemokines in COPD Claudia Costa1, Suzanne L. Traves1, Susan J. Tudhope1, Peter S. Fenwick1, Kylie B.R. Belchamber1, Richard E.K. Russell2, Peter J. Barnes1 and Louise E. Donnelly1 Affiliations: 1Airway Disease, National Heart and Lung Institute, Imperial College London, London, UK. 2Chest Clinic, King Edward King VII Hospital, Windsor, UK. Correspondence: Louise E. Donnelly, Airway Disease, National Heart and Lung Institute, Dovehouse Street, London, SW3 6LY, UK. E-mail: [email protected] ABSTRACT Chronic obstructive pulmonary disease (COPD) patients exhibit chronic inflammation, both in the lung parenchyma and the airways, which is characterised by an increased infiltration of macrophages and T-lymphocytes, particularly CD8+ cells. Both cell types can express chemokine (C-X-C motif) receptor (CXCR)3 and C-C chemokine receptor 5 and the relevant chemokines for these receptors are elevated in COPD. The aim of this study was to compare chemotactic responses of lymphocytes and monocytes of nonsmokers, smokers and COPD patients towards CXCR3 ligands and chemokine (C-C motif) ligand (CCL)5. Migration of peripheral blood mononuclear cells, monocytes and lymphocytes from nonsmokers, smokers and COPD patients toward CXCR3 chemokines and CCL5 was analysed using chemotaxis assays. There was increased migration of peripheral blood mononuclear cells from COPD patients towards all chemokines studied when compared with nonsmokers and smokers. Both lymphocytes and monocytes contributed to this enhanced response, which was not explained by increased receptor expression.
    [Show full text]
  • Mouse CD163 Deficiency Strongly Enhances Experimental Collagen-Induced Arthritis
    www.nature.com/scientificreports OPEN Mouse CD163 defciency strongly enhances experimental collagen‑induced arthritis Pia Svendsen1,2, Anders Etzerodt 3, Bent W. Deleuran3,4 & Søren K. Moestrup1,2,5* The scavenger receptor CD163 is highly expressed in macrophages in sites of chronic infammation where it has a not yet defned role. Here we have investigated development of collagen‑induced arthritis (CIA) and collagen antibody‑induced arthritis (CAIA) in CD163‑defcient C57BL/6 mice. Compared to wild‑type mice, the CIA in CD163‑defcient mice had a several‑fold higher arthritis score with early onset, prolonged disease and strongly enhanced progression. Further, the serum anti‑ collagen antibody isotypes as well as the cytokine profles and T cell markers in the infamed joints revealed that CD163‑defcient mice after 52 days had a predominant Th2 response in opposition to a predominant Th1 response in CD163+/+ mice. Less diference in disease severity between the CD163+/+ and CD163−/− mice was seen in the CAIA model that to a large extent induces arthritis independently of T‑cell response and endogenous Th1/Th2 balance. In conclusion, the present set of data points on a novel strong anti‑infammatory role of CD163. Te scavenger receptor CD163 is expressed exclusively in cells of monocytic origin with a high expression in M2-type macrophages where it has an established role in scavenging hemoglobin (Hb) released into plasma 1. Te receptor and its function have been most intensively studied in human systems, but the selective myelomonocytic expression of CD163 with a high upregulation in the M2-type macrophages is also seen in animals including rodents2,3.
