The Necroptosis Adaptor RIPK3 Promotes Injury-Induced Cytokine Expression and Tissue Repair

Programmed necrosis or necroptosis is an inflammatory form of cell death that critically requires the receptor-interacting protein kinase 3 (RIPK3). Here we showed that RIPK3 controls a separate, necrosis-independent pathway of inflammation by regulating cytokine expression in dendritic cells (DCs). Ripk3(-/-) bone-marrow-derived dendritic cells (BMDCs) were highly defective in lipopolysaccharide (LPS)-induced expression of inflammatory cytokines. These effects were caused by impaired NFkB subunit ReIB and p50 activation and by impaired caspase 1-mediated processing of interleukin-1 beta (IL-1 beta). This DC-specific function of RIPK3 was critical for injury-induced inflammation and tissue repair in response to dextran sodium sulfate (DSS). Ripk3(-/-) mice exhibited an impaired axis of injury-induced IL-1 beta, IL-23, and IL-22 cytokine cascade, which was partially corrected by adoptive transfer of wildtype DCs, but not Ripk3(-/-) DCs. These results reveal an unexpected function of RIPK3 in NF-kappa B activation, DC biology, innate inflammatory-cytokine expression, and injury-induced tissue repair.