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J Clin Invest. 2018 Dec 3;128(12):5399-5412. doi: 10.1172/JCI121901. Epub 2018 Oct 29.

TLR-stimulated IRAKM activates caspase-8 inflammasome in microglia and promotes neuroinflammation.

Author information

1
Medical School of Nanjing University, Nanjing, Jiangsu, China.
2
Department of Neurology, Tianjin Medical University General Hospital, Tianjin, China.
3
Department of Immunology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA.
4
Institute of Radiation Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China.
5
Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China.
6
Wuhan Institute of Biotechnology, Wuhan, China.
7
Department of Microbiology and Immunology, Emory Vaccine Center, Atlanta, Georgia, USA.
8
Department of Immunology and Medicine, St. Marianna University School of Medicine, Kawasaki, Japan.
9
Research Institute for Biomedical Sciences, Tokyo University of Science, Yamazaki, Noda, Japan.
10
Discovery Biology, Bristol-Myers Squibb, Princeton, New Jersey, USA.
11
Department of Physiology and Biophysics, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA.
12
Department of Pathology, Case Western Reserve University/University Hospitals Case Medical Center, Cleveland, Ohio, USA.
13
Department of Neurology, Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, Arizona, USA.
14
Department of Cell Biology, Harvard Medical School, Boston, Massachusetts, USA.

Abstract

NLRP3 inflammasome plays a critical spatiotemporal role in the pathogenesis of experimental autoimmune encephalomyelitis (EAE). This study reports a mechanistic insight into noncanonical NLRP3 inflammasome activation in microglia for the effector stage of EAE. Microglia-specific deficiency of ASC (apoptosis-associated speck-like protein containing a C-terminal caspase-activation and recruitment [CARD] domain) attenuated T cell expansion and neutrophil recruitment during EAE pathogenesis. Mechanistically, TLR stimulation led to IRAKM-caspase-8-ASC complex formation, resulting in the activation of caspase-8 and IL-1β release in microglia. Noncanonical inflammasome-derived IL-1β produced by microglia in the CNS helped to expand the microglia population in an autocrine manner and amplified the production of inflammatory cytokines/chemokines. Furthermore, active caspase-8 was markedly increased in the microglia in the brain tissue from patients with multiple sclerosis. Taken together, our study suggests that microglia-derived IL-1β via noncanonical caspase-8-dependent inflammasome is necessary for microglia to exert their pathogenic role during CNS inflammation.

KEYWORDS:

Autoimmune diseases; Autoimmunity; Inflammation

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