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IL-11 Induces Encephalitogenic Th17 Cells in Multiple Sclerosis and Experimental Autoimmune Encephalomyelitis

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IL-11 Induces Encephalitogenic Th17 Cells in Multiple Sclerosis and Experimental Autoimmune Encephalomyelitis IL-11 Induces Encephalitogenic Th17 Cells in Multiple Sclerosis and Experimental Autoimmune Encephalomyelitis This information is current as Xin Zhang, Nazanin Kiapour, Sahil Kapoor, Tabish Khan, of September 27, 2021. Madhan Thamilarasan, Yazhong Tao, Stephanie Cohen, Ryan Miller, Raymond A. Sobel and Silva Markovic-Plese J Immunol published online 24 July 2019 http://www.jimmunol.org/content/early/2019/07/23/jimmun ol.1900311 Downloaded from Supplementary http://www.jimmunol.org/content/suppl/2019/07/23/jimmunol.190031 Material 1.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 27, 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 Author Choice Freely available online through The Journal of Immunology Author Choice option 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 July 24, 2019, doi:10.4049/jimmunol.1900311 The Journal of Immunology IL-11 Induces Encephalitogenic Th17 Cells in Multiple Sclerosis and Experimental Autoimmune Encephalomyelitis Xin Zhang,* Nazanin Kiapour,* Sahil Kapoor,* Tabish Khan,* Madhan Thamilarasan,* Yazhong Tao,* Stephanie Cohen,† Ryan Miller,‡ Raymond A. Sobel,x and Silva Markovic-Plese*,{,‖ IL-11+CD4+ cells accumulate in the cerebrospinal fluid of patients with early relapsing-remitting multiple sclerosis (MS) and in active brain MS lesions. Mouse studies have confirmed a causal role of IL-11 in the exacerbation of relapsing-remitting exper- imental autoimmune encephalomyelitis (RREAE). Administration of IL-11 at the time of clinical onset of RREAE induced an acute exacerbation and increased clinical scores, which persisted during the entire course of the disease. IL-11 increased the numbers of spinal cord inflammatory foci, as well as the numbers of peripheral and CNS-infiltrating IL-17+CD4+ cells and IL-17A serum levels. Ag recall assays revealed that IL-11 induces IL-17A+, GM-CSF+, and IL-21+CD4+ myelin Ag-reactive cells. Passive Downloaded from transfer of these encephalitogenic CD4+ T cells induced severe RREAE with IL-17A+CCR6+ CD4+ and B cell accumulation within the CNS. Furthermore, passive transfer of nonmanipulated CNS-derived mononuclear cells from mice with RREAE after a single dose of IL-11 induced severe RREAE with increased accumulation of IL-17A+ and CCR6+ CD4+ cells within the CNS. These results suggest that IL-11 might serve as a biomarker of early autoimmune response and a selective therapeutic target for patients with early relapsing-remitting MS. The Journal of Immunology, 2019, 203: 000–000. http://www.jimmunol.org/ mmunomodulatory therapies are most effective when ad- cerebrospinal fluid (CSF) and serum in comparison with healthy ministered early in the course of relapsing-remitting multiple control (HC) subjects. Moreover, IL-11 serum levels were sig- I sclerosis (RRMS). Therefore, we have been searching for nificantly higher in relapses than in the remissions of untreated biomarkers of the early autoimmune response to accurately RRMS patients, suggesting the involvement of this cytokine in the identify patients with clinically isolated syndrome (CIS) suggestive pathogenesis of RRMS. In vitro studies have revealed that IL-11 of multiple sclerosis (MS), who are amenable to early disease- induces Th17 cell differentiation and expansion in CIS patients modifying therapies (1). Our previous study in CIS patients has (2). Our human studies have identified that CD4+ cells represent a identified IL-11 as the most significantly increased cytokine in the predominant source of IL-11 within the peripheral circulation. In by guest on September 27, 2021 comparison with healthy donors, IL-11+CD4+ cells from CIS patients were significantly increased in the peripheral circulation *Department of Neurology, University of North Carolina at Chapel Hill, Chapel Hill, + NC 27599; †Lineberger Cancer Institute, University of North Carolina at Chapel Hill, and exhibited the highest CCR6 expression (86%) among CD4 Chapel Hill, NC 27599; ‡Department of Pathology, University of North Carolina at T cell subsets, which implied their potential for early migration to Chapel Hill, Chapel Hill, NC 27599; xDepartment of Pathology, Stanford University, { the CNS (3). Palo Alto, CA 94394; Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599; and ‖Department of Neurol- IL-11 is a member of the IL-6 cytokine family, whose proto- ogy, Thomas Jefferson University, Philadelphia, PA 19107 typical cytokine promotes Th17 differentiation in both mice and ORCIDs: 0000-0002-7473-415X (N.K.); 0000-0003-3553-382X (S.K.); 0000-0002- humans (4). However, IL-6 alone does not induce Th17 differ- 