Myeloid caspase-8 restricts RIPK3-dependent

Autoimmune demyelination is driven by pathogenic T cells and inflammatory myeloid cells. How myeloid and T cells functionally interact and contribute to inflammatory demyelinating disease, such as multiple sclerosis, remains incompletely understood.

This study identifies a caspase-8-mediated pathway in macrophages that suppresses inflammasome-dependent interleukin-1β production and autoimmunity during inflammatory demyelination. The study provides insights into the interaction between infiltrated myeloid cells and autoreactive T cells in multiple sclerosis that may also have implications for other autoimmune inflammatory diseases.

Caspase-8 functions at the crossroads of programmed cell death and inflammation. Here, using genetic approaches and the experimental autoimmune encephalomyelitis model of inflammatory demyelination, we have identified a negative regulatory pathway for caspase-8 in infiltrated macrophages through which it functions to limit autoimmune inflammation. induced by interleukin (IL)-1β. Caspase-8 is partially activated in macrophages/microglia in active multiple sclerosis lesions.

Selective ablation of Casp8 in myeloid cells, but not in microglia, exacerbated autoimmune demyelination. The increased production of IL-1β by caspase-8-deficient macrophages underlies the exacerbated activation of encephalitogenic T cells and the production of GM-CSF and interferon-γ. Mechanically, IL-1β overproduction by primed caspase-8-deficient macrophages was mediated by RIPK1/RIPK3 via NLRP3 inflammasome engagement 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, release a significant amount of IL-1β which in turn acts via the IL-1R to amplify T-cell activation.

Moreover, the worsening progression of experimental autoimmune encephalomyelitis in Casp8 myeloid mutant mice was completely reversed when Ripk3 was simultaneously suppressed. Together, these data reveal a functional link between T cell-directed autoimmunity and inflammatory IL-1β that is negatively regulated by caspase-8, and suggest that dysregulation of the pathway may contribute to autoimmune diseases. inflammatory immune diseases, such as multiple sclerosis.