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Impaired SNX9 Expression in Immune Cells during Chronic Inflammation: Prognostic and Diagnostic Implications This information is current as Eliran Ish-Shalom, Yaron Meirow, Moshe Sade-Feldman, of September 27, 2021. Julia Kanterman, Lynn Wang, Olga Mizrahi, Yair Klieger and Michal Baniyash J Immunol 2016; 196:156-167; Prepublished online 25 November 2015; doi: 10.4049/jimmunol.1402877 Downloaded from http://www.jimmunol.org/content/196/1/156 Supplementary http://www.jimmunol.org/content/suppl/2015/11/25/jimmunol.140287 Material 7.DCSupplemental http://www.jimmunol.org/ References This article cites 50 articles, 23 of which you can access for free at: http://www.jimmunol.org/content/196/1/156.full#ref-list-1 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision by guest on September 27, 2021 • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *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 © 2015 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Impaired SNX9 Expression in Immune Cells during Chronic Inflammation: Prognostic and Diagnostic Implications Eliran Ish-Shalom,*,† Yaron Meirow,*,1 Moshe Sade-Feldman,*,1 Julia Kanterman,* Lynn Wang,* Olga Mizrahi,† Yair Klieger,*,† and Michal Baniyash* Chronic inflammation is associated with immunosuppression and downregulated expression of the TCR CD247. In searching for new biomarkers that could validate the impaired host immune status under chronic inflammatory conditions, we discovered that sorting nexin 9 (SNX9), a protein that participates in early stages of clathrin-mediated endocytosis, is downregulated as well under such conditions. SNX9 expression was affected earlier than CD247 by the generated harmful environment, suggesting that it is a potential marker sensing the generated immunosuppressive condition. We found that myeloid-derived suppressor cells, which are elevated in the course of chronic inflammation, are responsible for the observed SNX9 reduced expression. Moreover, SNX9 down- regulation is reversible, as its expression levels return to normal and immune functions are restored when the inflammatory response Downloaded from and/or myeloid-derived suppressor cells are neutralized. SNX9 downregulation was detected in numerous mouse models for pa- thologies characterized by chronic inflammation such as chronic infection (Leishmania donovani), cancer (melanoma and colorectal carcinoma), and an autoimmune disease (rheumatoid arthritis). Interestingly, reduced levels of SNX9 were also observed in blood samples from colorectal cancer patients, emphasizing the feasibility of its use as a diagnostic and prognostic biomarker sensing the host’s immune status and inflammatory stage. Our new discovery of SNX9 as being regulated by chronic inflammation and its association with immunosuppression, in addition to the CD247 regulation under such conditions, show the global impact of http://www.jimmunol.org/ chronic inflammation and the generated immune environment on different cellular pathways in a diverse spectrum of dis- eases. The Journal of Immunology, 2016, 196: 156–167. hronic inflammation is a common factor underlying various mation leads to complications such as immunosuppression and pathologies that differ in their etiology and physiology such tissue damage (8), which predispose the host to cancer, opportu- C as cancer and autoimmune and infectious diseases. As these nistic infections, and limited success of immune-based therapies diseases progress, immune suppression of T cells and NK cells is (2, 9, 10). Currently, the lack of biomarkers that enable distinction evident in association with downregulation of the TCR CD247 between acute (beneficial) versus chronic (harmful) inflammation by guest on September 27, 2021 subunit. This protein is essential for T and NK cell activation and prevents accurate diagnosis and improved treatment of the above- function (1, 2). Various studies, including ours, have shown that described diseases. It is therefore of great interest to identify chronic inflammation leads to immunosuppression mediated by sensitive biomarkers that could predict developing chronic in- myeloid-derived suppressor cells (MDSCs). MDSCs comprise a flammation and immunosuppression to allow better clinical heterogeneous immature cell population coexpressing Gr-1+CD11b+ management of these conditions. 