Neutrophil-Specific Syk Expression Is Crucial for Skin Disease in Experimental Epidermolysis Bullosa Acquisita

Abstract

Autoantibodies against the dermal-epidermal junction component type VII collagen (C7) trigger skin disease in the inflammatory form of epidermolysis bullosa acquisita. We have previously identified the Syk tyrosine kinase as a crucial participant in anti-C7 antibody-induced experimental epidermolysis bullosa acquisita. However, it is still unclear which cellular lineage needs to express Syk during the disease process. In this study, we show that the loss of Syk, specifically from neutrophils, results in complete protection from the anti-C7 antibody-initiated skin disease both macroscopically and microscopically. Mice with a neutrophil-specific Syk deletion had decreased neutrophil accumulation and abrogated CXCL2 and IL-1β levels in the skin upon anti-C7 treatment, whereas isolated Syk-deficient neutrophils had decreased superoxide release, cell spreading, and cytokine release on C7-anti-C7 immune complex surfaces. Entospletinib and lanraplenib, two second-generation Syk-specific inhibitors, effectively abrogated immune complex-induced responses of human neutrophils and decreased the anti-C7 antibody-initiated, neutrophil-mediated exvivo dermal-epidermal separation in human skin samples. Taken together, these results point to a crucial role for Syk in neutrophils in the development and progression of epidermolysis bullosa acquisita and suggest Syk inhibition as a potential therapeutic strategy.