Synergism of TNF and IFNγ promotes cell death, but TNF drives innate immune-mediated colitis independent of IFNγ.

The cause of inflammatory bowel disease (IBD) is not known, but both innate and adaptive immunity contribute to IBD pathogenesis. To better understand the contributions of innate immunity to IBD, we have generated a mouse model of IBD that occurs spontaneously in the absence of adaptive immunity. This model is 100% penetrant, early onset, and driven by microbes. Here, we report that the colitis in this model exhibits extensive cell death in the gut mucosa, including cell death with features of apoptosis, necroptosis, and pyroptosis. This innate colitis and mucosal cell death was dependent on tumor necrosis factor (TNF). Deletion of interferon γ (IFNγ) markedly suppressed cell death and release of interleukin 1 (IL1) in the intestinal mucosa but did not prevent colitis. Production of TNF by monocyte lineage cells was dependent on IFNγ, but neutrophil production of TNF was independent of IFNγ. Depletion of TNF in IFNγ-deficient mice suppressed innate colitis. Thus, IFNγ is required for cell death and release of IL1 in the gut mucosa but is dispensable for innate colitis. These results indicate that TNF and IFNγ synergize to promote gut mucosal cell death but that TNF alone can drive innate colitis when cell death and IL1 release are reduced by the absence of IFNγ.