The glucocorticoid receptor in monocyte-derived macrophages is critical for cardiac infarct repair and remodeling.

Cell- and tissue-specific actions of glucocorticoids are mediated by the glucocorticoid receptor. Here, we demonstrate that the glucocorticoid receptor (GR) in macrophages is essential for cardiac healing after myocardial infarction. Compared with GRflox (wild-type controls), GRLysMCre mice that lacked GR in myeloid cells showed increased acute mortality as a result of cardiac rupture. Seven days after left coronary artery ligation, GRLysMCre mice exhibited worse cardiac function and adverse remodeling associated with impaired scar formation and angiogenic response to ischemic injury. Inactivation of GR altered the functional differentiation/maturation of monocyte-derived macrophages in the infarcted myocardium. Mechanistically, CD45+/CD11b+/Ly6G-/F4/80+ macrophages isolated from GRLysMCre infarcts showed deregulation of factors that control inflammation, neovascularization, collagen degradation, and scar tissue formation. Moreover, we demonstrate that cardiac fibroblasts sorted from the ischemic myocardium of GRLysMCre mice compared with cells isolated from injured GRflox hearts displayed higher matrix metalloproteinase 2 expression, and we provide evidence that the macrophage GR regulates myofibroblast differentiation in the infarct microenvironment during the early phase of wound healing. In summary, GR signaling in macrophages, playing a crucial role in tissue-repairing mechanisms, could be a potential therapeutic target during wound healing after ischemic myocardial injury.-Galuppo, P., Vettorazzi, S., Hövelmann, J., Scholz, C.-J., Tuckermann, J. P., Bauersachs, J., Fraccarollo, D. The glucocorticoid receptor in monocyte-derived macrophages is critical for cardiac infarct repair and remodeling.

Decreased expression of the glucocorticoid receptor-GILZ pathway in Kupffer cells promotes liver inflammation in obese mice.

BACKGROUND & AIMS: Kupffer cells (KC) play a key role in the onset of inflammation in non-alcoholic steatohepatitis (NASH). The glucocorticoid receptor (GR) induces glucocorticoid-induced leucine zipper (GILZ) expression in monocytes/macrophages and is involved in several inflammatory processes. We hypothesized that the GR-GILZ axis in KC may contribute to the pathophysiology of obesity-induced liver inflammation. METHODS: By using a combination of primary cell culture, pharmacological experiments, mice deficient for the Gr specifically in macrophages and transgenic mice overexpressing Gilz in macrophages, we explored the involvement of the Gr-Gilz axis in KC in the pathophysiology of obesity-induced liver inflammation. RESULTS: Obesity was associated with a downregulation of the Gr and Gilz, and an impairment of Gilz induction by lipopolysaccharide (LPS) and dexamethasone (DEX) in KC. Inhibition of Gilz expression in isolated KC transfected with Gilz siRNA demonstrated that Gilz downregulation was sufficient to sensitize KC to LPS. Conversely, liver inflammation was decreased in obese transgenic mice specifically overexpressing Gilz in macrophages. Pharmacological inhibition of the Gr showed that impairment of Gilz induction in KC by LPS and DEX in obesity was driven by a downregulation of the Gr. In mice specifically deficient for Gr in macrophages, Gilz expression was low, leading to an exacerbation of obesity-induced liver inflammation. CONCLUSIONS: Obesity is associated with a downregulation of the Gr-Gilz axis in KC, which promotes liver inflammation. The Gr-Gilz axis in KC is an important target for the regulation of liver inflammation in obesity.

ACTH controls thymocyte homeostasis independent of glucocorticoids.

