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• W2026778930 abstract "Interleukin-17 (IL-17) secreted by T helper 17 (Th17) cells is essential in the development of experimental autoimmune encephalomyelitis (EAE). However, it remains unclear how IL-17-mediated signaling in different cellular compartments participates in the central nervous system (CNS) inflammatory process. We examined CNS inflammation in mice with specific deletion of Act1, a critical component required for IL-17 signaling, in endothelial cells, macrophages and microglia, and neuroectoderm (neurons, astrocytes, and oligodendrocytes). In Act1-deficient mice, Th17 cells showed normal infiltration into the CNS but failed to recruit lymphocytes, neutrophils, and macrophages. Act1 deficiency in endothelial cells or in macrophages and microglia did not substantially impact the development of EAE. However, targeted Act1 deficiency in neuroectoderm-derived CNS-resident cells resulted in markedly reduced severity in EAE. Specifically, Act1-deficient astrocytes showed impaired IL-17-mediated inflammatory gene induction. Thus, astroctyes are critical in IL-17-Act1-mediated leukocyte recruitment during autoimmune-induced inflammation of the CNS. Interleukin-17 (IL-17) secreted by T helper 17 (Th17) cells is essential in the development of experimental autoimmune encephalomyelitis (EAE). However, it remains unclear how IL-17-mediated signaling in different cellular compartments participates in the central nervous system (CNS) inflammatory process. We examined CNS inflammation in mice with specific deletion of Act1, a critical component required for IL-17 signaling, in endothelial cells, macrophages and microglia, and neuroectoderm (neurons, astrocytes, and oligodendrocytes). In Act1-deficient mice, Th17 cells showed normal infiltration into the CNS but failed to recruit lymphocytes, neutrophils, and macrophages. Act1 deficiency in endothelial cells or in macrophages and microglia did not substantially impact the development of EAE. However, targeted Act1 deficiency in neuroectoderm-derived CNS-resident cells resulted in markedly reduced severity in EAE. Specifically, Act1-deficient astrocytes showed impaired IL-17-mediated inflammatory gene induction. Thus, astroctyes are critical in IL-17-Act1-mediated leukocyte recruitment during autoimmune-induced inflammation of the CNS. Th17 cell-mediated leukocyte infiltration was attenuated in Act1-deficient CNS Act1 in endothelial cells, macrophage, and microglia was dispensable for EAE Act1 deficiency in neuroectoderm resulted in markedly reduced severity in EAE IL-17-dependent cytokines and chemokines in astrocytes are critical for EAE Multiple sclerosis (MS) is an autoimmune disease in which T lymphocytes reactive to myelin antigens initiate an inflammatory response in the central nervous system (CNS) leading to demyelination and subsequent axonal injury (Becher et al., 2006Becher B. Bechmann I. Greter M. Antigen presentation in autoimmunity and CNS inflammation: How T lymphocytes recognize the brain.J. Mol. Med. 2006; 84: 532-543Crossref PubMed Scopus (172) Google Scholar, Gold et al., 2006Gold R. Linington C. Lassmann H. Understanding pathogenesis and therapy of multiple sclerosis via animal models: 70 years of merits and culprits in experimental autoimmune encephalomyelitis research.Brain. 2006; 129: 1953-1971Crossref PubMed Scopus (748) Google Scholar, Sospedra and Martin, 2005Sospedra M. Martin R. Immunology of multiple sclerosis.Annu. Rev. Immunol. 2005; 23: 683-747Crossref PubMed Scopus (1686) Google Scholar). Experimental autoimmune encephalomyelitis (EAE) is an animal model commonly used to study the immunopathogenesis of multiple sclerosis (Stromnes and Goverman, 2006Stromnes I.M. Goverman J.M. Active induction of experimental allergic encephalomyelitis.Nat. Protoc. 