Myeloid caspase-8 restricts RIPK3-dependent proinflammatory IL-1β production and CD4 T cell activation in autoimmune demyelination.

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-

SUBMITTER: Kim S 

PROVIDER: S-EPMC9214530 | biostudies-literature | 2022 Jun

REPOSITORIES: biostudies-literature