Receptor interacting serine/threonine protein kinase (RIPK) 1 and 3 are key signaling factors in cellular inflammation and programmed death. In particular, the interaction of RIPK1 and RIPK3 through their conserved RHIM domains results in necroptosis, where membrane pore formation releases danger-associated molecular patterns that drive an inflammatory response. Consequently, many viruses and bacteria have evolved pathogenic mechanisms that target RIPK for inactivation. The diarrhoeagenic gut bacteria enteropathogenic Escherichia coli (EPEC) has recently been described to carry an effector that cleaves the RHIM domains of RIPK1/3, however the physiological significance of this action to host immunity remains to be examined.
Using Citrobacter rodentium – the model organism for EPEC, evaluation of disease in a panel of RIPK knockout mice revealed that the absence of both RIPK1 and RIPK3 greatly heightened the diarrhoeal severity and bacterial burden experienced at peak infection. Notably, only RIPK3 had a significant role in moderating local gut pathology and in a manner independent from necroptosis. More interestingly, flow cytometry analysis in RIP1/3-deficient mice also found a marked reduction in the T-helper 17 and T-regulatory cell populations in the colonic lamina propria, which are important for mediating bacteria-induced colitis. These results are consistent with the improved disease phenotype exhibited by wildtype mice infected with an espL deleted C. rodentium mutant. Here, qPCR evaluation of inflammatory cytokine levels found an increased expression of Il22, but not Il17a in the colons of mutant C. rodentium infected mice, suggesting RIPK1/3 skews towards an anti-inflammatory response.
Here we show for the first time, a novel link between RIPK1/3 (innate immunity) and T cell responses (adaptive immunity) that is involved in host mucosal protection. Further characterisation of the underlying signaling pathways will be important to inform future management and treatment of serious enteric diseases.