2006; 1: 1810-1819Crossref PubMed Scopus (384) Google Scholar). EAE is induced by either immunization of animals with myelin antigens or the adoptive transfer of myelin antigen-specific T cells. EAE can be subdivided into an initiation stage involving activation and expansion of myelin-specific T cells in the periphery, which then cross the blood brain barrier (BBB), an effector stage involving reactivation of myelin-specific T cells in the CNS, resulting in cytokine-induced chemokine expression in CNS-resident cells, thereby mediating recruitment of hematogenously derived inflammatory cells, and a stage of remission and repair in which the immune response is downregulated (McFarland and Martin, 2007McFarland H.F. Martin R. Multiple sclerosis: A complicated picture of autoimmunity.Nat. Immunol. 2007; 8: 913-919Crossref PubMed Scopus (768) Google Scholar, Steinman, 2001Steinman L. Multiple sclerosis: A two-stage disease.Nat. Immunol. 2001; 2: 762-764Crossref PubMed Scopus (503) Google Scholar). Whereas T helper 1 (Th1) cells were shown to play a critical role in the initiation of inflammatory responses in CNS (Agrawal et al., 2006Agrawal A. Dillon S. Denning T.L. Pulendran B. ERK1-/- mice exhibit Th1 cell polarization and increased susceptibility to experimental autoimmune encephalomyelitis.J. Immunol. 2006; 176: 5788-5796PubMed Google Scholar, Bettelli et al., 2004Bettelli E. Sullivan B. Szabo S.J. Sobel R.A. Glimcher L.H. Kuchroo V.K. Loss of T-bet, but not STAT1, prevents the development of experimental autoimmune encephalomyelitis.J. Exp. Med. 2004; 200: 79-87Crossref PubMed Scopus (370) Google Scholar, Korn et al., 2009Korn T. Bettelli E. Oukka M. Kuchroo V.K. IL-17 and Th17 cells.Annu. Rev. Immunol. 2009; 27: 485-517Crossref PubMed Scopus (3466) Google Scholar, Yang et al., 2009Yang Y. Weiner J. Liu Y. Smith A.J. Huss D.J. Winger R. Peng H. Cravens P.D. Racke M.K. Lovett-Racke A.E. T-bet is essential for encephalitogenicity of both Th1 and Th17 cells.J. Exp. Med. 2009; 206: 1549-1564Crossref PubMed Scopus (206) Google Scholar), Th2 cells were considered as counterinflammatory (Butti et al., 2008Butti E. Bergami A. Recchia A. Brambilla E. Del Carro U. Amadio S. Cattalini A. Esposito M. Stornaiuolo A. Comi G. et al.IL4 gene delivery to the CNS recruits regulatory T cells and induces clinical recovery in mouse models of multiple sclerosis.Gene Ther. 2008; 15: 504-515Crossref PubMed Scopus (80) Google Scholar, Kleinschek et al., 2007Kleinschek M.A. Owyang A.M. Joyce-Shaikh B. Langrish C.L. Chen Y. Gorman D.M. Blumenschein W.M. McClanahan T. Brombacher F. Hurst S.D. et al.IL-25 regulates Th17 function in autoimmune inflammation.J. Exp. Med. 2007; 204: 161-170Crossref PubMed Scopus (314) Google Scholar, Ramírez and Mason, 2000Ramírez F. Mason D. Induction of resistance to active experimental allergic encephalomyelitis by myelin basic protein-specific Th2 cell lines generated in the presence of glucocorticoids and IL-4.Eur. J. Immunol. 2000; 30: 747-758Crossref PubMed Scopus (31) Google Scholar). This Th1-Th2 cell paradigm was challenged by the fact that lack of interferon-γ (IFN-γ) leads to increased EAE phenotype (Cua et al., 2003Cua D.J. Sherlock J. Chen Y. Murphy C.A. Joyce B. Seymour B. Lucian L. To W. Kwan S. Churakova T. et al.Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain.Nature. 2003; 421: 744-748Crossref PubMed Scopus (2246) Google Scholar, Ferber et al., 1996Ferber I.A. Brocke S. Taylor-Edwards C. Ridgway W. Dinisco C. Steinman L. Dalton D. Fathman C.G. Mice with a disrupted IFN-gamma gene are susceptible to the induction of experimental autoimmune encephalomyelitis (EAE).J. Immunol. 