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 FcγRIIb 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 FcγRIIb−/− than WT mice. The higher lethality rate was associated with greater tissue injury and bacterial translocation to other organs. FcγRIIb−/− 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 FcγRIIb−/− mice submitted to I/R. We also observed increased production of ROS on neutrophils harvested from the intestines of FcγRIIb−/− mice submitted to I/R. In contrast, FcγRIII−/− mice presented reduced tissue damage and neutrophil influx after reperfusion injury, a phenotype reversed by FcγRIIb blockade. In addition, we observed reduced IFN‐β expression in the intestines of FcγRIII−/− mice after I/R, a phenotype that was also reverted by blocking FcγRIIb. IFNAR−/− mice submitted to I/R presented reduced lethality and TNF release. Altogether our results demonstrate that antibody deposition triggers FcγRIIb to control IFN‐β and IFNAR activation and subsequent TNF release, tailoring tissue damage, and death induced by reperfusion injury. A‐ In FcγIIb+/+ mice, microbial products are released in intestine and presented to B cells to induce antibody production, including IgG (1). Immune complex formed by IgG and microbial products lead to crosslinking with BCR and FcγIIb (2) controlling production of IgG relevant to reperfusion injury. After IIR, this IgG binds to intestinal antigens exposed during reperfusion (3) and activates FcγIIb in neutrophils (4) downregulating IFN‐1, production, IFNAR receptor activation and consequent TNF production (5) and favoring resistance to IIR‐induced death. B‐ In the absence of FcγIIb, there is increased production of IgG relevant to reperfusion injury (1, and 2). These IgG bind to intestinal antigens exposed during reperfusion, depositing in intestine, leading to early tissue injury (3). Lack of FcγIIb al