    [Show full text]
  • Microrna-155 Modulates Bile Duct Inflammation by Targeting the Suppressor of Cytokine Signaling 1 in Biliary Atresia
    nature publishing group Basic Science Investigation | Articles MicroRNA-155 modulates bile duct inflammation by targeting the suppressor of cytokine signaling 1 in biliary atresia Rui Zhao1, Rui Dong1, Yifan Yang1, Yuqing Wang1, Jin Ma2, Jiang Wang1, Hao Li1 and Shan Zheng1 BACKGROUND: Biliary atresia (BA) is an etiologically etiology and pathogenesis of BA remains largely unknown. A perplexing disease, manifested by neonatal cholestasis, leading hypothesis for the pathogenesis of BA is a virus repeated cholangitis, and progressive biliary fibrosis. MiR-155 infection-initiated bile duct injury (possibly prenatal), which has been implicated to modulate the immune response, is then followed by an exaggerated inflammatory or which contributes to biliary injury. However, its potential role autoimmune response targeting the bile duct epithelium. in the pathogenesis of BA has not been addressed so far. This ultimately results in progressive bile duct injury, METHODS: The microRNA changes from BA patients and obliteration, and secondary biliary cirrhosis (3,4). controls were identified via microarray. The immunomodula- Gene expression is primarily regulated at a post- tory function of miR-155 was investigated via cell transfection transcriptional level by microRNAs (miRNAs), which exert and reporter assay. The lentiviral vector pL-miR-155 inhibitor their function by targeting complementary mRNA molecules, was transfected into a mouse model to investigate its thus inhibiting their translation by binding to the 3′ role in BA. untranslated region (UTR) (5). Many miRNAs have been RESULTS: The expression of miR-155 in livers of BA patients reported to be differentially expressed in autoimmune diseases was significantly increased, and an inverse correlation and consequently may have a pivotal role in the regulation of between miR-155 and suppressor of cytokine signaling 1 both immune responses and autoimmunity.
    [Show full text]
  • US7572600.Pdf
    US007572600B2 (12) United States Patent (10) Patent No.: US 7,572,600 B2 Berahovich et al. (45) Date of Patent: Aug. 11, 2009 (54) ENZYMATIC ACTIVITIES IN WO WO90, 13332 11, 1990 CHEMOKNE-MEDIATED INFLAMMATION WO WO 91/12779 9, 1991 WO WO 91f17271 11, 1991 (75) WO WO91, 1898O 12/1991 Inventors: Robert D. Berahovich, Berkeley, CA WO WO92fO1047 1, 1992 (US); Zhenhua Miao, San Jose, CA WO WO93,06121 4f1993 (US); Brett Premack, San Francisco, WO WO93, 17706 9, 1993 CA (US); Thomas J. Schall, Palo Alto, WO WO93/24640 12/1993 CA (US) WO WO94,08051 4f1994 WO WO94/20142 9, 1994 (73) Assignee: Chemocentryx, Inc., Mt. View, CA (US) WO WO95/12608 5, 1995 WO WO95/30642 11, 1995 (*) Notice: Subject to any disclaimer, the term of this WO WO95/35503 12/1995 patent is extended or adjusted under 35 WO WO 98.04554 2, 1998 U.S.C. 154(b) by 486 days. OTHER PUBLICATIONS (21) Appl. No.: 11/198,935 Al-Obeidi (1998), Mol. Biotechnol. 9:205-223. Aoyama, Y. et al. (2001), Bioorg Med. Chem. Lett. 11: 1691-4. (22) Filed: Aug. 4, 2005 Amour, A., et al. (1998), J. Pharm. Pharmacol. 50:593-600. Berger, M.S. etal (1993), DNA Cell Biol 12:839-847. (65) Prior Publication Data Bao, L., et al. (1992), Genomics 13:437-40. US 2006/OO63223 A1 Mar. 23, 2006 Berman et al. (1988), Immunol. Invest. 17: 625-677. Baici, A. (1993), Biochem. Pharmacol. 46:1545-9. Bae, Y.-S. et al. (2004) J Immunol. 173:607-614.
