Endocrine Abstracts

Chronic inflammatory disease is often accompanied by angiogenesis and fibrosis. Glucocorticoids (GCs) exert anti-inflammatory and anti-angiogenic effects, in which macrophages are a major target. Local endogenous GC action is controlled by 11β-hydroxysteroid dehydrogenase (11β-HSD), with the type 1 isozyme, 11β-HSD1 converting inactive GCs into active forms. Mice deficient in 11β-HSD1 have a phenotype consistent with reduced glucocorticoid action, including increased angiogenesis and more severe acute inflammation.

To elucidate the role of 11β-HSD1 in macrophages, MKO mice with conditional disruption of 11β-HSD1 in macrophages were generated by crossing LysM-Cre with Hsd11b1^flox/flox mice. Cre-negative littermates were controls. 11β-HSD1 reductase activity was reduced by 82% in resident peritoneal macrophages of MKO mice.

To investigate angiogenesis, sponge implants were inserted subcutaneously into each flank of adult male mice and harvested after 21 d. Chalkley counting on H&E stained sponge sections showed significantly increased angiogenesis in MKO mice (score: 5.2±1.0 vs 4.3±0.7; P<0.05, n=9–11). Cdh5 expression (encoding VE-cadherin) was higher in sponges from MKO mice (relative expression: 1.5±0.9 vs 0.8±0.6; –P<0.05), as was Il1b (relative expression: 6.5±6.4 vs 1.5±0.9; P<0.05). Vegfa mRNA was unchanged.

Inflammation was investigated following i.p. injection of 125 μl K/BxN serum to induce arthritis. Onset of inflammation (d1-8) was similar to controls (n=6–7). MKO mice exhibited greater clinical inflammation scores in the resolution phase of arthritis (d13–21; area under the curve: 86.6±14.7 vs 60.1±13.4; P<0.005), indistinguishable from global 11β-HSD1-deficient mice. H&E staining revealed pronounced fibroplasia predominantly in the supporting mesenchyme associated with the tenosynovium.

These data suggest that intracellular regeneration of active glucocorticoids by 11β-HSD1 in macrophages is crucial to promote resolution of inflammation and limit fibro-proliferation. Moreover, macrophage 11β-HSD1 contributes to the anti-angiogenic effects of endogenous glucocorticoids. Targeted delivery of inactive glucocorticoid precursors to macrophages may be of benefit in chronic joint inflammatory disease.

Declaration of funding

This work was supported by the Medical Research Council project grant (G0800235) and Welcome Trust Programme (WT083184) grant Z Zhang is a student sponsored by China Scholarships Council/University of Edinburgh Scholarships.