Macrophages are key immune cells in mediating both the acute inflammatory phase and the repair phase after tissue damage. Macrophages switch from pro-inflammatory to anti-inflammatory cells that sustain tissue repair and return to homeostasis. We show that the metabolic sensor, AMP-activated protein kinase (AMPK) is essential for glucocorticoid induction of an anti-inflammatory macrophage phenotype. While canonical gene regulation by glucocorticoids was not affected by loss of AMPK, we identified glucocorticoid-regulated genes in macrophages, which are dependent on AMPK expression and related to efferocytosis. AMPK-deficient macrophages do not acquire the phenotypic and functional anti-inflammatory features upon glucocorticoid exposure. Loss of AMPK in macrophages in vivo abrogates glucocorticoid anti-inflammatory actions in both sterile muscle damage and endotoxin induced acute lung injury. These data highlight that the glucocorticoid receptor is dependent on AMPK for its immune modulatory actions in macrophages, linking their metabolic status to transcriptional control in operating the resolution of inflammation.

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