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Differential Induction of SOCS Isoforms by Leishmania Donovani Impairs Macrophage−T Cell Cross-Talk and Host Defense

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Differential Induction of SOCS Isoforms by Leishmania Donovani Impairs Macrophage−T Cell Cross-Talk and Host Defense Differential Induction of SOCS Isoforms by Leishmania donovani Impairs Macrophage−T Cell Cross-Talk and Host Defense This information is current as Pragya Chandrakar, Naveen Parmar, Albert Descoteaux and of September 30, 2021. Susanta Kar J Immunol published online 27 December 2019 http://www.jimmunol.org/content/early/2019/12/26/jimmun ol.1900412 Downloaded from Supplementary http://www.jimmunol.org/content/suppl/2019/12/26/jimmunol.190041 Material 2.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 30, 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 © 2019 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Published December 27, 2019, doi:10.4049/jimmunol.1900412 The Journal of Immunology Differential Induction of SOCS Isoforms by Leishmania donovani Impairs Macrophage–T Cell Cross-Talk and Host Defense Pragya Chandrakar,*,† Naveen Parmar,*,† Albert Descoteaux,‡ and Susanta Kar*,† Immune evasion strategies adopted by Leishmania donovani involve the exploitation of suppressor of cytokine signaling (SOCS) proteins that are well-known negative regulators of the JAK/STAT pathway. However, the cellular mechanism underpinning the induction of SOCS isoforms and their role in breaching the multilevel regulatory circuit connecting the innate and adaptive arms of immunity are still ambiguous during experimental visceral leishmaniasis. Using bone marrow–derived macrophages (BMMvs) and CD4+ T cells, we observed that L. donovani preferentially upregulates SOCS1 and SOCS3 expression in macrophages and T cells, respectively, whereas the SOCS1 level remains consistently high in BMMvs and SOCS3 expression is pronounced and Downloaded from long lasting in T cells. Consequently, this inhibits STAT1-mediated IL-12 induction in macrophages & STAT4-mediated IFN-g synthesis in T cells. Mechanistically, PI3K/Akt–mediated SRF activation promotes nuclear translocation and binding of Egr2 to SOCS1 promoter for its early induction in infected BMMvs. Additionally, L. donovani activates IDO/kynurenine/AHR signaling in BMMvs to maintain prolonged SOCS1 expression. Later, PGE2, secreted from infected BMMvs induces cAMP–PKA pathway by binding to the EP2/EP4 receptor of CD4+ T cells, leading to SP1, CREB, and GATA1 activation and SOCS3 expression. Small interfering RNA–mediated silencing of SOCS1 and SOCS3 in macrophage and T cells, respectively, restored IL-12 and IFN-g http://www.jimmunol.org/ cytokine levels and BMMv–T cell interaction. Vivo morpholino–mediated silencing of SOCS1 and SOCS3 resulted in protective cytokine responses, thereby reducing organ parasite burden significantly in L. donovani–infected BALB/c mice. Collectively, our results imply that L. donovani orchestrates different SOCS isoforms to impair macrophage–T cell cross-talk and preserve its own niche. The Journal of Immunology, 2020, 204: 000–000. he severity of visceral leishmaniasis (VL) is primarily due or Th2 mode (3). Early studies using mouse models of VL have to parasite migration to the vital organs, such as the liver, revealed a clear dichotomy between Th1-associated cytokines me- spleen and bone marrow of the mammalian host, that diating protection and Th2-associated cytokines mediating suscep- T by guest on September 30, 2021 eventually causes immunological dysfunctions of T cells, NK cells, tibility (2, 4). In human and experimental models of VL, control and macrophages (1, 2). In different forms of leishmaniasis, it of infection is critically dependent upon the early induction of an has been well documented that disease progression or resolution is IL-12–driven Th1-type immune response and the production of ultimately dictated by CD4+ T cell differentiation to either the Th1 IFN-g by CD4+ T cells (4, 5). IFN-g plays a critical role in the activation of macrophages by inducing production of NO, which is critical for the elimination of parasites (2). *Division of Molecular Parasitology and Immunology, Council of Scientific and Industrial Research-Central Drug Research Institute, Lucknow 226031, India; Most cytokines use the so-called JAK/STAT pathways for †Academy of Scientific and Innovative Research, Ghaziabad, Uttar Pradesh 201002, immune-functioning, and suppressor of cytokine signaling (SOCS) India; and ‡Institut National de la Recherche