Experimental food-induced anaphylaxis is driven by C5aR1 actvivation on mast cells

Abstract

Abstract Food-induced anaphylaxis is a serious allergic reaction mainly caused by antigen cross-linking of IgE-loaded Fce-receptors on mast cells (MCs). Such MC activation leads to the release of pro-inflammatory mediators which results in the manifestation of the disease. Here, we demonstrate that the complement fragment C5a plays an important and until now not recognized role in the development and severity of food allergy. We subjected C5aR1−/− and wild-type (wt) Balb/c mice to oral ovalbumin (OVA)-induced anaphylaxis. We observed that 78% of wt but only 9% of C5aR1−/− mice suffered from diarrhea and hypothermia after the 7th oral OVA challenge. Importantly, peritoneal MCs strongly expressed C5aR1 after the 7th oral OVA treatment. OVA-specific serum IgE and MCPT-1 levels were significantly decreased in C5aR1-deficient as compared with wt mice. To directly examine the impact of the C5a/C5aR1 axis on MC function, we generated bone marrow-derived MCs (BMMCs) and tested their activation and degranulation potency in response to FceR1 cross-linking. Degranulation of C5aR1−/− BMMCs was reduced by 50% and IL-6 production was decreased by 35% as compared with wt cells. Also, FceR1 cross-linking markedly upregulated C5aR1 MC expression. Further, in contrast to wt mice, C5aR1−/− mice were largely protected from histamine-induced temperature drop in vivo. In line with this finding, C5aR targeting protected human endothelial cells from histamine-induced barrier dysfunction and disruption of tight junction proteins in vitro. Our findings identify a critical role of the C5a/C5aR1 axis in IgE-mediated oral antigen-induced anaphylaxis. C5aR1 may serve as a novel therapeutic target to suppress the inflammatory response in food-induced anaphylaxis.