Editors' ChoiceImmunology

Steroids make inflamed tissues less sticky

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Science Signaling  25 Feb 2020:
Vol. 13, Issue 620, eabb4096
DOI: 10.1126/scisignal.abb4096

The steroid hormone DHEA reduces inflammation by restoring production of the integrin antagonist DEL-1.

During inflammation, cytokines such as tumor necrosis factor (TNF) activate the vascular endothelium to promote leukocyte recruitment into the affected tissues. Leukocytes in the blood first roll along the endothelium and then undergo firm arrest, which depends on adhesive interactions between leukocyte integrins and the endothelial cell surface. The leukocytes then extravasate and migrate to the inflamed site. Ziogas et al. investigated the mechanism underlying the anti-inflammatory properties of the steroid hormone dehydroepiandrosterone (DHEA). In a mouse model of cremaster muscle inflammation, DHEA inhibited leukocyte adhesion to the endothelium, although it had no direct effects on integrin activation or the abundance of endothelial adhesion molecules. Exposure of human endothelial cells (HUVECs) to TNF reduced the mRNA and protein amounts of DEL-1, a secreted glycoprotein that blocks the β2-integrin–mediated adhesion of leukocytes to endothelial cells. Pretreatment with DHEA reversed the effect of TNF on DEL-1 production, which depended on the DHEA-mediated activation of the kinases PI3K and Akt and on the cell surface receptor tropomyosin-related kinase A (TRKA). In a mouse model of lipopolysaccharide-induced lung inflammation, pretreatment of mice with DHEA reduced the number of neutrophils recruited to the lung compared with that in vehicle-pretreated mice; however, the anti-inflammatory effect of DHEA was lost in DEL-1–deficient mice. Together, these data suggest that DHEA reduces inflammation through a TRKA-PI3K-Akt axis by restoring the expression of DEL-1, which subsequently inhibits leukocyte adhesion and recruitment to inflamed tissues. Therapeutic targeting of this pathway may help to treat inflammatory diseases.

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