Timing of Glucocorticoid Treatment Dictates Glucocorticoid Receptor Actions Modulating the NLRP3-Inflammasome...

Glucocorticoids (GCs) are lifesaving medicines prescribed to treat inflammatory diseases. Macrophages play a pivotal role during hyperinflammation and cytokine storm, two processes intricately linked to NLRP3 inflammasome activation. Macrophages undergo a process of transcriptional reprogramming to resolve inflammation and restore homeostasis. We hypothesized that glucocorticoid receptor (GR) signaling contributes to macrophage metabolic reprogramming to overcome the NLRP3-inflammasome activation through genomic effects induced by GCs. Glucocorticoid administration following prolonged exposure to lipopolysaccharide (LPS) decreases the expression of iNOS and ACOD1 and their respective metabolic products, nitric oxide and itaconate, to maintain an intact tricarboxylic acid (TCA) cycle in WT mouse pro-inflammatory macrophages. Glucocorticoids also antagonize the LPS-induced glycolytic switch through their regulation of mitochondrial dynamics. In addition, we show that glucocorticoids inhibit NLRP3 inflammasome activation and subsequent pyroptosis following extended LPS priming. These suppressive glucocorticoid actions were associated with a marked expansion in the GR cistrome following LPS-mediated changes in the chromatin landscape. The glucocorticoid inhibition of the late NLRP3 inflammasome activation also was preserved in human monocyte-derived macrophages. The glucocorticoid effects were attenuated when LPS and glucocorticoids were added together, and they were largely absent in myeloid-GR knockout mice. This study, employing a glucocorticoid treatment regimen with clinically relevant timing, suggests an underlying metabolic mechanism by which glucocorticoids preserve the integrity of the TCA cycle and inhibit the glycolytic switch induced by LPS. The glucocorticoid regulation precedes the second signal for the NLRP3 inflammasome activation to strategically prevent hyperinflammation and pyroptosis in macrophages.