It has been known for decades that lowering the circulating glucocorticoid (GC) concentration as in Addison's disease or after removing the adrenals results in thymus enlargement, largely due to thymocyte expansion. This has been attributed to the loss of the proapoptotic effects on thymocytes by adrenal GCs. Here, we test this concept and report that ACTH directly controls thymic growth post-adrenalectomy (ADX) independent of the proapoptotic effect of GCs. This was supported by the finding that ADX caused thymus enlargement and a 1.7-fold (P < 0.001) increase in thymocyte number in GR(LckCre) mice resistant to GC-induced thymocyte apoptosis, similar to the increase seen in wild-type mice (2.2-fold; P < 0.01). We show by immunostaining that melanocortin receptor subtype 2, which selectively binds ACTH, is partly expressed on the thymic epithelium. Furthermore, ACTH in comparison to vehicle induced a 2.0-fold (P < 0.01) increase in fetal thymic organ culture thymocyte numbers in vitro and enhanced 2.2-fold (P < 0.05) the expression of delta-like ligand 4, a factor that supports T-cell development. Additionally, adrenalectomized GR(LckCre) mice treated with ACTH under conditions that repressed endogenous ACTH secretion showed increased thymocyte cellularity (1.9-fold; P < 0.01) and splenic naive T-cell numbers (2.5-fold; P < 0.001) compared to when treated with PBS. Altogether, our results show that ACTH directly controls thymocyte homeostasis independent of GCs. These results revise the old paradigm behind compensatory thymus growth following ADX, now demonstrating that ACTH has a central role in regulating thymocyte expansion when systemic GC concentration is low.

PPARß/δ governs Wnt signaling and bone turnover.

Peroxisome proliferator-activated receptors (PPARs) act as metabolic sensors and central regulators of fat and glucose homeostasis. Furthermore, PPARγ has been implicated as major catabolic regulator of bone mass in mice and humans. However, a potential involvement of other PPAR subtypes in the regulation of bone homeostasis has remained elusive. Here we report a previously unrecognized role of PPARß/δ as a key regulator of bone turnover and the crosstalk between osteoblasts and osteoclasts. In contrast to activation of PPARγ, activation of PPARß/δ amplified Wnt-dependent and ß-catenin-dependent signaling and gene expression in osteoblasts, resulting in increased expression of osteoprotegerin (OPG) and attenuation of osteoblast-mediated osteoclastogenesis. Accordingly, PPARß/δ-deficient mice had lower Wnt signaling activity, lower serum concentrations of OPG, higher numbers of osteoclasts and osteopenia. Pharmacological activation of PPARß/δ in a mouse model of postmenopausal osteoporosis led to normalization of the altered ratio of tumor necrosis factor superfamily, member 11 (RANKL, also called TNFSF11) to OPG, a rebalancing of bone turnover and the restoration of normal bone density. Our findings identify PPARß/δ as a promising target for an alternative approach in the treatment of osteoporosis and related diseases.

Calgranulins S100A8 and S100A9 are negatively regulated by glucocorticoids in a c-Fos-dependent manner and overexpressed throughout skin carcinogenesis.

The two calgranulins S100A8 and S100A9 were found to be differentially expressed at sites of acute and chronic inflammation. Here we have employed the phorbol ester-induced multistage skin carcinogenesis protocol in mice to determine the expression of both genes in inflamed skin and in skin tumors. We show that expression is coordinately induced by the phorbol ester TPA in epithelial cells as well as infiltrating leukocytes. By comparing S100A8 and S100A9 mRNA levels in wild type and c-Fos deficient mice (c-fos(-/-)) we found that expression is negatively regulated by c-Fos/AP-1. Glucocorticoids, which exhibit potent anti-inflammatory and anti-tumor promoting activities repressed TPA-mediated S100A8 and S100A9 induction in wild type, but not in c-fos(-/-) mice, thus identifying both genes as the first examples of AP-1 target genes whose repression of TPA-induced transcription by glucocorticoids depends on c-Fos. Finally, we show that enhanced expression is not restricted to the initial TPA-induced inflammatory response but is observed at all stages of skin carcinogenesis. These data identify S100A8 and S100A9 as novel, tumor-associated genes and may point to an as yet unrecognized function of both genes in the development of epithelial skin tumors.