Colonic Complement Factor B Production Is Required To Respond To Tissue Injury 2310076

Abstract

Abstract Introduction The complement system is an evolutionarily conserved arm of immunity. Key components of this system such as C3 and Factor B are activated in inflammatory bowel disease (IBD), however coding variant in Factor B (rs4151651) is associated with severe IBD complications, thus, suggesting two sides to Factor B in IBD. First, its chronic upregulation is associated with excessive inflammation, but second its absence correlates with increased risk for developing colitis. Although these proteins are primarily derived from the liver and operative in the circulation, we and others have shown that they are active in the gut. Yet, major knowledge gaps remain regarding the production, activation and regulation of Factor B in IBD in order to develop tailored therapies for modulating complement activity in the gut. Methods We conducted transcriptomic and proteomic analyses of human and mouse colon, and generated conditional knockout mice lacking systemic (liver-derived) Factor B, and cell type-specific inducible Factor B deletion to alter colonic Factor B production. To determine contribution of tissue derived Factor B, we induced chemical-induced colitis in these models and assessed the severity of mucosal injury. Results Transcriptomic and proteomic analysis of colonic tissue from patients with ulcerative colitis reveal an increase in activators of the complement cascade, notably Factor B. Additionally, local Factor B production is upregulated in colonic structural cells such as epithelial cells and fibroblasts upon stimulation with inflammatory cytokines such as rIL-1β and rTNF-α. In vivo studies reveal that local Factor B production protects against chemical-induced colitis, independent of circulating Factor B. Conclusion These observations indicate that local Factor B production by intestinal cells is required for mucosal response to injury, and creates the precedent for its regulation locally, rather than inhibition, in IBD. Funding Source Institutional funding, foundation award Topic Categories Mucosal and Regional Immunology (MUC)