Phospholipase Cγ2 Is Essential for Experimental Models of Epidermolysis Bullosa Acquisita

Phospholipase C gamma 2 (PLC gamma 2) mediates tyrosine kinase-coupled receptor signaling in various hematopoietic lineages. Although PLC gamma 2 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 PLC gamma 2 in a mouse model of epidermolysis bullosa acquisita triggered by antibodies against type VII collagen (C7), a component of the dermo-epidermal junction. PLC gamma 2-deficient (Plcg2(-/-)) mice and bone marrow chimeras with a Plcg2(-/-) hematopoietic 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. PLC gamma 2 was required for the tissue infiltration of neutrophils, eosinophils, and monocytes/macrophages as well as for the accumulation of proinflammatory mediators (including IL-1 beta, MIP-2, and LTB4) and reactive oxygen species. Mechanistic experiments revealed a role for PLC gamma 2 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 PLC gamma 2 in the pathogenesis of the inflammatory form of epidermolysis bullosa acquisita.

Automated summary

Phospholipase C gamma 2 (PLC gamma 2) plays a critical role in the pathogenesis of inflammatory epidermolysis bullosa acquisita by regulating the tissue infiltration of immune cells and the release of proinflammatory mediators.