    [Show full text]
  • DIL — Rm R2328 Lab Hours: Monday – Friday, 8 Am – 5 Pm EST 3333 Burnet Avenue • [email protected] Cincinnati, OH 45229-3039
    DIAGNOSTIC IMMUNOLOGY LABORATORY Ship First Overnight to: CCHMC — Julie Beach Phone: 513-636-4685 • Fax: 513-636-3861 DIL — Rm R2328 Lab Hours: Monday – Friday, 8 am – 5 pm EST 3333 Burnet Avenue www.cincinnatichildrens.org/DIL • [email protected] Cincinnati, OH 45229-3039 DIL — TEST REQUISITION FORM Patient Information MUST BE RECEIVED MONDAY – FRIDAY WITHIN 1 DAY OF COLLECTION UNLESS OTHERWISE INDICATED Patient Name (Last, First) , Date of Birth: / / Medical Record Number: Collection Date: / / Time of Sample: Gender: Male Female Relevant Medications: BMT: Yes — Date: / / No Unknown Diagnosis/reason for testing: TESTS OFFERRED: MAX VOLUME LISTED IS THE PREFERRED WHOLE BLOOD VOLUME 2–3 mL Sodium Heparin Mitogen Stimulation See #1 on page 2 Alemtuzumab Plasma Level See #5 on page 2 1–3ml EDTA or 0.5-1ml CSF, See #3 or ALPS Panel by Flow Need CBC/Diff result 1–3 ml EDTA, See #2 on page 2 Neopterin, Plasma or CSF #4 on page 2 Antigen Stimulation See #1 on page 2 Neutrophil Adhesion Mrkrs: CD18/11b 1–3ml EDTA Apoptosis (Fas, mediated) 10-20ml ACD-A Neutrophil Oxidative Burst (DHR) 1–3ml EDTA Note: Only draw Apoptosis on Wed. for Thurs. delivery NK Function (STRICT 28 HOUR CUT-OFF) See #1 on page 2 B Cell Panel Need CBC/Diff result 1–3ml EDTA, See #2 on page 2 1–3ml EDTA BAFF 1–3ml EDTA, See #4 on page 2 Perforin/Granzyme B 1–3ml EDTA CD40L / ICOS 3–5ml Sodium Heparin pSTAT5 2 (0.3mL) Gold serum aliquots, frozen CD45RA/RO 1–3ml EDTA S100A8/A9 Heterodimer w/in 4 hours of collection CD52 Expression 1–3ml EDTA 2 (0.3mL) Gold serum aliquots, frozen S100A12 w/in 4 hours of collection CD107a Mobilization (NK Cell Degran) See #1 on page 2 Note: Only draw CD107a Mon.
    [Show full text]
  • Retinoid X Receptor Α Controls Innate Inflammatory Responses Through The
    Retinoid X receptor α controls innate inflammatory responses through the up-regulation of chemokine expression Vanessa Núñeza,1, Daniel Alamedaa,1, Daniel Ricoa,2, Rubén Motab, Pilar Gonzalob, Marta Cedenillaa, Thierry Fischerc, Lisardo Boscád, Christopher K. Glasse, Alicia G. Arroyob, and Mercedes Ricotea,3 Departments of aRegenerative Cardiology and bVascular Biology and Inflammation, Centro Nacional de Investigaciones Cardiovasculares, Madrid 28029, Spain; cDepartment of Immunology and Oncology, Centro Nacional de Biotecnología, Madrid 28049, Spain; dInstituto de Investigaciones Biomédicas “Alberto Sols” (CSIC-UAM), Madrid 28029, Spain; and eDepartment of Medicine, Department of Cellular and Molecular Medicine, University of California, La Jolla, CA 92093 Edited* by Daniel Steinberg, University of California, La Jolla, CA, and approved April 19, 2010 (received for review November 25, 2009) The retinoid X receptor α (RXRα) plays a central role in the regulation Chemokines and their receptors have been implicated in the of many intracellular receptor signaling pathways and can mediate modulation of leukocyte trafficking, immune/inflammatory respon- ligand-dependent transcription by forming homodimers or hetero- ses, sepsis, and multiorgan failure (18, 19). Clinical studies have also dimers with other nuclear receptors. Although several members of identified elevated levels of chemokines associated with human the nuclear hormone receptor superfamily have emerged as impor- sepsis and acute lung injury (20). tant regulators of macrophage gene expression, the existence in vivo We have examined the role of RXRα in the innate immune of an RXR signaling pathway in macrophages has not been estab- system by conditionally disrupting RXRα in myeloid cells. We lished. Here, we provide evidence that RXRα regulates the transcrip- show that chemokines Ccl6 and Ccl9 are novel target genes for tion of the chemokines Ccl6 and Ccl9 in macrophages independently RXRα in primary peritoneal macrophages.
