C5a receptor 1-/- mice are protected from the development of IgE-mediated experimental food allergy
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C5a receptor 1-/- mice are protected from the development of IgE-mediated experimental food allergy. / Kordowski, Anna; Reinicke, Anna T; Wu, David; Orinska, Zane; Hagemann, Philipp; Huber-Lang, Markus; Lee, Jee-Boong; Wang, Yui-Hsi; Hogan, Simon P; Köhl, Jörg.
In: ALLERGY, Vol. 74, No. 4, 04.2019, p. 767-779.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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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
N1 - © 2018 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.
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.
KW - Anaphylaxis
KW - Animals
KW - Cell Degranulation
KW - Chymases/blood
KW - Female
KW - Food Hypersensitivity/etiology
KW - Immunoglobulin E/blood
KW - Male
KW - Mast Cells/metabolism
KW - Mice
KW - Mice, Inbred BALB C
KW - Mice, Knockout
KW - Receptor, Anaphylatoxin C5a/deficiency
KW - Receptors, IgE/immunology
KW - Sex Factors
U2 - 10.1111/all.13637
DO - 10.1111/all.13637
M3 - SCORING: Journal article
C2 - 30341777
VL - 74
SP - 767
EP - 779
JO - ALLERGY
JF - ALLERGY
SN - 0105-4538
IS - 4
ER -