Scientifique-Centre Armand-Frappier Sante´ Biotechnologie, Laval, Quebec H7V 1B7, Canada proteins are one of the crucial negative regulators of these pathways and cytokine-mediated immune homeostasis (6). Studies using ORCIDs: 0000-0002-0633-5309 (A.D.); 0000-0002-9907-539X (S.K.). conditional knockout (KO) mice have shown that SOCS proteins Received for publication April 10, 2019. Accepted for publication November 24, 2019. are key physiological and pathological regulators of immune ho- This work was supported by the Indian National Science Academy (SP/YSP/115/ meostasis, as they bind to JAK or cytokine receptors, thereby sup- 2015), the Department of Science and Technology (Grant SB/FT/LS-310/2012), and pressing subsequent signaling events associated with host immune the Council of Scientific and Industrial Research (CSIR) (NWP BSC0114). P.C. response (7). SOCS, consisting of eight members (SOCS1 to received a fellowship from CSIR (New Delhi) and N.P. received a fellowship from the University Grants Commission (New Delhi). A.D. is the holder of the Canada SOCS7 and CIS) all share a central SH2 domain and a C-terminal Research Chair on the Biology of Intracellular Parasitism. The funders had no role in SOCS box (8). The expression of SOCS is induced by multiple study design, data collection and analysis, decision to publish, or preparation of the cytokines, growth factors (9), LPS (10), and Gram-positive bacteria manuscript. This manuscript has Central Drug Research Institute Communication number 10010. (11). The SOCS group of proteins positively and negatively regulate Address correspondence and reprint requests to Dr. Susanta Kar, Council of macrophage and dendritic cell activation and are essential for Scientific and Industrial Research-Central Drug Research Institute, Sector-10, T cell development and differentiation (12). It has been postulated Jankipuram Extension, Sitapur Road, Lucknow 226031, Uttar Pradesh, India. that the JAK/STAT signaling is interrupted by lack of appropriate E-mail address: [email protected] phosphorylation of STAT transcription factors, which inhibits The online version of this article contains supplemental material. macrophage activation. For example, SOCS1 and 3 inhibit STAT1 Abbreviations used in this article: BMMv, bone marrow–derived macrophage; CDRI, Central Drug Research Institute; ChIP, chromatin immunoprecipitation; CSIR, phosphorylation, SOCS3 and 4 inhibit STAT3 phosphorylation, Council of Scientific and Industrial Research; KO, knockout; LPG, lipophosphogly- SOCS3 and 5 modulate STAT4 and STAT6 activation, respectively can; PKA, protein kinase A; siRNA, small interfering RNA; SOCS, suppressor of (13). These, in turn, regulate synthesis of different cytokines, such cytokine signaling; VL, visceral leishmaniasis; WT, wild-type. as STAT1, which is essential for biological effects of IFN-g; Copyright Ó 2019 by The American Association of Immunologists, Inc. 0022-1767/19/$37.50 STAT4 is important for the cellular effect of IL-12; STAT3 plays www.jimmunol.org/cgi/doi/10.4049/jimmunol.1900412 2 SOCS1 AND SOCS3 BREACH MACROPHAGE–T CELL CROSS-TALK IN VL a conserved role in IL-10 signaling; and STAT6 is important determined on cultures run in parallel. Infection was allowed to proceed for 4 h; cells were washed at least four times to remove uningested par- for IL-4– and IL-13–mediated response (14). Moreover, the role + of SOCS isoforms in modulating cellular immune response in asites and left for 20 h. CD4 T cells were activated (cultured with plate- bound anti-CD3, 2 mg/ml) and were incubated with L. donovani–infected various infectious diseases is well documented. For instances, BMMv-derived supernatant for different time periods, and later, T cells Toxoplasma gondii induces SOCS1 expression, leading to inhi- were isolated and analyzed for different immunological assays. bition of cytokine signaling and suppression of immune responses Ethics statement (15). Mycobacterium bovis also increases SOCS1 and SOCS3 to inhibit IFN-g–induced STAT1 activation (16, 17). Similarly, mice All animal experiments for this study were officially approved by the lacking SOCS1 were protected from Plasmodium berghei, Animal Ethics Committee of the Council of Scientific and Industrial Research (CSIR)–Central Drug Research Institute (CDRI), Lucknow, which cause cerebral malaria, and expression of SOCS1 ham- India (Institutional Animal Ethics Committee approval number: IAEC/ pered Chlamydia pneumonia clearance (18, 19). In the context 2017/191). All animals were housed
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