11β-Hydroxysteroid Dehydrogenase Type 1 Is Expressed in Neutrophils and Restrains an Inflammatory Response in Male Mice

Abstract

Endogenous glucocorticoid action within cells is enhanced by prereceptor metabolism by 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), which converts intrinsically inert cortisone and 11-dehydrocorticosterone into active cortisol and corticosterone, respectively. 11β-HSD1 is highly expressed in immune cells elicited to the mouse peritoneum during thioglycollate-induced peritonitis and is down-regulated as the inflammation resolves. During inflammation, 11β-HSD1-deficient mice show enhanced recruitment of inflammatory cells and delayed acquisition of macrophage phagocytic capacity. However, the key cells in which 11β-HSD1 exerts these effects remain unknown. Here we have identified neutrophils (CD11b+,Ly6G+,7/4+ cells) as the thioglycollate-recruited cells that most highly express 11β-HSD1 and show dynamic regulation of 11β-HSD1 in these cells during an inflammatory response. Flow cytometry showed high expression of 11β-HSD1 in peritoneal neutrophils early during inflammation, declining at later states. In contrast, expression in blood neutrophils continued to increase during inflammation. Ablation of monocytes/macrophages by treatment of CD11b-diphtheria-toxin receptor transgenic mice with diphtheria toxin prior to thioglycollate injection had no significant effect on 11β-HSD1 activity in peritoneal cells, consistent with neutrophils being the predominant 11β-HSD1 expressing cell type at this time. Similar to genetic deficiency in 11β-HSD1, acute inhibition of 11β-HSD1 activity during thioglycollate-induced peritonitis augmented inflammatory cell recruitment to the peritoneum. These data suggest that neutrophil 11β-HSD1 increases during inflammation to contribute to the restraining effect of glucocorticoids upon neutrophil-mediated inflammation. In human neutrophils, lipopolysaccharide activation increased 11β-HSD1 expression, suggesting the antiinflammatory effects of 11β-HSD1 in neutrophils may be conserved in humans.

Cellular and genetic models of H6PDH and 11β‐HSD1 function in skeletal muscle

“…We propose that, in a stable system and at any one time, the rate of functional 11β‐HSD1 accumulated from unrecombined alleles is greater than the rate of clearance through proteasomal degradation, and so the tissue can essentially retain WT levels of activity. In support of this, previous reports have suggested a long protein half‐life for 11β‐HSD1 leading to persistence of protein, and thus enzyme activity, in a range of cell types and models using similar genetic knockout or knockdown strategies . However, this remains to be formally tested in the context of HSD1MKO mice.…”

“…In support of this, previous reports have suggested a long protein half-life for 11β-HSD1 leading to persistence of protein, and thus enzyme activity, in a range of cell types and models using similar genetic knockout or knockdown strategies. [24][25][26] However, this remains to be formally tested in the context of mice. E, Generation of NADPH from NADP by H6PDH in microsomes isolated from H6MKO muscle.…”

Imbalanced cortisol concentrations in glycogen storage disease type I: evidence for a possible link between endocrine regulation and metabolic derangement

“…In GSDIb the lack of G6P in ER has been associated to decreased 11βHSD1 activity [2]. 11βHSD1 is widely expressed in immune cells [31]. 11βHSD1 expression has been associated with a switch in energy metabolism suggesting that 11βHSD1 deficiency might worsen tissue damage in the case of chronic inflammation [32,33].…”

Getting to the heart of intracellular glucocorticoid regeneration: 11β-HSD1 in the myocardium

“…3). This results at least in part from loss of 11β-HSD1 in neutrophils themselves, where its activity restrains recruitment to inflamed tissues through modulation of adhesion molecule availability at the cell surface (Cavalcanti et al 2006, Tiganescu et al 2011, Coutinho et al 2016). Loss of 11β-HSD1 activity in the heart itself is also likely to contribute.…”