1996; 156: 5-7PubMed Google Scholar). Importantly, both Th1 and Th17 cells can independently induce EAE possibly through different mechanisms (Lees et al., 2008Lees J.R. Golumbek P.T. Sim J. Dorsey D. Russell J.H. Regional CNS responses to IFN-gamma determine lesion localization patterns during EAE pathogenesis.J. Exp. Med. 2008; 205: 2633-2642Crossref PubMed Scopus (137) Google Scholar, Kroenke et al., 2008Kroenke M.A. Carlson T.J. Andjelkovic A.V. Segal B.M. IL-12- and IL-23-modulated T cells induce distinct types of EAE based on histology, CNS chemokine profile, and response to cytokine inhibition.J. Exp. Med. 2008; 205: 1535-1541Crossref PubMed Scopus (458) Google Scholar, Stromnes et al., 2008Stromnes I.M. Cerretti L.M. Liggitt D. Harris R.A. Goverman J.M. Differential regulation of central nervous system autoimmunity by T(H)1 and T(H)17 cells.Nat. Med. 2008; 14: 337-342Crossref PubMed Scopus (461) Google Scholar, Park et al., 2005Park H. Li Z. Yang X.O. Chang S.H. Nurieva R. Wang Y.H. Wang Y. Hood L. Zhu Z. Tian Q. Dong C. A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17.Nat. Immunol. 2005; 6: 1133-1141Crossref PubMed Scopus (3248) Google Scholar), and even Th2 cells can lead to a mild atypical form of EAE (Das et al., 1997Das M.P. Nicholson L.B. Greer J.M. Kuchroo V.K. Autopathogenic T helper cell type 1 (Th1) and protective Th2 clones differ in their recognition of the autoantigenic peptide of myelin proteolipid protein.J. Exp. Med. 1997; 186: 867-876Crossref PubMed Scopus (55) Google Scholar, Jäger et al., 2009Jäger A. Dardalhon V. Sobel R.A. Bettelli E. Kuchroo V.K. Th1, Th17, and Th9 effector cells induce experimental autoimmune encephalomyelitis with different pathological phenotypes.J. Immunol. 2009; 183: 7169-7177Crossref PubMed Scopus (528) Google Scholar, Steinman, 2008Steinman L. A rush to judgment on Th17.J. Exp. Med. 2008; 205: 1517-1522Crossref PubMed Scopus (150) Google Scholar). Th17 cells are generated as a discrete lineage after priming in the presence of the cytokines TGF-β and IL-6 and acquisition of encephalitogenicity after proliferation in the presence of IL-23 (Cua et al., 2003Cua D.J. Sherlock J. Chen Y. Murphy C.A. Joyce B. Seymour B. Lucian L. To W. Kwan S. Churakova T. et al.Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain.Nature. 2003; 421: 744-748Crossref PubMed Scopus (2246) Google Scholar, Mangan et al., 2006Mangan P.R. Harrington L.E. O'Quinn D.B. Helms W.S. Bullard D.C. Elson C.O. Hatton R.D. Wahl S.M. Schoeb T.R. Weaver C.T. Transforming growth factor-beta induces development of the T(H)17 lineage.Nature. 2006; 441: 231-234Crossref PubMed Scopus (2467) Google Scholar, Veldhoen et al., 2006Veldhoen M. Hocking R.J. Atkins C.J. Locksley R.M. Stockinger B. TGFbeta in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells.Immunity. 2006; 24: 179-189Abstract Full Text Full Text PDF PubMed Scopus (2856) Google Scholar). Th17 cells are now recognized at least as one of the major mediators of tissue damage in EAE (Haak et al., 2009Haak S. Croxford A.L. Kreymborg K. Heppner F.L. Pouly S. Becher B. Waisman A. IL-17A and IL-17F do not contribute vitally to autoimmune neuro-inflammation in mice.J. Clin. Invest. 2009; 119: 61-69PubMed Google Scholar, Yang et al., 2009Yang Y. Weiner J. Liu Y. Smith A.J. Huss D.J. Winger R. Peng H. Cravens P.D. Racke M.K. Lovett-Racke A.E. T-bet is essential for encephalitogenicity of both Th1 and Th17 cells.J. Exp. Med. 2009; 206: 1549-1564Crossref PubMed Scopus (206) Google Scholar, Steinman, 2009Steinman L. Shifting therapeutic attention in MS to osteopontin, type 1 and type 2 IFN.Eur. J. Immunol. 