A novel role for the C5a/C5aR1 axis in food allergy.
In a joint effort, the Köhl lab at the University of Lübeck and the Hogan lab at Cincinnati Children's Hospital uncovered a novel role for the C5a/C5aR1 axis in food allergy.
Food-induced anaphylaxis is a serious allergic reaction caused by Fce-receptor activation on mast cells (MCs).The exact mechanisms breaking oral tolerance and the effector pathways driving food allergy remain elusive. As complement is activated in food-induced anaphylaxis, the researchers aimed to assess the role of C5a in disease pathogenesis. Oral antigen-induced food-induced anaphylaxis was induced in BALB/c wildtype (wt) and C5ar1-/- mice. Readouts included diarrhea development, changes in rectal temperature, hematocrit, antigen-specific serum IgE, MCPT-1 and intestinal MC numbers as well as FcεR1-mediated MC functions including C5a receptor 1 (C5aR1) regulation. Further, histamine-mediated hypothermia and regulation of endothelial tight junctions were determined.
Repeated oral OVA challenge resulted in diarrhea, hypothermia, increased hematocrit, high OVA-specific serum IgE and MCPT-1 levelsin wt mice. Male C5ar1-/-mice were completely whereas female C5ar1-/- were partially protected from anaphylaxis development. Serum MCPT-1 levels were reduced gender-independent, whereas IgE levels were reduced in male but not in female C5ar1-/- mice. Mechanistically, IgE-mediated degranulation and IL-6 production from C5ar1-/- BMMCs of both sexes were significantly reduced. Importantly, FcεR1 cross-linking strongly upregulated C5aR1 MC expression in vitroand in vivo. Finally, C5ar1-/- male mice were largely protected from histamine-induced hypovolemic shock, which was associated with protection from histamine-induced barrier dysfunction in vitrofollowing C5aR targeting. Thesefindings identify C5aR1 activation as an important driver of IgE-mediated food allergy through regulation of allergen specific IgE production, FcεR1-mediated MC degranulation and histamine-driven effector functions preferentially in male mice. They suggest that C5aR1 may serve as potential new therapeutic target in this emerging disease.
- The C5a/C5aR1 axis controls the production of allergen-specific IgE in male mice
- FcϵR1 aggregation upregulates C5aR1 expression in mast cells which amplifies IgE-driven mediator release
- C5aR1 signaling controls histamine-mediated effector functions in vivo and in vitro