TYROSINE KINASE SIGNALING PATHWAYS IN EXPERIMENTAL AUTOIMMUNE SKIN BLISTERING MODELS
Szilveszter Kata Petra
Molecular Medicine
Dr. Enyedi Péter
SE Élettani Intézet könyvtára
2023-06-12 12:00:00
Cellular and Molecular Physiology
Dr. Hunyady László
Dr. Mócsai Attila
Dr. Ruisanchez Éva
Ralf Ludwig
Dr. Bödör Csaba
Dr. Manczinger Máté
Dr. Gyöngyösi Norbert
Subepidermal autoimmune blistering skin diseases are often severe and treatment-resistant disorders. They are characterized by autoantibody formation against components of the dermal-epidermal junction (DEJ), leading to blister formation. Such conditions exert serious impact on the quality of life, without an available effective targeted therapy. Elucidation of the molecular mechanisms driving autoantibody-induced pathology and the identification of targetable pathways are particularly important. Therefore, we aimed to characterize the role of phospholipase Cγ2 (PLCγ2), an enzyme involved in immunoreceptor signaling, and in less detail Janus kinases in the development of autoantibody-induced skin blistering.
Plcg2–/– mice, as well as chimeras with Plcg2–/– hematopoietic system remained completely protected from autoantibody-induced skin blistering. Disease was induced by the passive transfer of anti-C7 antibodies recognizing the crucial DEJ component collagen type VII. PLCγ2 deficiency prevented dermal-epidermal separation and the infiltration of multiple myeloid cells including neutrophils to the skin, without affecting autoantibody deposition. The intrinsic migratory capacity of myeloid cells remained intact in Plcg2–/– mice, but in vivo accumulation of proinflammatory mediators, as well as the in vivo production of reactive oxygen species were completely blocked in the absence of PLCγ2. In vitro C7/anti-C7 immune complex-induced release of proinflammatory mediators from neutrophils was also dependent on PLCγ2. Moreover, neutrophil-specific deletion of PLCγ2 strongly diminished macroscopic and microscopic signs of anti-C7-induced skin blistering in vivo. Underlining the human relevance of our studies, we demonstrated that pharmacological inhibition of PLC enzymes was able to inhibit dermal-epidermal separation in an ex vivo human skin separation assay.
Pharmacological inhibition of Janus kinases by tofacitinib also dose-dependently reduced macroscopic signs of anti-C7-induced skin blistering in mice.
Our results identify PLCγ2 as a critical component of anti-C7-induced skin blistering. PLCγ2, in particular when expressed in neutrophils, is supposedly involved in creating the proinflammatory milieu after autoantibody deposition in the skin. Our results also suggests that Janus kinases also have an important role in the development of this model.