2009; 39: 2358-2360Crossref PubMed Scopus (21) Google Scholar). EAE is markedly suppressed in mice lacking IL-17 or IL-17 receptor, and IL-17-specific inhibition attenuates inflammation indicating that IL-17-mediated signaling plays a critical role in the effector stage of EAE (Gonzalez-García et al., 2009Gonzalez-García I. Zhao Y. Ju S. Gu Q. Liu L. Kolls J.K. Lu B. IL-17 signaling-independent central nervous system autoimmunity is negatively regulated by TGF-beta.J. Immunol. 2009; 182: 2665-2671Crossref PubMed Scopus (34) Google Scholar, Komiyama et al., 2006Komiyama Y. Nakae S. Matsuki T. Nambu A. Ishigame H. Kakuta S. Sudo K. Iwakura Y. IL-17 plays an important role in the development of experimental autoimmune encephalomyelitis.J. Immunol. 2006; 177: 566-573PubMed Google Scholar, Park et al., 2005Park H. Li Z. Yang X.O. Chang S.H. Nurieva R. Wang Y.H. Wang Y. Hood L. Zhu Z. Tian Q. Dong C. A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17.Nat. Immunol. 2005; 6: 1133-1141Crossref PubMed Scopus (3248) Google Scholar, Harrington et al., 2005Harrington L.E. Hatton R.D. Mangan P.R. Turner H. Murphy T.L. Murphy K.M. Weaver C.T. Interleukin 17-producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages.Nat. Immunol. 2005; 6: 1123-1132Crossref PubMed Scopus (3566) Google Scholar, Veldhoen et al., 2006Veldhoen M. Hocking R.J. Atkins C.J. Locksley R.M. Stockinger B. TGFbeta in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells.Immunity. 2006; 24: 179-189Abstract Full Text Full Text PDF PubMed Scopus (2856) Google Scholar). However, the precise mechanism by which IL-17 participates in EAE development and pathogenesis remains unclear. A major function of IL-17 involves coordination of local tissue inflammation through upregulation of proinflammatory and neutrophil-mobilizing cytokines and chemokines including IL-6, G-CSF, TNF-α, IL-1, CXCL1(KC), CCL2(MCP-1), CXCL2(MIP-2), CCL7(MCP-3), and CCL20(MIP-3A) as well as matrix metalloproteases (MMPs) to allow activated T cells to penetrate the extracellular matrix (Awane et al., 1999Awane M. Andres P.G. Li D.J. Reinecker H.C. NF-kappa B-inducing kinase is a common mediator of IL-17-, TNF-alpha-, and IL-1 beta-induced chemokine promoter activation in intestinal epithelial cells.J. Immunol. 1999; 162: 5337-5344PubMed Google Scholar, Weaver et al., 2005Weaver A. Goncalves da Silva A. Nuttall R.K. Edwards D.R. Shapiro S.D. Rivest S. Yong V.W. An elevated matrix metalloproteinase (MMP) in an animal model of multiple sclerosis is protective by affecting Th1/Th2 polarization.FASEB J. 2005; 19: 1668-1670Crossref PubMed Scopus (120) Google Scholar, Jovanovic et al., 1998Jovanovic D.V. Di Battista J.A. Martel-Pelletier J. Jolicoeur F.C. He Y. Zhang M. Mineau F. Pelletier J.P. IL-17 stimulates the production and expression of proinflammatory cytokines, IL-beta and TNF-alpha, by human macrophages.J. Immunol. 1998; 160: 3513-3521PubMed Google Scholar). Several new studies have shown that IL-17 signals through a heteromeric receptor complex, consisting of IL-17R (IL-17RA) and IL-17RC, which are single-pass transmembrane proteins expressed by a variety of cells including astrocytes and microglia (Inoue et al., 2006Inoue D. Numasaki M. Watanabe M. Kubo H. Sasaki T. Yasuda H. Yamaya M. Sasaki H. IL-17A promotes the growth of airway epithelial cells through ERK-dependent signaling pathway.Biochem. Biophys. Res. Commun. 2006; 347: 852-858Crossref PubMed Scopus (47) Google Scholar, Kolls and Lindén, 2004Kolls J.K. Lindén A. Interleukin-17 family members and inflammation.Immunity. 2004; 21: 467-476Abstract Full Text Full Text PDF PubMed Scopus (1891) Google Scholar, Toy et al., 2006Toy D. Kugler D. Wolfson M. Vanden Bos T. Gurgel J. Derry J. Tocker J. Peschon J. Cutting edge: Interleukin 17 signals through a heteromeric receptor complex.J. Immunol. 