The C5a/C5aR1 Axis Drives Experimental Food-Induced Anaphylaxis

Food-induced anaphylaxis is a life-threatening allergic reaction mainly driven by antigen cross-linking of IgE-loaded Fce-receptors on mast cells (MCs). Such MC activation leads to the release of pro-inflammatory mediators eventually resulting in anaphylaxis. The complement fragment C5a can activate MCs through its cognate C5a receptor 1 (C5aR1). Here, we subjected C5aR1^-/- and wild-type (wt) Balb/c mice to oral ovalbumin (OVA)-induced anaphylaxis. In wt mice but not in C5aR1^-/- male mice, we observed a severe clinical phenotype. More specifically, 78% of wt but only 9% of C5aR1^-/- mice suffered from diarrhea and hypothermia. The lower incidence of evidence of anaphylaxis in C5aR1^-/- mice was associated with decreased OVA-specific serum IgE and MC activation (MCPT-1 levels). Further, histamine treatment resulted in a milder temperature drop in C5aR1^-/- than in wt mice. To link the observed phenotype with MC function, we examined activation and degranulation of bone marrow-derived MCs (BMMCs) in response to FceR cross-linking. Degranulation of C5aR1^-/- BMMCs was reduced by 50% and IL-6 production was reduced by 35% as compared with wt cells. Our findings identify a critical role of the C5a/C5aR1 axis in IgE-mediated oral antigen-induced anaphylaxis. C5aR1 targeting may prove useful to suppress the inflammatory response in food-induced anaphylaxis.