0096-8762 (R.M.); 0000-0002-0477-9002 (R.A.S.). entiation, in contrast to IL-11, which induces Th17 cell differen- Received for publication March 14, 2019. Accepted for publication July 1, 2019. tiation and expansion that were selectively blocked by aIL-11 This work was supported by National Multiple Sclerosis Society Research Grant G mAb and not by aIL-6 mAb (2). These previously reported human 4820-A-1; National Institutes of Health Grants R03 AI111592, R01 AI 131238, and R01 AI 131238; and University of North Carolina Translational and Clinical Sciences in vitro studies prompted current in vivo studies of the causative Pilot Award 550KR61329. role of IL-11 in the development of the Th17 autoimmune responses X.Z. designed and performed experiments and wrote the manuscript; N.K., S.K., T.K., in relapsing-remitting experimental autoimmune encephalomyelitis M.T., and Y.T. performed experiments; S.C. quantified human immunohistochemistry (RREAE), an animal model of RRMS. studies; R.M. analyzed MS lesion pathology; R.A.S. analyzed mice pathology; and S.M.-P. designed the study and wrote the manuscript. In the presence of the ligand-binding subunits IL-6Ra and IL-11Ra, IL-6 and IL-11 bind to the signal transduction unit Address correspondence and reprint requests to Dr. Silva Markovic-Plese, Depart- ment of Neurology, Thomas Jefferson University, 900 Walnut Street, Philadelphia, gp130 at overlapping epitopes, leading to the formation of ternary PA 19107. E-mail address: [email protected] complexes with similar downstream signaling (5). STAT3, a tran- The online version of this article contains supplemental material. scription factor involved in Th17 differentiation (6), is activated in Abbreviations used in this article: BBB, blood–brain barrier; CIS, clinically isolated response to IL-6/IL-6R and IL-11/IL-11R signaling (5). Our labo- syndrome; CSF, cerebrospinal fluid; EAE, experimental autoimmune encephalomy- ratory and others have reported that IL-11Ra is expressed by mul- elitis; EC, endothelial cell; HC, healthy control; LN, lymph node; MRI, magnetic resonance imaging; MS, multiple sclerosis; PLP, proteolipid protein; RR, relapsing- tiple PBMC subsets, with predominant expression in T cells (2, 7). remitting; RREAE, relapsing-remitting experimental autoimmune encephalomyelitis; Zhang et al. (8) reported that IL-11 expression in chronic brain RRMS, relapsing-remitting multiple sclerosis. MS lesions is primarily localized to activated astrocytes at the This article is distributed under The American Association of Immunologists, Inc., lesion border, whereas IL-11Ra is expressed on oligodendrocytes. Reuse Terms and Conditions for Author Choice articles. However, the inflammatory cells within lesions were not studied. Copyright Ó 2019 by The American Association of Immunologists, Inc. 0022-1767/19/$37.50 In vitro studies conducted by the same group have demonstrated www.jimmunol.org/cgi/doi/10.4049/jimmunol.1900311 2 IL-11 INDUCES ENCEPHALITOGENIC Th17 CELLS that IL-11Ra signaling increases oligodendrocyte survival and peripheral lymphoid tissues. Spinal cord and brain tissue were cut into proliferation via STAT3 phosphorylation (9). Although we ac- small pieces and digested in PBS containing Collagenase D (5 mg/ml) knowledge the reported findings on the role of IL-11 in chronic (Roche) for 45 min at 37˚C, with a short vortex every 15 min. After digestion, the cells were passed through a cell strainer and washed MS that suggest increased in vitro oligodendrocyte differentiation with PBS, followed by 38% Percoll gradient for separation of the CNS and survival, we propose that the proinflammatory effect of IL-11 mononuclear cells. may prevail in the context of active MS lesions and the expression of IL-11R on T cells, monocytes (1), and B cells (10), which Flow cytometry (FACS) exhibit an inflammatory response to IL-11. Cells were separated from the blood and CSF samples of RRMS patients or In the current study, we found that IL-11+CD4+ cells are sig- from the blood and tissues of mice with RREAE that received a single nificantly enriched in the CSF of RRMS patients in comparison injection of IL-11 or control vehicle as well as from the recipients of the LN CD4+ cells or CNS-derived mononuclear cells. The cells were stimulated with their matched blood samples. Immunohistochemistry studies with PMA (50 ng/ml) and ionomycin (500 ng/ml) (Sigma-Aldrich) for 2 h of active brain MS lesion biopsy samples revealed an enrichment and with BFA (1:1000 dilution) (eBioscience) for an additional 3 h for the of IL-11+CD4+ cells in comparison with the peripheral circulation, intracellular staining, as previously reported (2, 12). The cells were har- suggesting a role for this cytokine in the development of inflam- vested, fixed, permeabilized, and stained with fluorescently conjugated matory CNS lesions.
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