FcγRIIb protects from reperfusion injury by controlling antibody and type I IFN-mediated tissue injury and death

Intestinal ischemia and reperfusion (I/R) is accompanied by an exacerbated inflammatory response characterized by deposition of IgG, release of inflammatory mediators, and intense neutrophil influx in the small intestine, resulting in severe tissue injury and death. We hypothesized that Fc(gamma)RIIb activation by deposited IgG could inhibit tissue damage during I/R. Our results showed that I/R induction led to the deposition of IgG in intestinal tissue during the reperfusion phase. Death upon I/R occurred earlier and was more frequent in Fc(gamma)RIIb(-/-) than WT mice. The higher lethality rate was associated with greater tissue injury and bacterial translocation to other organs. Fc(gamma)RIIb(-/-) mice presented changes in the amount and repertoire of circulating IgG, leading to increased IgG deposition in intestinal tissue upon reperfusion in these mice. Depletion of intestinal microbiota prevented antibody deposition and tissue damage in Fc(gamma)RIIb(-/-) mice submitted to I/R. We also observed increased production of ROS on neutrophils harvested from the intestines of Fc(gamma)RIIb(-/-) mice submitted to I/R. In contrast, Fc(gamma)RIII(-/-) mice presented reduced tissue damage and neutrophil influx after reperfusion injury, a phenotype reversed by Fc(gamma)RIIb blockade. In addition, we observed reduced IFN-beta expression in the intestines of Fc(gamma)RIII(-/-) mice after I/R, a phenotype that was also reverted by blocking Fc(gamma)RIIb. IFNAR(-/-) mice submitted to I/R presented reduced lethality and TNF release. Altogether our results demonstrate that antibody deposition triggers Fc(gamma)RIIb to control IFN-beta and IFNAR activation and subsequent TNF release, tailoring tissue damage, and death induced by reperfusion injury.

Automated summary

Intestinal ischemia and reperfusion (I/R) result in severe tissue injury and death due to exacerbated inflammatory response. The deposition of IgG triggers Fc(gamma)RIIb activation, which controls the release of inflammatory mediators, reducing tissue damage and death.