LAUSR

&NA; Inflammatory bowel disease is a chronic, relapsing condition with two subtypes, Crohn's disease (CD) and ulcerative colitis (UC). Genome‐wide association studies (GWASs) in UC implicate a FCGR2A variant that alters the binding affinity of the antibody receptor it encodes, Fc&ggr;RIIA, for immunoglobulin G (IgG). Here, we aimed to understand the mechanisms whereby changes in Fc&ggr;RIIA affinity would affect inflammation in an IgA‐dominated organ. We found a profound induction of anti‐commensal IgG and a concomitant increase in activating Fc&ggr;R signaling in the colonic mucosa of UC patients. Commensal‐IgG immune complexes engaged gut‐resident Fc&ggr;R‐expressing macrophages, inducing NLRP3‐ and reactive‐oxygen‐species‐dependent production of interleukin‐1&bgr; (IL‐1&bgr;) and neutrophil‐recruiting chemokines. These responses were modulated by the FCGR2A genotype. In vivo manipulation of macrophage Fc&ggr;R signal strength in a mouse model of UC determined the magnitude of intestinal inflammation and IL‐1&bgr;‐dependent type 17 immunity. The identification of an important contribution of IgG‐Fc&ggr;R‐dependent inflammation to UC has therapeutic implications. Graphical Abstract Figure. No caption available. HighlightsIntestinal inflammation in UC is associated with increased anti‐commensal IgGCommensal‐IgG cross‐link Fc&ggr;R on colonic MNPs, inducing IL‐1&bgr; productionMNP Fc&ggr;R A:I ratio determines magnitude of type 17 immunity and local inflammationIdentifies cellular mechanisms by which Fc&ggr;RIIA H/R131 confers UC susceptibility