DHEA Inhibits Leukocyte Recruitment through Regulation of the Integrin Antagonist DEL-1
| Autor: | Tomoki Maekawa, Kyoung-Jin Chung, Sylvia Grossklaus, Triantafyllos Chavakis, Ales Neuwirth, David Sprott, Vasiliki Anastasopoulou, Markus Sperandio, George Hajishengallis, Johannes R. Wiessner, Vasileia Ismini Alexaki, Maria Troullinaki, Athanasios Ziogas, Thi Trang Le |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
medicine.medical_specialty
Endothelium medicine.medical_treatment Immunology Dehydroepiandrosterone Inflammation Immune Regulation 03 medical and health sciences Mice Phosphatidylinositol 3-Kinases 0302 clinical medicine Downregulation and upregulation Internal medicine medicine Cell Adhesion Leukocytes Immunology and Allergy Animals Receptor trkA Promoter Regions Genetic Protein kinase B PI3K/AKT/mTOR pathway 030304 developmental biology 0303 health sciences Chemistry CCAAT-Enhancer-Binding Protein-beta Calcium-Binding Proteins Steroid hormone Endocrinology medicine.anatomical_structure Gene Expression Regulation CD18 Antigens Tumor necrosis factor alpha Female Endothelium Vascular medicine.symptom Cell Adhesion Molecules Proto-Oncogene Proteins c-akt 030217 neurology & neurosurgery hormones hormone substitutes and hormone antagonists Signal Transduction |
| Zdroj: | The Journal of Immunology |
| ISSN: | 0022-1767 |
| DOI: | 10.4049/jimmunol.1900746 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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