title: Blockade of CD47 ameliorates autoimmune inflammation in CNS by suppressing IL-1-triggered infiltration of pathogenic Th17 cells.
abstract: The migration of Th17 cells into central nervous system (CNS) tissue is the key pathogenic step in experimental autoimmune encephalomyelitis (EAE) model. However, the mechanism underlying the pathogenic Th17 cell migration remains elusive. Here we report that blockade of CD47 with CD47-Fc fusion protein is effective in preventing and curing EAE by impairing infiltration of Th17 cells into CNS. However, CD47 deficiency does not directly impair the migration of Th17 cells. Mechanistic studies showed that CD47 deficiency inhibited degradation of inducible nitric oxide synthase (iNOS) in proteasome of macrophages by Src activation and led to the increased nitric oxide (NO) production. Then NO suppressed inflammasome activation-induced IL-1β production. This lower IL-1β reduces the expression of IL-1R1 and migration-related chemokine receptors on CD47(-/-) Th17 cells, inhibiting the ability of Th17 cells to infiltrate into the CNS of CD47(-/-) mice and therefore suppressing EAE development. In vivo administration of exogenous IL-1β indeed promoted the infiltration CD47(-/-) Th17 cells into CNS and antagonized the protective role of CD47 deficiency in EAE pathogenesis. Our results demonstrate a potential preventive and therapeutic application of CD47 blockade in controlling EAE development.
authors.affiliation: National Key Laboratory of Medical Immunology & Institute of Immunology, Second Military Medical University, Shanghai, 200433, China; Department of Cell Biology, Third Military Medical University, Chongqing, 400038, China. Electronic address: qiangguogao@163.com.
authors.forename: Qiangguo
authors.initials: Q
authors.lastname: Gao
authors.affiliation: National Key Laboratory of Medical Immunology & Institute of Immunology, Second Military Medical University, Shanghai, 200433, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: National Key Laboratory of Medical Immunology & Institute of Immunology, Second Military Medical University, Shanghai, 200433, China.
authors.forename: Chaofeng
authors.initials: C
authors.lastname: Han
authors.affiliation: National Key Laboratory of Medical Molecular Biology & Department of Immunology, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, 100005, China.
authors.forename: Xiang
authors.initials: X
authors.lastname: Hu
authors.affiliation: National Key Laboratory of Medical Immunology & Institute of Immunology, Second Military Medical University, Shanghai, 200433, China.
authors.forename: Hua
authors.initials: H
authors.lastname: Zhang
authors.affiliation: National Key Laboratory of Medical Immunology & Institute of Immunology, Second Military Medical University, Shanghai, 200433, China.
authors.forename: Xiongfei
authors.initials: X
authors.lastname: Xu
authors.affiliation: Institute of Immunology, Zhejiang University School of Medicine, Hangzhou, 310058, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Tian
authors.affiliation: Institute of Immunology, Zhejiang University School of Medicine, Hangzhou, 310058, China.
authors.forename: Yiqi
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Institute of Immunology, Zhejiang University School of Medicine, Hangzhou, 310058, China.
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Ding
authors.affiliation: National Key Laboratory of Medical Immunology & Institute of Immunology, Second Military Medical University, Shanghai, 200433, China.
authors.forename: Juan
authors.initials: J
authors.lastname: Liu
authors.affiliation: National Key Laboratory of Medical Molecular Biology & Department of Immunology, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, 100005, China.
authors.forename: Chunmei
authors.initials: C
authors.lastname: Wang
authors.affiliation: National Key Laboratory of Medical Immunology & Institute of Immunology, Second Military Medical University, Shanghai, 200433, China.
authors.forename: Zhenhong
authors.initials: Z
authors.lastname: Guo
authors.affiliation: First Hospital of Jilin University, Changchun, 130012, China.
authors.forename: Yongguang
authors.initials: Y
authors.lastname: Yang
authors.affiliation: National Key Laboratory of Medical Immunology & Institute of Immunology, Second Military Medical University, Shanghai, 200433, China; National Key Laboratory of Medical Molecular Biology & Department of Immunology, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, 100005, China; Institute of Immunology, Zhejiang University School of Medicine, Hangzhou, 310058, China. Electronic address: caoxt@immunol.org.
authors.forename: Xuetao
authors.initials: X
authors.lastname: Cao
mesh_terms: D000818:Animals; D019138:Antibodies, Blocking / Q000494:pharmacology; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D015551:Autoimmunity; D001854:Bone Marrow Cells; D051928:CD47 Antigen / Q000235:genetics / Q000378:metabolism*; D002465:Cell Movement / Q000235:genetics / Q000276:immunology; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D007141:Immunoglobulin Fc Fragments / Q000235:genetics; D007375:Interleukin-1 / Q000378:metabolism*; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009103:Multiple Sclerosis / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011993:Recombinant Fusion Proteins; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D058504:Th17 Cells / Q000276:immunology* / Q000378:metabolism*; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: D019138:Antibodies, Blocking; D000911:Antibodies, Monoclonal; D051928:CD47 Antigen; D007141:Immunoglobulin Fc Fragments; D007375:Interleukin-1; D011993:Recombinant Fusion Proteins; D052247:Nitric Oxide Synthase Type II; D019061:src-Family Kinases; D046988:Proteasome Endopeptidase Complex
keywords: CD47; Cell infiltration; EAE; IL-1β; Th17 cells; iNOS