2006; 177: 36-39PubMed Google Scholar, Trajkovic et al., 2001Trajkovic V. Stosic-Grujicic S. Samardzic T. Markovic M. Miljkovic D. Ramic Z. Mostarica Stojkovic M. Interleukin-17 stimulates inducible nitric oxide synthase activation in rodent astrocytes.J. Neuroimmunol. 2001; 119: 183-191Abstract Full Text Full Text PDF PubMed Scopus (84) Google Scholar). The important questions are whether and how these CNS-resident cells respond to IL-17 to mediate inflammatory response in the central nervous system leading to demyelination and subsequent axonal injury. Both IL-17RA and IL-17RC belong to a newly defined SEFIR protein family with a conserved sequence segment called SEFIR in their cytoplasmic domain (Novatchkova et al., 2003Novatchkova M. Leibbrandt A. Werzowa J. Neubüser A. Eisenhaber F. The STIR-domain superfamily in signal transduction, development and immunity.Trends Biochem. Sci. 2003; 28: 226-229Abstract Full Text Full Text PDF PubMed Scopus (182) Google Scholar). We recently described the signaling molecule Act1 as a key component in IL-17 signaling (Qian et al., 2007Qian Y. Liu C. Hartupee J. Altuntas C.Z. Gulen M.F. Jane-Wit D. Xiao J. Lu Y. Giltiay N. Liu J. et al.The adaptor Act1 is required for interleukin 17-dependent signaling associated with autoimmune and inflammatory disease.Nat. Immunol. 2007; 8: 247-256Crossref PubMed Scopus (400) Google Scholar). Act1 contains two TRAF binding sites: a helix-loop-helix domain at the N terminus and a coiled-coil domain at the C terminus (Li et al., 2000Li X. Commane M. Nie H. Hua X. Chatterjee-Kishore M. Wald D. Haag M. Stark G.R. Act1, an NF-kappa B-activating protein.Proc. Natl. Acad. Sci. USA. 2000; 97: 10489-10493Crossref PubMed Scopus (136) Google Scholar, Qian et al., 2002Qian Y. Zhao Z. Jiang Z. Li X. Role of NF kappa B activator Act1 in CD40-mediated signaling in epithelial cells.Proc. Natl. Acad. Sci. USA. 2002; 99: 9386-9391Crossref PubMed Scopus (51) Google Scholar, Leonardi et al., 2000Leonardi A. Chariot A. Claudio E. Cunningham K. Siebenlist U. CIKS, a connection to Ikappa B kinase and stress-activated protein kinase.Proc. Natl. Acad. Sci. USA. 2000; 97: 10494-10499Crossref PubMed Scopus (129) Google Scholar). Act1 contains a SEFIR domain in its coiled-coil region at the C terminus and therefore Act1 is a member of the SEFIR protein family (Novatchkova et al., 2003Novatchkova M. Leibbrandt A. Werzowa J. Neubüser A. Eisenhaber F. The STIR-domain superfamily in signal transduction, development and immunity.Trends Biochem. Sci. 2003; 28: 226-229Abstract Full Text Full Text PDF PubMed Scopus (182) Google Scholar). Upon IL-17 stimulation, Act1 is recruited to IL-17R through the IL-17R conserved cytoplasmic SEFIR domain, which is followed by recruitment of the kinase TAK1 and E3 ubiquitin ligase TRAF6 that mediate “downstream” NF-κB activation. Act1 deficiency results in reduced EAE severity in the presence of normal activation and expansion of encephalitogenic Th17 T cells, indicating that IL-17-induced Act1-mediated signaling plays a critical role in the effector stage of EAE development. However, it remains unclear how IL-17-mediated signaling in different cellular compartments participates in CNS inflammation during EAE. In the current study, we aimed to define the specific cell types that are critical for IL-17-dependent autoimmune inflammation of the CNS. By cell type-specific deletion of Act1, we showed that Act1 deficiency in the CNS-resident cells originated from neuroectodermal cells (neurons, astrocytes, and oligodendrocytes) delayed the onset and reduced the severity of EAE induced by either active immunization with the encephalitogenic MOG 35-55 peptide or by adoptive transfer of