    [Show full text]
  • CCL9 Is Secreted by the Follicle-Associated Epithelium and Recruits Dome Region Peyer's Patch Cd11b+ Dendritic Cells
    CCL9 Is Secreted by the Follicle-Associated Epithelium and Recruits Dome Region Peyer's Patch CD11b+ Dendritic Cells This information is current as Xinyan Zhao, Ayuko Sato, Charles S. Dela Cruz, Melissa of October 1, 2021. Linehan, Andreas Luegering, Torsten Kucharzik, Aiko-Konno Shirakawa, Gabriel Marquez, Joshua M. Farber, Ifor Williams and Akiko Iwasaki J Immunol 2003; 171:2797-2803; ; doi: 10.4049/jimmunol.171.6.2797 http://www.jimmunol.org/content/171/6/2797 Downloaded from References This article cites 32 articles, 19 of which you can access for free at: http://www.jimmunol.org/content/171/6/2797.full#ref-list-1 http://www.jimmunol.org/ Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication by guest on October 1, 2021 *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts Errata An erratum has been published regarding this article. Please see next page or: /content/172/11/7220.2.full.pdf The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2003 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology CCL9 Is Secreted by the Follicle-Associated Epithelium and Recruits Dome Region Peyer’s Patch CD11b؉ Dendritic Cells1 Xinyan Zhao,2* Ayuko Sato,* Charles S.
    [Show full text]
  • Myelin-Specific CD8 T Cells Exacerbate Brain Inflammation in CNS Autoimmunity
    Myelin-specific CD8 T cells exacerbate brain inflammation in CNS autoimmunity Catriona A. Wagner, … , Denny Liggitt, Joan M. Goverman J Clin Invest. 2019. https://doi.org/10.1172/JCI132531. Research In-Press Preview Autoimmunity Graphical abstract Find the latest version: https://jci.me/132531/pdf Myelin-specific CD8 T cells exacerbate brain inflammation in CNS autoimmunity Catriona A. Wagner1, Pamela J. Roqué1, Trevor R. Mileur1, Denny Liggitt2, and Joan M. Goverman1* 1Departments of Immunology and 2Comparative Medicine, University of Washington, Seattle, WA, USA *Corresponding author: Dr. Joan M. Goverman Department of Immunology, University of Washington Box 358059 750 Republican St, Seattle, WA 98109 Tel: +1 206-685-7604 Fax: +1 206-616-4561 Email: [email protected] The authors declare no competing financial interests. Abstract Multiple sclerosis (MS) is an inflammatory, demyelinating disease of the CNS. Although CD4 T cells are implicated in MS pathogenesis and have been the main focus of MS research using the animal model experimental autoimmune encephalomyelitis (EAE), substantial evidence from patients with MS points to a role for CD8 T cells in disease pathogenesis. We previously showed that an MHC class I-restricted epitope of myelin basic protein (MBP) is presented in the CNS during CD4 T cell-initiated EAE. Here, we investigated whether naïve MBP-specific CD8 T cells recruited to the CNS during CD4 T cell-initiated EAE engaged in determinant-spreading and influenced disease. We found that the MBP-specific CD8 T cells exacerbated brain but not spinal cord inflammation. We show that a higher frequency of monocytes and monocyte-derived cells presented the MHC class I-restricted MBP ligand in the brain compared to the spinal cord.
    [Show full text]
  • Chemokine Signatures of Pathogen-Specific T Cells II: Memory T Cells in Acute and Chronic Infection
    Chemokine Signatures of Pathogen-Specific T Cells II: Memory T Cells in Acute and Chronic Infection This information is current as Bennett Davenport, Jens Eberlein, Tom T. Nguyen, of September 24, 2021. Francisco Victorino, Verena van der Heide, Maxim Kuleshov, Avi Ma'ayan, Ross Kedl and Dirk Homann J Immunol published online 18 September 2020 http://www.jimmunol.org/content/early/2020/09/17/jimmun ol.2000254 Downloaded from Supplementary http://www.jimmunol.org/content/suppl/2020/09/17/jimmunol.200025 Material 4.DCSupplemental http://www.jimmunol.org/ Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication by guest on September 24, 2021 *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2020 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Published September 18, 2020, doi:10.4049/jimmunol.2000254 The Journal of Immunology Chemokine Signatures of Pathogen-Specific T Cells II: Memory T Cells in Acute and Chronic Infection Bennett Davenport,*,†,‡,x,{ Jens Eberlein,*,† Tom T. Nguyen,*,‡ Francisco Victorino,*,†,‡ Verena van der Heide,x,{ Maxim Kuleshov,‖,# Avi Ma’ayan,‖,# Ross Kedl,† and Dirk Homann*,†,‡,x,{ Pathogen-specific memory T cells (TM) contribute to enhanced immune protection under conditions of reinfection, and their effective recruitment into a recall response relies, in part, on cues imparted by chemokines that coordinate their spatiotemporal positioning.
