title: T cell-intrinsic ASC critically promotes T(H)17-mediated experimental autoimmune encephalomyelitis.
abstract: Interleukin 1β (IL-1β) is critical for the in vivo survival, expansion and effector function of IL-17-producing helper T (T(H)17) cells during autoimmune responses, including experimental autoimmune encephalomyelitis (EAE). However, the spatiotemporal role and cellular source of IL-1β during EAE pathogenesis are poorly defined. In the present study, we uncovered a T cell-intrinsic inflammasome that drives IL-1β production during T(H)17-mediated EAE pathogenesis. Activation of T cell antigen receptors induced expression of pro-IL-1β, whereas ATP stimulation triggered T cell production of IL-1β via ASC-NLRP3-dependent caspase-8 activation. IL-1R was detected on T(H)17 cells but not on type 1 helper T (T(H)1) cells, and ATP-treated T(H)17 cells showed enhanced survival compared with ATP-treated T(H)1 cells, suggesting autocrine action of T(H)17-derived IL-1β. Together these data reveal a critical role for IL-1β produced by a T(H)17 cell-intrinsic ASC-NLRP3-caspase-8 inflammasome during inflammation of the central nervous system.
authors.affiliation: Department of Immunology, Cleveland Clinic Lerner Research Institute, Cleveland, Ohio, USA.|Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA.
authors.forename: Bradley N
authors.initials: BN
authors.lastname: Martin
authors.affiliation: Department of Immunology, Cleveland Clinic Lerner Research Institute, Cleveland, Ohio, USA.|Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Chenhui
authors.initials: C
authors.lastname: Wang
authors.affiliation: Department of Immunology, Cleveland Clinic Lerner Research Institute, Cleveland, Ohio, USA.|Department of Neurology, Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin, China.|Department of Immunology, Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin, China.
authors.forename: Cun-jin
authors.initials: CJ
authors.lastname: Zhang
authors.affiliation: Shanghai Institute of Immunology, Shanghai Jiaotong University School of Medicine, Shanghai, China.
authors.forename: Zizhen
authors.initials: Z
authors.lastname: Kang
authors.affiliation: Department of Immunology, Cleveland Clinic Lerner Research Institute, Cleveland, Ohio, USA.
authors.forename: Muhammet Fatih
authors.initials: MF
authors.lastname: Gulen
authors.affiliation: Department of Immunology, Cleveland Clinic Lerner Research Institute, Cleveland, Ohio, USA.
authors.forename: Jarod A
authors.initials: JA
authors.lastname: Zepp
authors.affiliation: Department of Immunology, Cleveland Clinic Lerner Research Institute, Cleveland, Ohio, USA.
authors.forename: Junjie
authors.initials: J
authors.lastname: Zhao
authors.affiliation: Department of Immunology, Cleveland Clinic Lerner Research Institute, Cleveland, Ohio, USA.
authors.forename: Guanglin
authors.initials: G
authors.lastname: Bian
authors.affiliation: Department of Immunology, Cleveland Clinic Lerner Research Institute, Cleveland, Ohio, USA.
authors.forename: Jeong-su
authors.initials: JS
authors.lastname: Do
authors.affiliation: Department of Immunology, Cleveland Clinic Lerner Research Institute, Cleveland, Ohio, USA.
authors.forename: Booki
authors.initials: B
authors.lastname: Min
authors.affiliation: Department of Immunology, Cleveland Clinic Lerner Research Institute, Cleveland, Ohio, USA.
authors.forename: Paul G
authors.initials: PG
authors.lastname: Pavicic
authors.affiliation: Department of Physiology and Biophysics, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA.
authors.forename: Caroline
authors.initials: C
authors.lastname: El-Sanadi
authors.affiliation: Department of Cellular and Molecular Medicine, Cleveland Clinic Lerner Research Institute, Cleveland, Ohio, USA.
authors.forename: Paul L
authors.initials: PL
authors.lastname: Fox
authors.affiliation: Research Institute for Biomedical Sciences, Tokyo University of Science, Yamazaki, Noda, Japan.
authors.forename: Aoi
authors.initials: A
authors.lastname: Akitsu
authors.affiliation: Research Institute for Biomedical Sciences, Tokyo University of Science, Yamazaki, Noda, Japan.
authors.forename: Yoichiro
authors.initials: Y
authors.lastname: Iwakura
authors.affiliation: Davis Heart and Lung Research Institute, Ohio State University College of Medicine, Columbus, Ohio, USA.
authors.forename: Anasuya
authors.initials: A
authors.lastname: Sarkar
authors.affiliation: Davis Heart and Lung Research Institute, Ohio State University College of Medicine, Columbus, Ohio, USA.
authors.forename: Mark D
authors.initials: MD
authors.lastname: Wewers
authors.affiliation: Department of Microbiology and Immunology, Emory Vaccine Center, Atlanta, Georgia, USA.
authors.forename: William J
authors.initials: WJ
authors.lastname: Kaiser
authors.affiliation: Department of Microbiology and Immunology, Emory Vaccine Center, Atlanta, Georgia, USA.
authors.forename: Edward S
authors.initials: ES
authors.lastname: Mocarski
authors.affiliation: Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
authors.forename: Marc E
authors.initials: ME
authors.lastname: Rothenberg
authors.affiliation: Center for Global Health and Diseases, Case Western Reserve University, Cleveland, Ohio, USA.
authors.forename: Amy G
authors.initials: AG
authors.lastname: Hise
authors.affiliation: Department of Physiology and Biophysics, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA.
authors.forename: George R
authors.identifier: http://orcid.org/0000-0001-9720-4226
authors.initials: GR
authors.lastname: Dubyak
authors.affiliation: Department of Neurosciences, Cleveland Clinic Lerner Research Institute, Cleveland, Ohio, USA.
authors.forename: Richard M
authors.initials: RM
authors.lastname: Ransohoff
authors.affiliation: Department of Immunology, Cleveland Clinic Lerner Research Institute, Cleveland, Ohio, USA.
authors.forename: Xiaoxia
authors.initials: X
authors.lastname: Li
mesh_terms: D000255:Adenosine Triphosphate / Q000494:pharmacology; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D053468:CARD Signaling Adaptor Proteins; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D053181:Caspase 8 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D002470:Cell Survival / Q000235:genetics / Q000276:immunology; D002478:Cells, Cultured; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D005434:Flow Cytometry; D015870:Gene Expression / Q000276:immunology; D015151:Immunoblotting; D058847:Inflammasomes / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D020381:Interleukin-17 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D053583:Interleukin-1beta / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D058504:Th17 Cells / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism
chemical_list: D051017:Apoptosis Regulatory Proteins; D053468:CARD Signaling Adaptor Proteins; D002352:Carrier Proteins; D058847:Inflammasomes; D020381:Interleukin-17; D053583:Interleukin-1beta; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; C498534:Pycard protein, mouse; D000255:Adenosine Triphosphate; D053181:Caspase 8