DHEA Inhibits Leukocyte Recruitment through Regulation of the Integrin Antagonist DEL-1

Ziogas, Athanasios; Maekawa, Tomoki; Wiessner, Johannes R.; Thi, Trang Le; Sprott, David; Troullinaki, Maria; Neuwirth, Ales; Anastasopoulou, Vasiliki; Grossklaus, Sylvia; Chung, Kyoung-Jin; Sperandio, Markus; Chavakis, Triantafyllos; Hajishengallis, George und Alexaki, Vasileia Ismini (2020): DHEA Inhibits Leukocyte Recruitment through Regulation of the Integrin Antagonist DEL-1. In: Journal of Immunology, Bd. 204, Nr. 5: S. 1214-1224

Abstract

Leukocytes are rapidly recruited to sites of inflammation via interactions with the vascular endothelium. The steroid hormone dehydroepiandrosterone (DHEA) exerts anti-inflammatory properties;however, the underlying mechanisms are poorly understood. In this study, we show that an anti-inflammatory mechanism of DHEA involves the regulation of developmental endothelial locus 1 (DEL-1) expression. DEL-1 is a secreted homeostatic factor that inhibits beta 2-integrin-dependent leukocyte adhesion, and the subsequent leukocyte recruitment and its expression is downregulated upon inflammation. Similarly, DHEA inhibited leukocyte adhesion to the endothelium in venules of the inflamed mouse cremaster muscle. Importantly, in a model of lung inflammation, DHEA limited neutrophil recruitment in a DEL-1-dependent manner. Mechanistically, DHEA counteracted the inhibitory effect of inflammation on DEL-1 expression. Indeed, whereas TNF reduced DEL-1 expression and secretion in endothelial cells by diminishing C/EBP beta binding to the DEL-1 gene promoter, DHEA counteracted the inhibitory effect of TNF via activation of tropomyosin receptor kinase A (TRKA) and downstream PI3K/AKT signaling that restored C/EBP beta binding to the DEL-1 promoter. In conclusion, DHEA restrains neutrophil recruitment by reversing inflammation-induced downregulation of DEL-1 expression. Therefore, the anti-inflammatory DHEA/DEL-1 axis could be harnessed therapeutically in the context of inflammatory diseases.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• ISSN: 0022-1767
• Sprache: Englisch