Epidermolysis bullosa acquisita (EBA) is a rare blistering skin disease induced by autoantibodies directed against type VII collagen. The transfer of antibodies against murine type VII collagen into mice mimics the effector phase of EBA and results in a subepidermal blistering phenotype. Activation of the complement system, and especially the C5a/C5aR1 axis driving neutrophil activation, is critical for EBA pathogenesis. However, the role of the alternative C5a receptor, C5aR2, which is commonly thought to be more immunosuppressive, in the pathogenesis of EBA is still elusive. Therefore, we sought to delineate the functional relevance of C5aR2 during the effector phase of EBA. Interestingly, C5ar2-/- mice showed an attenuated disease phenotype, suggesting a pathogenic contribution of C5aR2 in disease progression. In vitro, C5ar2-/- neutrophils exhibited significantly reduced intracellular calcium flux, ROS release, and migratory capacity when activated with immune complexes or exposed to C5a. These functions were completely absent when C5ar1-/- neutrophils were activated. Moreover, C5aR2 deficiency lowered the ratio of activating and inhibitory FcγRs, impeding the sustainment of inflammation. Collectively, we show here a proinflammatory contribution of C5aR2 in the pathogenesis of antibody-induced tissue damage in experimental EBA.

C5aR2 Deficiency Ameliorates Inflammation in Murine Epidermolysis Bullosa Acquisita by Regulating Fcγ Receptor Expression on Neutrophils / Seiler, Daniel Leonard; Kleingarn, Marie; Kähler, Katja Hendrika; Gruner, Caroline; Schanzenbacher, Jovan; Ehlers-Jeske, Elvira; Kenno, Samyr; Sadik, Christian David; Schmidt, Enno; Bieber, Katja; Köhl, Jörg; Ludwig, Ralf J.; Karsten, Christian Marcel. - In: JOURNAL OF INVESTIGATIVE DERMATOLOGY. - ISSN 0022-202X. - 142:10(2022), pp. 2715-2723. [10.1016/j.jid.2021.12.029]

C5aR2 Deficiency Ameliorates Inflammation in Murine Epidermolysis Bullosa Acquisita by Regulating Fcγ Receptor Expression on Neutrophils

Kenno, Samyr;
2022

Abstract

Epidermolysis bullosa acquisita (EBA) is a rare blistering skin disease induced by autoantibodies directed against type VII collagen. The transfer of antibodies against murine type VII collagen into mice mimics the effector phase of EBA and results in a subepidermal blistering phenotype. Activation of the complement system, and especially the C5a/C5aR1 axis driving neutrophil activation, is critical for EBA pathogenesis. However, the role of the alternative C5a receptor, C5aR2, which is commonly thought to be more immunosuppressive, in the pathogenesis of EBA is still elusive. Therefore, we sought to delineate the functional relevance of C5aR2 during the effector phase of EBA. Interestingly, C5ar2-/- mice showed an attenuated disease phenotype, suggesting a pathogenic contribution of C5aR2 in disease progression. In vitro, C5ar2-/- neutrophils exhibited significantly reduced intracellular calcium flux, ROS release, and migratory capacity when activated with immune complexes or exposed to C5a. These functions were completely absent when C5ar1-/- neutrophils were activated. Moreover, C5aR2 deficiency lowered the ratio of activating and inhibitory FcγRs, impeding the sustainment of inflammation. Collectively, we show here a proinflammatory contribution of C5aR2 in the pathogenesis of antibody-induced tissue damage in experimental EBA.
2022
142
10
2715
2723
C5aR2 Deficiency Ameliorates Inflammation in Murine Epidermolysis Bullosa Acquisita by Regulating Fcγ Receptor Expression on Neutrophils / Seiler, Daniel Leonard; Kleingarn, Marie; Kähler, Katja Hendrika; Gruner, Caroline; Schanzenbacher, Jovan; Ehlers-Jeske, Elvira; Kenno, Samyr; Sadik, Christian David; Schmidt, Enno; Bieber, Katja; Köhl, Jörg; Ludwig, Ralf J.; Karsten, Christian Marcel. - In: JOURNAL OF INVESTIGATIVE DERMATOLOGY. - ISSN 0022-202X. - 142:10(2022), pp. 2715-2723. [10.1016/j.jid.2021.12.029]
Seiler, Daniel Leonard; Kleingarn, Marie; Kähler, Katja Hendrika; Gruner, Caroline; Schanzenbacher, Jovan; Ehlers-Jeske, Elvira; Kenno, Samyr; Sadik, Christian David; Schmidt, Enno; Bieber, Katja; Köhl, Jörg; Ludwig, Ralf J.; Karsten, Christian Marcel
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11380/1332533
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