Phospholipase Cγ2 Is Essential for Experimental Models of Epidermolysis Bullosa Acquisita.

Abstract

Phospholipase Cγ2 (PLCγ2) mediates tyrosine kinase‒coupled receptor signaling in various hematopoietic lineages. Although PLCγ2 has been implicated in certain human and mouse inflammatory disorders, its contribution to autoimmune and inflammatory skin diseases is poorly understood. In this study, we tested the role of PLCγ2 in a mouse model of epidermolysis bullosa acquisita triggered by antibodies against type VII collagen (C7), a component of the dermo-epidermal junction. PLCγ2-deficient (Plcg2) mice and bone marrow chimeras with a Plcg2hematopoietic system were completely protected from signs of anti-C7-induced skin disease, including skin erosions, dermal‒epidermal separation, and inflammation, despite normal circulating levels and skin deposition of anti-C7 antibodies. PLCγ2 was required for the tissue infiltration of neutrophils, eosinophils, and monocytes/macrophages as well as for the accumulation of proinflammatory mediators (including IL-1β, MIP-2, and LTB) and reactive oxygen species. Mechanistic experiments revealed a role for PLCγ2 in the release of proinflammatory mediators and reactive oxygen species but not in the intrinsic migratory capacity of leukocytes. The phospholipase C inhibitor U73122 inhibited dermal-epidermal separation of human skin sections incubated with human neutrophils in the presence of anti-C7 antibodies. Taken together, our results suggest a critical role for PLCγ2 in the pathogenesis of the inflammatory form of epidermolysis bullosa acquisita.