2 2 2 in mice and CD11b+CD14 CD33+,LIN HLA-DR CD33+ or In searching for new biomarkers that could indicate an impaired CD14+CD11b+ in humans (3–7). In most cases, chronic inflam- host immune function associated with chronic inflammation, we discovered sorting nexin 9 (SNX9) as a potential candidate that meets this criterion. SNX9 is a ubiquitously expressed protein *Lautenberg Center for General and Tumor Immunology, Israel–Canada Medical Research Institute, Faculty of Medicine, Hebrew University, Jerusalem 91120, Israel; sharing common structural and functional characteristics with and †ImProDia Ltd., Herzliya Pituah 46723, Israel SNX18 and SNX33 (11–13). It participates in early stages of 1Y.M. and M.S.-F. contributed equally to this work. clathrin-mediated endocytosis, coordinates actin polymerization ORCID: 0000-0003-2017-1926 (O.M.). with vesicle release (14), binds the GTPase dynamin, adaptor Received for publication November 13, 2014. Accepted for publication October 25, protein 2 clathrin (15), and activates the actin regulator neural 2015. Wiskott–Aldrich syndrome protein (N-WASp) (16). Moreover, This work was supported by the Israel Science Foundation, the Israeli Ministry of SNX9 plays a role in CD28 endocytosis after T cell stimulation Health, the Joint German–Israeli Research Program, the Israel Cancer Research and in coupling WASp to p85 and CD28, thus linking CD28 en- Fund, the United States–Israel Binational Science Foundation, and by Joseph and Matilda Melnick funds. gagement to its internalization, actin remodeling, and cosignaling Address correspondence and reprint requests to Prof. Michal Baniyash, Lautenberg (16). Center for General and Tumor Immunology, Israel–Canada Medical Research Insti- In this study, we describe novel characteristics and expression tute, Faculty of Medicine, Hebrew University, P.O. Box 12272, Jerusalem 91120, pattern of SNX9 in various cell types during the course of chronic Israel. E-mail address: [email protected] inflammation. To this end, we employed mouse models for human The online version of this article contains supplemental material. diseases such as chronic infection (Leishmania donovani), cancer Abbreviations used in this article: alum, Al(OH)3; AOM, azoxymethane; BCG, ba- cillus Calmette–Gue´rin; CIA, collagen-induced arthritis; CRC, colorectal cancer car- (melanoma and colon carcinoma), and autoimmunity (rheumatoid cinoma; DSS, dextran sulfate sodium; 5FU, 5-fluorouracil; MDSC, myeloid-derived arthritis [RA]). Importantly, we demonstrate the clinical relevance suppressor cell; N-WASp, neural Wiskott–Aldrich syndrome protein; RA, rheuma- of our observations indicating decreased SNX9 levels in the blood toid arthritis; SNX9, sorting nexin 9; WASp, Wiskott–Aldrich syndrome protein. of colorectal cancer carcinoma (CRC) patients, as compared with Copyright Ó 2015 by The American Association of Immunologists, Inc. 0022-1767/15/$30.00 healthy donors. Additionally, we show the wide range of effects www.jimmunol.org/cgi/doi/10.4049/jimmunol.1402877 The Journal of Immunology 157 generated by the inflammatory milieu on different cell types and Hadassah University Hospital blood bank facility after signing a written processes, which determine the general host immune status. informed consent. In all experiments, patient and control blood samples We suggest that SNX9 could be a useful biomarker for chronic were processed and handled in the same way, and all samples were always tested at the same time. inflammation-induced immunosuppression. MDSC depletion Materials and Methods For in vivo MDSC depletion, purified anti–Gr-1 (anti-Ly6G/Ly6C rat mAb, Mice clone RB6-8C5, a gift from Prof. Alberto Mantovani, University of Milan, Milan, Italy) were injected (0.5 mg/mouse) i.p. to the inflamed mice 2 d Female/male BALB/c, DBA/1, B10.A, and C57BL/6 mice, 6–8 wk of age, and 1 d before the mice were sacrificed. Splenic MDSC depletion was were bred at the Hebrew University specific pathogen-free facility. Animal verified by flow cytometry. use followed protocols approved by the Hebrew University–Hadassah Medical School Institutional Animal Care and Use Committee. In vivo and ex vivo T cell proliferation assay In vivo mouse models for Th1 and Th2 immune responses In vivo proliferation of T cells was performed as previously described (17). In brief, CD45.2+ C57BL/6 mice were injected with 50 mg CMV-OVA Female C57BL/6 mice repeatedly exposed to heat-killed Mycobacterium plasmid into the ear pinna by a 31-gauge needle. Seven days later, chronic tuberculosis (bacillus Calmette–Gue´rin [BCG]) (Difco
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