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-Hydroxysteroid Dehydrogenase Type 1 Promotes Macrophage Phagocytosis of Apoptotic Leukocytes1
* Endocrinology Unit, Centre for Cardiovascular Sciences,
Medical Research Council Centre for Inflammation Research, and
Molecular Physiology Laboratory, Centre for Cardiovascular Sciences, The Queen’s Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom
Glucocorticoids promote macrophage phagocytosis of leukocytes undergoing apoptosis. Prereceptor metabolism of glucocorticoids by 11
-hydroxysteroid dehydrogenases (11-HSDs) modulates cellular steroid action. 11-HSD type 1 amplifies intracellular levels of active glucocorticoids in mice by reactivating corticosterone from inert 11-dehydrocorticosterone in cells expressing the enzyme. In this study we describe the rapid (within 3 h) induction of 11-HSD activity in cells elicited in the peritoneum by a single thioglycolate injection in mice. Levels remained high in peritoneal cells until resolution. In vitro experiments on mouse macrophages demonstrated that treatment with inert 11-dehydrocorticosterone for 24 h increased phagocytosis of apoptotic neutrophils to the same extent as corticosterone. This effect was dependent upon 11-HSD1, as 11-HSD1 mRNA, but not 11-HSD2 mRNA, was expressed in these cells; 11-dehydrocorticosterone was ineffective in promoting phagocytosis by Hsd11b1–/– macrophages, and carbenoxolone, an 11-HSD inhibitor, prevented the increase in phagocytosis elicited in wild-type macrophages by 11-dehydrocorticosterone. Importantly, as experimental peritonitis progressed, clearance of apoptotic neutrophils was delayed in Hsd11b1–/– mice. These data point to an early role for 11-HSD1 in promoting the rapid clearance of apoptotic cells during the resolution of inflammation and indicate a novel target for therapy.
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