MOG-specific Th17 T cells. Our previous studies have shown that the onset and severity of EAE are greatly reduced in mice lacking Act1, the key adaptor molecule of IL-17R (Figure S1 available online). Act1-deficient (Act1−/−) mice had fewer CNS inflammatory cells, including neutrophils, macrophages, CD4+, and CD8+ T cells compared to wild-type control mice (Figures 1A and 1B ). Furthermore, histological examination revealed abundant CD4+ T cells and CD11b+ leukocytes in the meninges and in the spinal cord parenchyma, accompanied by severe demyelination in the white matter in wild-type mice (Figure 1C). In contrast, inflammatory cells were reduced in spinal cords from Act1−/− mice coincident with minimum signs of demyelination (Figure 1C). The absence of Act1 therefore leads to impaired CNS inflammation, resulting in reduced demyelination and subsequent axonal injury. Supernatants from primed lymph node cells of Act1−/− mice showed increased production of Th1 (IFN-γ) and Th17 (IL-17) cell-associated cytokines relative to primed wild-type mice (Figure 2A ). Consistent with this finding, intracellular staining showed increased numbers of IFN-γ- and IL-17-producing CD4+ T cells in the primed lymph node cells of Act1−/− mice than that in wild-type mice. IL-17-producing γδ T cells were also increased in the primed lymph node cells of Act1−/− mice compared to that in wild-type mice (Figure S2A). The impact of Act1 deficiency on IFN-γ- and IL-17-producing CD4+ and γδ T cells in periphery might be related to the hyper T cell-dependent immune responses previously observed in the Act1−/− mice (Qian et al., 2007Qian Y. Liu C. Hartupee J. Altuntas C.Z. Gulen M.F. Jane-Wit D. Xiao J. Lu Y. Giltiay N. Liu J. et al.The adaptor Act1 is required for interleukin 17-dependent signaling associated with autoimmune and inflammatory disease.Nat. Immunol. 2007; 8: 247-256Crossref PubMed Scopus (400) Google Scholar), although the detailed mechanism remains unclear. Importantly, activated MOG 35-55-specific Th1 (Qian et al., 2007Qian Y. Liu C. Hartupee J. Altuntas C.Z. Gulen M.F. Jane-Wit D. Xiao J. Lu Y. Giltiay N. Liu J. et al.The adaptor Act1 is required for interleukin 17-dependent signaling associated with autoimmune and inflammatory disease.Nat. Immunol. 2007; 8: 247-256Crossref PubMed Scopus (400) Google Scholar) and Th17 cells derived from primed Act1−/− mice were both fully encephalitogenic because they were able to passively transfer EAE in wild-type recipients (Figures 2B–2D; Figures S2B and S2C). Thus, Act1−/− mice had no defect in the activation of MOG 35-55-specific Th17 or Th1 cells. Both wild-type and Act1−/− MOG 35-55-specific Th17 cells induced EAE in wild-type recipients. However, the onset and severity of EAE were greatly reduced in Act1−/− recipients, independent of the genotype of the transfer population (Figures 2B and 2C). These results demonstrate that Act1 is required for the effector stage of EAE induced by Th17 cells. However, recent studies and the results described above indicate that Th1 cells can also induce EAE. To show that Act1 only acts through Th17 cells and not Th1 cells, the activated MOG-specific Th1 cells polarized from wild-type mice were tested for EAE induction. Act1−/−-recipient mice of Th1 cells exhibited similar onset and severity of EAE as wild-type recipients, indicating that Act1 deficiency has no obvious impact on the effector stage of Th1 cell-induced EAE (Figures 2D–2F). Our results clearly indicate that Act1 deficiency does not impair peripheral activation of MOG 35-55-specific T cells, but rather affects functions within the CNS. Furthermore, Th17 cell responses in the CNS are associated with recruitment of bone marrow-derived myeloid cells (Park et al., 2005Park H. Li Z. Yang X.O. Chang S.H. Nurieva R. Wang Y.H. Wang Y. Hood L. Zhu Z. Tian Q. Dong C. A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17.Nat. Immunol. 