Year: 2020
Type: article
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.
Source: The Journal of Immunology
Institutions: University Hospital Carl Gustav Carus, Technische Universität Dresden, Niigata University, University of Pennsylvania, Institut für Chirurgische Forschung, Institut für Kardiovaskuläre Physiologie und Pathophysiologie, Ludwig-Maximilians-Universität München, The Queen's Medical Research Institute, University of Edinburgh
Language: English
Subfield: Immunology and Allergy
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
Awards: G102452286, G1666510090, G1753370800, G1803204493, Therapeutic strategies against inflammation and bone loss associated with Del-1 production, P. gingivalis as a keystone pathogen, G2129814137, Del-1: Molecular and Cellular Targets in Periodontitis, Challenges to the identification of neutrophil subsets involved in the development and remission of inflammation, Neutrophil homeostasis and periodontitis: Novel concepts and treatments, G434337789, Integrated understanding of Del-1 functions on osteobiology and Inflammation, G7010675113, G7056168477, A European training network for the discovery of neurotrophins small molecule mimetics as candidate therapeutic agents for neurodegeneration and neuroinflammation, Local endogenous regulators of functional immune plasticity in the periodontium
OpenAlex ID: W3000776202