Reducing IRF5 expression attenuates colitis in mice, but impairs the clearance of intestinal pathogens

IRF5 genetic variants leading to decreased IRF5 expression reduce risk for ulcerative colitis. However, how IRF5 regulates intestinal inflammation and contributes to the balance between defenses against intestinal pathogens and inflammation in vivo, and the cells mediating this balance, are not known. We found that deleting IRF5 in mice led to reduced intestinal inflammation in the T cell transfer colitis model, with reduced Th1 and Th17, and increased Th2 cytokines. However, with orally-administered invasive S. Typhimurium, IRF5^-/- mice demonstrated an increased bacterial burden in the context of reduced Th1 and Th17 cytokines. IRF5 in macrophages was required for PDK1-dependent phagocytosis and for NFκB-dependent pathways mediating intracellular bacterial clearance. Despite reduced bacterial clearance pathways, in IRF5^-/- mice exposed to high levels of resident intestinal bacteria after DSS-induced injury, the lower levels of inflammatory cytokines were associated with reduced intestinal permeability, and in turn, reduced bacterial translocation and intestinal inflammation. Consistent with the myeloid cell-intrinsic roles for IRF5 in vitro, mice with IRF5 deleted from myeloid cells demonstrated outcomes similar to those observed in IRF5^-/- mice. While these data suggest that inhibition of IRF5 may be therapeutic in colitis, this needs to be balanced with the identified IRF5 role in protecting against intestinal pathogens.