TY - JOUR
T1 - C5a receptor 1 −/− mice are protected from the development of IgE-mediated experimental food allergy
AU - Kordowski, Anna
AU - Reinicke, Anna T.
AU - Wu, David
AU - Orinska, Zane
AU - Hagemann, Philipp
AU - Huber-Lang, Markus
AU - Lee, Jee Boong
AU - Wang, Yui Hsi
AU - Hogan, Simon P.
AU - Köhl, Jörg
PY - 2019/4
Y1 - 2019/4
N2 - Background: Food-induced anaphylaxis is a serious allergic reaction caused by Fcε-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, we aimed to assess the role of C5a in disease pathogenesis. Methods: Oral antigen-induced food-induced anaphylaxis was induced in BALB/c wild-type (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. Results: Repeated oral OVA challenge resulted in diarrhea, hypothermia, increased hematocrit, high OVA-specific serum IgE, and MCPT-1 levels in wt mice. Male C5ar1 −/− mice were completely whereas female C5ar1 −/− mice 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 vitro and 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 vitro following C5aR targeting. Conclusions: Our findings 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.
AB - Background: Food-induced anaphylaxis is a serious allergic reaction caused by Fcε-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, we aimed to assess the role of C5a in disease pathogenesis. Methods: Oral antigen-induced food-induced anaphylaxis was induced in BALB/c wild-type (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. Results: Repeated oral OVA challenge resulted in diarrhea, hypothermia, increased hematocrit, high OVA-specific serum IgE, and MCPT-1 levels in wt mice. Male C5ar1 −/− mice were completely whereas female C5ar1 −/− mice 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 vitro and 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 vitro following C5aR targeting. Conclusions: Our findings 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.
UR - http://www.scopus.com/inward/record.url?scp=85056342754&partnerID=8YFLogxK
U2 - 10.1111/all.13637
DO - 10.1111/all.13637
M3 - Journal articles
C2 - 30341777
AN - SCOPUS:85056342754
SN - 0105-4538
VL - 74
SP - 767
EP - 779
JO - Allergy: European Journal of Allergy and Clinical Immunology
JF - Allergy: European Journal of Allergy and Clinical Immunology
IS - 4
ER -