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Macrophages are key cells after tissue damage since they mediate both acute inflammatory phase and regenerative inflammation by shifting from pro‐inflammatory to restorative cells. Glucocorticoids (GCs) are the most potent anti‐inflammatory hormone in clinical use, still their actions on macrophages are not fully understood. We show that the metabolic sensor AMP‐activated protein kinase (AMPK) is required for GCs to induce restorative macrophages. GC Dexamethasone activates AMPK in macrophages and GC receptor (GR) phosphorylation is decreased in AMPK‐deficient macrophages. Loss of AMPK in macrophages abrogates the GC‐induced acquisition of their repair phenotype and impairs GC‐induced resolution of inflammation in vivo during post‐injury muscle regeneration and acute lung injury. Mechanistically, two categories of genes are impacted by GC treatment in macrophages. Firstly, canonical cytokine regulation by GCs is not affected by AMPK loss. Secondly, AMPK‐dependent GC‐induced genes required for the phenotypic transition of macrophages are co‐regulated by the transcription factor FOXO3, an AMPK substrate. Thus, beyond cytokine regulation, GR requires AMPK‐FOXO3 for immunomodulatory actions in macrophages, linking their metabolic status to transcriptional control in regenerative inflammation.

Mutations of the postsynaptic scaffold protein Shank2 lead to autism spectrum disorders (ASD). These patients frequently suffer from higher fracture risk. Here, we investigated whether Shank2 directly regulates bone mass. We show that Shank2 is expressed in bone and that Shank2 levels are increased during osteoblastogenesis. Knockdown of Shank2 by siRNA targeting the encoding regions for PDZ and SAM domain inhibits osteoblastogenesis of primary murine calvarial osteoblasts. Shank2 knockout mice (Shank2 À/À ) have a decreased bone mass due to reduced osteoblastogenesis and bone formation, whereas bone resorption remains unaffected. Induced pluripotent stem cells (iPSCs)-derived osteoblasts from a loss-of-function Shank2 mutation in a patient showed a significantly reduced osteoblast differentiation potential. Moreover, silencing of known Shank2 interacting proteins revealed that a majority of them promote osteoblast differentiation. From this we conclude that Shank2 and interacting proteins known from the central nervous system are decisive regulators in osteoblast differentiation.

Insulin resistance (IR) during obesity is linked to adipose tissue macrophage (ATM)-driven inflammation of adipose tissue. Whether anti-inflammatory glucocorticoids (GCs) at physiological levels modulate IR is unclear. Here, we report that deletion of the GC receptor (GR) in myeloid cells, including macrophages in mice, aggravates obesity-related IR by enhancing adipose tissue inflammation due to decreased anti-inflammatory ATM leading to exaggerated adipose tissue lipolysis and severe hepatic steatosis. In contrast, GR deletion in Kupffer cells alone does not alter IR. Co-culture experiments show that the absence of GR in macrophages directly causes reduced phospho-AKT and glucose uptake in adipocytes, suggesting an important function of GR in ATM. GR-deficient macrophages are refractory to alternative ATM-inducing IL-4 signaling, due to reduced STAT6 chromatin loading and diminished anti-inflammatory enhancer activation. We demonstrate that GR has an important function in macrophages during obesity by limiting adipose tissue inflammation and lipolysis to promote insulin sensitivity.

Regulation of cellular catabolic metabolism in immune cells has recently become a major concept for resolution of inflammation. Nuclear receptors (NRs), including peroxisome proliferator activator receptors, 1,25‐dihydroxyvitamin D (3) receptor, liver X receptors, glucocorticoid receptors, oestrogen‐related receptor α and nuclear receptor 4A1, have been identified as major modulators of inflammation, affecting innate immune cells, such as macrophages. Evidence emerges on how NRs regulate cellular metabolism in macrophages during inflammatory processes and contribute to the resolution of inflammation. This could have new implications for our understanding of how NRs shape immune responses and inform anti‐inflammatory drug design. This review will highlight the recent developments about NRs and their role in cellular metabolism in macrophages.

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Cushing’s syndrome (CS) is a rare disease caused by excess cortisol levels with high cardiovascular morbidity and mortality. Hypertension is a frequent feature of Cushing’s syndrome, promoting hypercortisolism-associated cardiovascular events. Adipose tissue is a highly plastic tissue with most of the major cell types strongly affected in their function by the excess cortisol exposure. We hypothesized that the molecular and cellular changes of visceral adipose tissue (VAT) in response to cortisol excess can impact on systemic blood pressure levels in patients with CS. We, therefore, investigated gene expression signatures in VAT from patients with CS collected during curative adrenal surgery identifying significant alterations. During active CS we observed a strong downregulation of gene programs associated with immunity and inflammation in the VAT. In addition, we observed an clustering of the patients based on VAT gene expression profiles into two groups (CSLowand CSHigh) according to blood pressure levels. The two clusters showed significant differences in gene expression pattens of the renin-angiotensin-aldosterone-system (RAAS). Renin (REN) was the strongest regulated gene compared to control patients and its expression correlated with increased blood pressure observed in our patients while systemic renin plasma levels were suppressed indicative of an abnormal blood pressure and volume status in response to VAT RAAS activation. Here we show for the first time a relevant contribution of the local RAAS system on systemic blood pressure levels in patients with CS. Patients from the CSHighgroup had still a significant increased blood pressure levels 6 months into remission, highlighting the importance of local tissue effects on long-term systemic effects observed in CS.