IL17A Blockade with Ixekizumab Suppresses MuvB Signaling in Clinical Psoriasis.

Autor:	Ochsner SA; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, USA; Department of Medicine, Baylor College of Medicine, Houston, Texas, USA., Pedroza M; Department of Medicine, Baylor College of Medicine, Houston, Texas, USA., Pillich RT; Department of Medicine, University of California San Diego, California, USA., Krishnan V; Eli Lilly and Company, Indianapolis, Indiana, USA., Konicek BW; Eli Lilly and Company, Indianapolis, Indiana, USA., Dow ER; Eli Lilly and Company, Indianapolis, Indiana, USA., Park SY; Eli Lilly and Company, Indianapolis, Indiana, USA., Agarwal SK; Department of Medicine, Baylor College of Medicine, Houston, Texas, USA., McKenna NJ; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, USA. Electronic address: nmckenna@bcm.edu.
Jazyk:	angličtina
Zdroj:	The Journal of investigative dermatology [J Invest Dermatol] 2023 Sep; Vol. 143 (9), pp. 1689-1699. Date of Electronic Publication: 2023 Mar 24.
DOI:	10.1016/j.jid.2023.03.1658
Abstrakt:	Unbiased informatics approaches have the potential to generate insights into uncharacterized signaling pathways in human disease. In this study, we generated longitudinal transcriptomic profiles of plaque psoriasis lesions from patients enrolled in a clinical trial of the anti-IL17A antibody ixekizumab (IXE). This dataset was then computed against a curated matrix of over 700 million data points derived from published psoriasis and signaling node perturbation transcriptomic and chromatin immunoprecipitation-sequencing datasets. We observed substantive enrichment within both psoriasis-induced and IXE-repressed gene sets of transcriptional targets of members of the MuvB complex, a master regulator of the mitotic cell cycle. These gene sets were similarly enriched for pathways involved in the regulation of the G2/M transition of the cell cycle. Moreover, transcriptional targets for MuvB nodes were strongly enriched within IXE-repressed genes whose expression levels correlated strongly with the extent and severity of the psoriatic disease. In models of human keratinocyte proliferation, genes encoding MuvB nodes were transcriptionally repressed by IXE, and depletion of MuvB nodes reduced cell proliferation. Finally, we made the expression and regulatory networks that supported this study available as a freely accessible, cloud-based hypothesis generation platform. Our study positions inhibition of MuvB signaling as an important determinant of the therapeutic impact of IXE in psoriasis. (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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