    [Show full text]
  • NF-Κb Dependent Chemokine Signaling in Pancreatic Cancer
    cancers Review NF-κB Dependent Chemokine Signaling in Pancreatic Cancer Claudia Geismann 1, Heiner Schäfer 1,2 , Jan-Paul Gundlach 3, Charlotte Hauser 3 , Jan-Hendrik Egberts 3, Günter Schneider 4 and Alexander Arlt 1,* 1 Laboratory of Molecular Gastroenterology & Hepatology, Department of Internal Medicine I, UKSH-Campus Kiel, 24105 Kiel, Germany; [email protected] (C.G.); [email protected] (H.S.) 2 Institute of Experimental Cancer Research, UKSH Campus Kiel, 24105 Kiel, Germany 3 Department of Surgery, UKSH-Campus Kiel, 24105 Kiel, Germany; [email protected] (J.-P.G.); [email protected] (C.H.); [email protected] (J.-H.E.) 4 Technische Universität München, Klinikum rechts der Isar, II. Medizinische Klinik, 81675 Munich, Germany; [email protected] * Correspondence: [email protected]; Tel.: +49-431-5002-2210 Received: 30 August 2019; Accepted: 24 September 2019; Published: 26 September 2019 Abstract: Pancreatic cancer is one of the carcinomas with the worst prognoses, as shown by its five-year survival rate of 9%. Although there have been new therapeutic innovations, the effectiveness of these therapies is still limited, resulting in pancreatic ductal adenocarcinoma (PDAC) becoming the second leading cause of cancer-related death in 2020 in the US. In addition to tumor cell intrinsic resistance mechanisms, this disease exhibits a complex stroma consisting of fibroblasts, immune cells, neuronal and vascular cells, along with extracellular matrix, all conferring therapeutic resistance by several mechanisms. The NF-κB pathway is involved in both the tumor cell-intrinsic and microenvironment-mediated therapeutic resistance by regulating the transcription of a plethora of target genes.
    [Show full text]
  • Inflammation in Lafora Disease: Evolution with Disease Progression in Laforin and Malin Knock-Out Mouse Models
    HHS Public Access Author manuscript Author ManuscriptAuthor Manuscript Author Mol Neurobiol Manuscript Author . Author Manuscript manuscript; Author available in PMC 2017 July 01. Published in final edited form as: Mol Neurobiol. 2017 July ; 54(5): 3119–3130. doi:10.1007/s12035-016-9884-4. Inflammation in Lafora Disease: evolution with disease progression in laforin and malin knock-out mouse models Irene López-González, MSc1,#, Rosa Viana, PhD4,#, Pascual Sanz, PhD4,5,CA, and Isidre Ferrer, MD, PhD1,2,3,CA 1Institute of Neuropathology, Bellvitge University Hospital, Idibell, Hospitalet de Llobregat, Barcelona, Spain 2University of Barcelona, Hospitalet de Llobregat, Barcelona, Spain 3CIBERNED (Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas), Ministry of Science and Innovation, Institute Carlos III, Spain 4Instituto de Biomedicina de Valencia, Consejo Superior de Investigaciones Científicas; Valencia, Spain 5CIBERER (Centro de Investigación Biomédica en Red de Enfermedades Raras), Institute Carlos III, Spain Abstract Lafora progressive myoclonus epilepsy (Lafora disease, LD) is a fatal rare autosomal recessive neurodegenerative disorder characterized by the accumulation of insoluble ubiquitinated polyglucosan inclusions in the cytoplasm of neurons, which is most commonly associated with mutations in two genes: EPM2A, encoding the glucan phosphatase laforin, and EPM2B, encoding the E3-ubiquitin ligase malin. The present study analyzes possible inflammatory responses in the mouse lines Epm2a−/− (laforin knock-out) and Epm2b−/− (malin knock-out) with disease progression. Increased numbers of reactive astrocytes (expressing the GFAP marker) and microglia (expressing the Iba1 marker) together with increased expression of genes encoding cytokines and mediators of the inflammatory response occur in both mouse lines although with marked genotype differences.
    [Show full text]