2005; 6: 1133-1141Crossref PubMed Scopus (3248) Google Scholar, Komiyama et al., 2006Komiyama Y. Nakae S. Matsuki T. Nambu A. Ishigame H. Kakuta S. Sudo K. Iwakura Y. IL-17 plays an important role in the development of experimental autoimmune encephalomyelitis.J. Immunol. 2006; 177: 566-573PubMed Google Scholar, Harrington et al., 2005Harrington L.E. Hatton R.D. Mangan P.R. Turner H. Murphy T.L. Murphy K.M. Weaver C.T. Interleukin 17-producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages.Nat. Immunol. 2005; 6: 1123-1132Crossref PubMed Scopus (3566) Google Scholar, Mangan et al., 2006Mangan P.R. Harrington L.E. O'Quinn D.B. Helms W.S. Bullard D.C. Elson C.O. Hatton R.D. Wahl S.M. Schoeb T.R. Weaver C.T. Transforming growth factor-beta induces development of the T(H)17 lineage.Nature. 2006; 441: 231-234Crossref PubMed Scopus (2467) Google Scholar, Kolls and Lindén, 2004Kolls J.K. Lindén A. Interleukin-17 family members and inflammation.Immunity. 2004; 21: 467-476Abstract Full Text Full Text PDF PubMed Scopus (1891) Google Scholar, Veldhoen et al., 2006Veldhoen M. Hocking R.J. Atkins C.J. Locksley R.M. Stockinger B. TGFbeta in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells.Immunity. 2006; 24: 179-189Abstract Full Text Full Text PDF PubMed Scopus (2856) Google Scholar). We therefore investigated a role of Act1 in CNS recruitment of MOG-specific T cells as well as subsequent recruitment of other mononuclear cells. MOG-specific T cells were isolated from the lymph nodes of Thy1.1 C57BL/6 mice 10 days after MOG 35-55 immunization, polarized to Th17 cells, and transferred into Thy1.2+ wild-type or Act1−/− mice. Similar numbers of Thy1.1+CD4+ donor T cells were detected in the brains of wild-type and Act1−/− brains at days 3 and 5, early after adoptive transfer. However, during the later phase at days 12 and 15, at the peak of the disease, significantly more Thy1.1+CD4+ T cells and monocytes accumulated in the brains of wild-type compared to Act1−/− mice (Figures 3A–3C ). Overall, the vast majority of CNS-derived CD4+ T cells were of donor Thy1.1 phenotype throughout disease induction (data not shown). We also examined the Thy1.1+CD4+ T cells in the spleen of wild-type and Act1−/− recipient mice after adoptive transfer. We detected more Thy1.1+CD4+ T cells in the spleen of the Act1−/− mice at day 5 and day 12 compared to that in wild-type control mice. By day 15, Thy1.1+CD4+ T cells disappeared from spleen. The temporal retention of Thy1.1+CD4+ T cells in the Act1−/− spleen might reflect the reduced recruitment of these cells to the Act1−/− CNS (Figure 3D). These results indicate that Th17 cells can infiltrate the CNS of Act1−/− mice but fail to initiate an effective inflammatory response, presumably because of the inability to propagate IL-17-mediated signaling. IL-17-induced signature cytokines and chemokines were indeed markedly reduced in the spinal cord of the Act1−/− recipient mice at the peak of disease after adoptive transfer of MOG-specific Thy1.1+ Th17 cells (Figure 3E). Of note, both CXCL1 and MMP9 associated with neutrophil recruitment, as well as IL-6 and CXCL12 involved in parenchymal leukocyte access, were reduced in Act1−/− recipients. As a result, the inflammatory amplification loop is blocked, leading to reduced recruitment of inflammatory cells. It is important to note that in addition to Thy1.1+CD4+ IL-17-producing cells in the brain of the recipient mice at the peak of the disease, IL-17-producing Thy1.1+γδ T cells were also detected in the brain of these mice (Figures 3F and 3G). Consistent