T cell-intrinsic ASC critically promotes T(H)17-mediated experimental autoimmune encephalomyelitis

Bradley N Martin; Chenhui Wang; Cun-jin Zhang; Zizhen Kang; Muhammet Fatih Gulen; Jarod A Zepp; Junjie Zhao; Guanglin Bian; Jeong-su Do; Booki Min; Paul G Pavicic Jr; Caroline El-Sanadi; Paul L Fox; Aoi Akitsu; Yoichiro Iwakura; Anasuya Sarkar; Mark D Wewers; William J Kaiser; Edward S Mocarski; Marc E Rothenberg; Amy G Hise; George R Dubyak; Richard M Ransohoff; Xiaoxia Li

doi:10.1038/ni.3389

T cell-intrinsic ASC critically promotes T(H)17-mediated experimental autoimmune encephalomyelitis

Nat Immunol. 2016 May;17(5):583-92. doi: 10.1038/ni.3389. Epub 2016 Mar 21.

Authors

Bradley N Martin^{1

2}, Chenhui Wang^{1

3}, Cun-jin Zhang^{1

4

5}, Zizhen Kang⁶, Muhammet Fatih Gulen¹, Jarod A Zepp¹, Junjie Zhao¹, Guanglin Bian¹, Jeong-su Do¹, Booki Min¹, Paul G Pavicic Jr¹, Caroline El-Sanadi⁷, Paul L Fox⁸, Aoi Akitsu⁹, Yoichiro Iwakura⁹, Anasuya Sarkar¹⁰, Mark D Wewers¹⁰, William J Kaiser¹¹, Edward S Mocarski¹¹, Marc E Rothenberg¹², Amy G Hise¹³, George R Dubyak⁷, Richard M Ransohoff¹⁴, Xiaoxia Li¹

Affiliations

¹ Department of Immunology, Cleveland Clinic Lerner Research Institute, Cleveland, Ohio, USA.
² Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA.
³ Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China.
⁴ Department of Neurology, Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin, China.
⁵ Department of Immunology, Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin, China.
⁶ Shanghai Institute of Immunology, Shanghai Jiaotong University School of Medicine, Shanghai, China.
⁷ Department of Physiology and Biophysics, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA.
⁸ Department of Cellular and Molecular Medicine, Cleveland Clinic Lerner Research Institute, Cleveland, Ohio, USA.
⁹ Research Institute for Biomedical Sciences, Tokyo University of Science, Yamazaki, Noda, Japan.
¹⁰ Davis Heart and Lung Research Institute, Ohio State University College of Medicine, Columbus, Ohio, USA.
¹¹ Department of Microbiology and Immunology, Emory Vaccine Center, Atlanta, Georgia, USA.
¹² Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
¹³ Center for Global Health and Diseases, Case Western Reserve University, Cleveland, Ohio, USA.
¹⁴ Department of Neurosciences, Cleveland Clinic Lerner Research Institute, Cleveland, Ohio, USA.

PMID: 26998763
PMCID: PMC5385929
DOI: 10.1038/ni.3389

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Adenosine Triphosphate / pharmacology
Animals
Apoptosis Regulatory Proteins / genetics
Apoptosis Regulatory Proteins / immunology*
Apoptosis Regulatory Proteins / metabolism
CARD Signaling Adaptor Proteins
CD4-Positive T-Lymphocytes / immunology
CD4-Positive T-Lymphocytes / metabolism
Carrier Proteins / genetics
Carrier Proteins / immunology
Carrier Proteins / metabolism
Caspase 8 / genetics
Caspase 8 / immunology
Caspase 8 / metabolism
Cell Survival / genetics
Cell Survival / immunology
Cells, Cultured
Encephalomyelitis, Autoimmune, Experimental / genetics
Encephalomyelitis, Autoimmune, Experimental / immunology*
Encephalomyelitis, Autoimmune, Experimental / metabolism
Flow Cytometry
Gene Expression / immunology
Immunoblotting
Inflammasomes / genetics
Inflammasomes / immunology
Inflammasomes / metabolism
Interleukin-17 / genetics
Interleukin-17 / immunology
Interleukin-17 / metabolism
Interleukin-1beta / genetics
Interleukin-1beta / immunology
Interleukin-1beta / metabolism
Mice, Inbred C57BL
Mice, Knockout
Mice, Transgenic
NLR Family, Pyrin Domain-Containing 3 Protein
Reverse Transcriptase Polymerase Chain Reaction
Signal Transduction / genetics
Signal Transduction / immunology
T-Lymphocytes / drug effects
T-Lymphocytes / immunology*
T-Lymphocytes / metabolism
Th17 Cells / drug effects
Th17 Cells / immunology*
Th17 Cells / metabolism

Substances

Apoptosis Regulatory Proteins
CARD Signaling Adaptor Proteins
Carrier Proteins
Inflammasomes
Interleukin-17
Interleukin-1beta
NLR Family, Pyrin Domain-Containing 3 Protein
Nlrp3 protein, mouse
Pycard protein, mouse
Adenosine Triphosphate
Caspase 8

Abstract

Publication types

MeSH terms

Substances

Grants and funding