Abstract
11β-Hydroxysteroid dehydrogenase-1 (11β-HSD1) predominantly converts inert glucocorticoids into active forms, thereby contributing to intracellular glucocorticoid levels. 11β-HSD1 is dynamically regulated during inflammation, including in macrophages where it regulates phagocytic capacity. The resolution of inflammation in some disease models including inflammatory arthritis is impaired by 11β-HSD1 deficiency or inhibition. However, 11β-HSD1 deficiency/inhibition also promotes angiogenesis, which is beneficial in mouse models of surgical wound healing, myocardial infarction or obesity. The cell types responsible for the anti-inflammatory and anti-angiogenic roles of 11β-HSD1 have not been characterised. Here, we generated Hsd11b1MKO mice with LysM-Cre mediated deletion of Hsd11b1 to investigate whether 11β-HSD1 deficiency in myeloid phagocytes is pro-angiogenic and/or affects the resolution of inflammation. Resolution of inflammatory K/BxN-induced arthritis was impaired in Hsd11b1MKO mice to a similar extent as in mice globally deficient in 11β-HSD1. This was associated with >2-fold elevation in levels of the endothelial marker Cdh5 mRNA, suggesting increased angiogenesis in joints of Hsd11b1MKO mice following arthritis. A pro-angiogenic phenotype was confirmed by measuring angiogenesis in subcutaneously implanted polyurethane sponges, in which Hsd11b1MKO mice showed 20% greater vessel density than their littermate controls, associated with higher expression of Cdh5. Thus, 11β-HSD1 deficiency in myeloid phagocytes promotes angiogenesis. Targeting 11β-HSD1 in macrophages may be beneficial in tissue repair.
Highlights
Glucocorticoids exert anti-inflammatory effects both in vivo and in vitro
These data suggest that the protein half-life of 11β-HSD1 exceeds the halflife of the thioglycollate-elicited monocyte/macrophage and neutrophil populations, but that 11β-HSD1 activity is markedly reduced in the longer-lived resident http://joe.endocrinology-journals.org
Our data in Hsd11b1MKO mice demonstrate that macrophages are a key cell type responsible for the proangiogenic phenotype conferred by 11β-HSD1 deficiency
Summary
Glucocorticoids exert anti-inflammatory effects both in vivo and in vitro. Whilst the potent effects of synthetic glucocorticoids have been widely exploited clinically to treat inflammatory disease, including rheumatoid arthritis, the role of endogenous corticosteroids in regulating inflammation is less well understood (Coutinho & Chapman 2011).macrophages have emerged as a key target for the anti-inflammatory and immunomodulatory effects of endogenous glucocorticoids (Bhattacharyya et al 2007, Tuckermann et al 2007). Glucocorticoids exert anti-inflammatory effects both in vivo and in vitro. Whilst the potent effects of synthetic glucocorticoids have been widely exploited clinically to treat inflammatory disease, including rheumatoid arthritis, the role of endogenous corticosteroids in regulating inflammation is less well understood (Coutinho & Chapman 2011). Macrophages have emerged as a key target for the anti-inflammatory and immunomodulatory effects of endogenous glucocorticoids (Bhattacharyya et al 2007, Tuckermann et al 2007). Macrophages are important in the excessive or dysregulated angiogenesis that contributes to the pathogenesis of many chronic inflammatory diseases, a maladaptive response in rheumatoid arthritis (Jackson et al 1997, Koch 1998)
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