The Syk Inhibitor Entospletinib Abolishes Dermal-Epidermal Separation in a Fully Human Ex Vivo Model of Bullous Pemphigoid.

Autor:	Vikár S; Department of Physiology, Faculty of Medicine, Semmelweis University, Budapest, Hungary., Szilveszter KP; Department of Physiology, Faculty of Medicine, Semmelweis University, Budapest, Hungary., Koszorú K; Department of Dermatology, Venereology and Dermatooncology, Faculty of Medicine, Semmelweis University, Budapest, Hungary., Sárdy M; Department of Dermatology, Venereology and Dermatooncology, Faculty of Medicine, Semmelweis University, Budapest, Hungary., Mócsai A; Department of Physiology, Faculty of Medicine, Semmelweis University, Budapest, Hungary; HUN-REN-SU Inflammation Physiology Research Group, Hungarian Research Network, Semmelweis University, Budapest, Hungary. Electronic address: mocsai.attila@semmelweis.hu.
Jazyk:	angličtina
Zdroj:	The Journal of investigative dermatology [J Invest Dermatol] 2024 Aug; Vol. 144 (8), pp. 1733-1742. Date of Electronic Publication: 2024 Jan 29.
DOI:	10.1016/j.jid.2024.01.009
Abstrakt:	Bullous pemphigoid (BP) is an autoantibody-mediated blistering skin disease characterized by local inflammation and dermal-epidermal separation, with no approved targeted therapy. The Syk tyrosine kinase is critical for various functions of the immune response. Second-generation Syk inhibitors such as entospletinib are currently being tested for hematological malignancies. Our aim was to test the effect of entospletinib in a fully human model system of BP. Incubating BP serum-treated human frozen skin sections with normal human granulocytes and fresh plasma triggered dermal-epidermal separation that was dependent on complement, NADPH oxidase, and protease activity. Entospletinib dramatically reduced dermal-epidermal separation with a half-maximal inhibitory concentration of ≈16 nM. Entospletinib also reduced ROS production, granule release, and spreading of human granulocytes plated on immobilized immune complexes consisting either of a generic antigen-antibody pair or of recombinant collagen type XVII (BPAg2) and BP serum components (supposedly autoantibodies). However, entospletinib did not affect the chemotactic migration of human granulocytes or their responses to nonphysiological stimulation by phorbol esters. Entospletinib had no effect on the survival of granulocytes either. Taken together, entospletinib abrogates dermal-epidermal separation, likely through inhibition of granulocyte responsiveness to deposited immune complexes. Entospletinib or other Syk inhibitors may provide therapeutic benefits in BP. (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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