with the clinical signs of the mice (Figure 3A), the absolute numbers of IFN-γ- and IL-17-producing Thy1.1+CD4+ T cells and Thy1.1+γδ T cells were significantly reduced at the peak of the disease in the brain of Act1−/−-recipient mice compared to that in the wild-type control mice. IL-17-producing CD4+ (Th17) cells activated in the presence of IL-23 in the primary culture (Figure S2C) were relatively stable in vivo (Figures 3F and 3G), whereas the IL-17-producing Thy1.1+γδ T cells showed more plasticity in vivo, becoming IFN-γ and IL-17 double-positive cells or IFN-γ-producing cells (Figures 3F and 3G). In contrast, the majority of both CD4+ T cells and γδ T cells activated in the presence of IL-12 in the primary culture (Figure S2B) remain as IFN-γ-producing cells in the brain of the recipient mice, indicating their stability in vivo (Figure S2D). This result is consistent with the fact that Act1 deficiency did not show any impact on Th1 cell-mediated EAE, because these “Th1” cells remain as IFN-γ-producing cells in the brain after adoptive transfer (Figure S2D). We further investigated whether the reduced IL-17-induced cytokine and chemokine production in the CNS has any impact on CD4+ T cell survival and/or proliferation. To test this possibility, MOG 35-55-specific Thy1.1+ Th17 cells were adoptively transferred into Thy1.2 Act1−/− and wild-type recipient mice. Thy1.1+ cells costained with Ki-67, indicating that the infiltrated Thy1.1+ cells were in a proliferating state irrespective of their wild-type or Act1−/− environment in recipients (Figure 4A ). Furthermore, the frequency of infiltrated CD4+Brdu+ cells in the spinal cord of wild-type mice was similar to that in Act1−/− mice (Figure 4B). Thus, the reduced accumulation of Thy1.1+ cells in the CNS of Act1−/− mice at the peak of disease cannot be attributed to their reduced proliferation or survival, but rather reflects impaired chemokine- and/or cytokine-mediated recruitment of activated myeloid cells, which in turn propagate ongoing inflammation. Laminin is present in both endothelial basement membrane and parenchymal basement membrane (Bauer et al., 2009Bauer M. Brakebusch C. Coisne C. Sixt M. Wekerle H. Engelhardt B. Fässler R. Beta1 integrins differentially control extravasation of inflammatory cell subsets into the CNS during autoimmunity.Proc. Natl. Acad. Sci. USA. 2009; 106: 1920-1925Crossref PubMed Scopus (94) Google Scholar, Sixt et al., 2001Sixt M. Engelhardt B. Pausch F. Hallmann R. Wendler O. Sorokin L.M. Endothelial cell laminin isoforms, laminins 8 and 10, play decisive roles in T cell recruitment across the blood-brain barrier in experimental autoimmune encephalomyelitis.J. Cell Biol. 2001; 153: 933-946Crossref PubMed Scopus (350) Google Scholar) providing a tool to visualize inflammatory cells in the perivascular space. No differences were noted in the distribution of MOG 35-55-specific Thy1.1+ Th17 cells in wild-type compared to Act1-deficient recipient mice (Figure 5A ). Although some Thy1.1 cells were in close proximity to laminin, a large proportion had spread into the parenchyma. These results negated a role for Act1 in influencing access of myelin-specific T cells through the BBB into the CNS parenchyma. Nevertheless, previous studies have shown that the IL-17 receptor is expressed on BBB endothelial cells (Kebir et al., 2007Kebir H. Kr" @default.
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• W2026778930 date "2010-03-01" @default.
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• W2026778930 title "Astrocyte-Restricted Ablation of Interleukin-17-Induced Act1-Mediated Signaling Ameliorates Autoimmune Encephalomyelitis" @default.
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