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Myeloid caspase-8 restricts RIPK3-dependent proinflammatory IL-1β production and CD4 T cell activation in autoimmune demyelination.
- Source :
- Proceedings of the National Academy of Sciences of the United States of America; 6/14/2022, Vol. 119 Issue 24, p1-12, 28p
- Publication Year :
- 2022
-
Abstract
- Caspase-8 functions at the crossroad of programmed cell death and inflammation. Here, using genetic approaches and the experimental autoimmune encephalomyelitis model of inflammatory demyelination, we identified a negative regulatory pathway for caspase-8 in infiltrated macrophages whereby it functions to restrain interleukin (IL)-1β-driven autoimmune inflammation. Caspase-8 is partially activated in macrophages/microglia in active lesions of multiple sclerosis. Selective ablation of Casp8 in myeloid cells, but not microglia, exacerbated autoimmune demyelination. Heightened IL-1β production by caspase-8-deficient macrophages underlies exacerbated activation of encephalitogenic T cells and production of GM-CSF and interferon-γ. Mechanistically, IL-1β overproduction by primed caspase-8-deficient macrophages was mediated by RIPK1/RIPK3 through the engagement of NLRP3 inflammasome and was independent of cell death. When instructed by autoreactive CD4 T cells in the presence of antigen, caspase-8-deficient macrophages, but not their wild-type counterparts, released significant amount of IL-1β that in turn acted through IL-1R to amplify T cell activation. Moreover, the worsened experimental autoimmune encephalomyelitis progression in myeloid Casp8 mutant mice was completely reversed when Ripk3 was simultaneously deleted. Together, these data reveal a functional link between T cell-driven autoimmunity and inflammatory IL-1β that is negatively regulated by caspase-8, and suggest that dysregulation of the pathway may contribute to inflammatory autoimmune diseases, such as multiple sclerosis. [ABSTRACT FROM AUTHOR]
- Subjects :
- CASPASES
T cells
MYELOID cells
DEMYELINATION
APOPTOSIS
INFORMATION literacy
Subjects
Details
- Language :
- English
- ISSN :
- 00278424
- Volume :
- 119
- Issue :
- 24
- Database :
- Complementary Index
- Journal :
- Proceedings of the National Academy of Sciences of the United States of America
- Publication Type :
- Academic Journal
- Accession number :
- 157335430
- Full Text :
- https://doi.org/10.1073/pnas.2117636119