Role of the soluble epoxide hydrolase in keratinocyte proliferation and sensitivity of skin to inflammatory stimuli.

Autor: Naeem Z; Institute for Vascular Signalling, Centre for Molecular Medicine, Goethe University, Frankfurt am Main, Germany., Zukunft S; Institute for Vascular Signalling, Centre for Molecular Medicine, Goethe University, Frankfurt am Main, Germany., Huard A; Institute of Biochemistry I, Goethe-University Frankfurt, Frankfurt am Main 60590, Germany., Hu J; Institute for Vascular Signalling, Centre for Molecular Medicine, Goethe University, Frankfurt am Main, Germany; Department of Embryology and Histology, School of Basic Medicine, Tongi Medical College, Huazhong University of Science and Technology, Wuhan, China., Hammock BD; Department of Entomology and Nematology and Comprehensive Cancer Center, University of California, Davis, CA, USA., Weigert A; Institute of Biochemistry I, Goethe-University Frankfurt, Frankfurt am Main 60590, Germany., Frömel T; Institute for Vascular Signalling, Centre for Molecular Medicine, Goethe University, Frankfurt am Main, Germany., Fleming I; Institute for Vascular Signalling, Centre for Molecular Medicine, Goethe University, Frankfurt am Main, Germany; German Center of Cardiovascular Research (DZHK), Partner site RheinMain, Frankfurt am Main, Germany; CardioPulmonary Institute, Goethe University, Frankfurt am Main, Germany. Electronic address: fleming@em.uni-frankfurt.de.
Jazyk: angličtina
Zdroj: Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie [Biomed Pharmacother] 2024 Feb; Vol. 171, pp. 116127. Date of Electronic Publication: 2024 Jan 09.
DOI: 10.1016/j.biopha.2024.116127
Abstrakt: The lipid content of skin plays a determinant role in its barrier function with a particularly important role attributed to linoleic acid and its derivatives. Here we explored the consequences of interfering with the soluble epoxide hydrolase (sEH) on skin homeostasis. sEH; which converts fatty acid epoxides generated by cytochrome P450 enzymes to their corresponding diols, was largely restricted to the epidermis which was enriched in sEH-generated diols. Global deletion of the sEH increased levels of epoxides, including the linoleic acid-derived epoxide; 12,13-epoxyoctadecenoic acid (12,13-EpOME), and increased basal keratinocyte proliferation. sEH deletion (sEH -/- mice) resulted in thicker differentiated spinous and corneocyte layers compared to wild-type mice, a hyperkeratosis phenotype that was reproduced in wild-type mice treated with a sEH inhibitor. sEH deletion made the skin sensitive to inflammation and sEH -/- mice developed thicker imiquimod-induced psoriasis plaques than the control group and were more prone to inflammation triggered by mechanical stress with pronounced infiltration and activation of neutrophils as well as vascular leak and increased 12,13-EpOME and leukotriene (LT) B4 levels. Topical treatment of LTB4 antagonist after stripping successfully inhibited inflammation and neutrophil infiltration both in wild type and sEH -/- skin. While 12,13-EpoME had no effect on the trans-endothelial migration of neutrophils, like LTB4, it effectively induced neutrophil adhesion and activation. These observations indicate that while the increased accumulation of neutrophils in sEH-deficient skin could be attributed to the increase in LTB4 levels, both 12,13-EpOME and LTB4 contribute to neutrophil activation. Our observations identify a protective role of the sEH in the skin and should be taken into account when designing future clinical trials with sEH inhibitors.
Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Ingrid Fleming reports financial support was provided by Deutsche Forschungsgemeinschaft (SFB1039 B6 - project ID 204083920). Ingrid Fleming reports a relationship with Deutsche Forschungsgemeinschaft (GRK 2336 TP5 - Project ID 321115009) that includes: funding grants.
(Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)
Databáze: MEDLINE
Externí odkaz: