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DHEA Inhibits Leukocyte Recruitment through Regulation of the Integrin Antagonist DEL-1.
- Source :
-
Journal of immunology (Baltimore, Md. : 1950) [J Immunol] 2020 Mar 01; Vol. 204 (5), pp. 1214-1224. Date of Electronic Publication: 2020 Jan 24. - Publication Year :
- 2020
-
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 β2-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/EBPβ 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/EBPβ 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.<br /> (Copyright © 2020 by The American Association of Immunologists, Inc.)
- Subjects :
- Animals
CCAAT-Enhancer-Binding Protein-beta immunology
CD18 Antigens immunology
Cell Adhesion immunology
Endothelium, Vascular immunology
Female
Gene Expression Regulation immunology
Leukocytes cytology
Mice
Phosphatidylinositol 3-Kinases immunology
Promoter Regions, Genetic immunology
Proto-Oncogene Proteins c-akt immunology
Receptor, trkA immunology
Calcium-Binding Proteins immunology
Cell Adhesion Molecules immunology
Dehydroepiandrosterone pharmacology
Leukocytes immunology
Signal Transduction immunology
Subjects
Details
- Language :
- English
- ISSN :
- 1550-6606
- Volume :
- 204
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- Journal of immunology (Baltimore, Md. : 1950)
- Publication Type :
- Academic Journal
- Accession number :
- 31980574
- Full Text :
- https://doi.org/10.4049/jimmunol.1900746