Glucocorticoid receptor dysfunction orchestrates inflammasome effects on chronic obstructive pulmonary...

Depression is highly prevalent among patients with chronic obstructive pulmonary disease (COPD). However, depression with COPD comorbidity is often underdiagnosed and undertreated, and pathogenic research is also insufficient. In the present study, we characterised pulmonary and hippocampal dysfunction by researching the interaction between inflammasome-regulated cytokines and glucocorticoid receptor (GR) signalling by investigating the role of fluoxetine (FLU), one of the most widely used antidepressants in clinical practice. Mice were exposed to cigarette smoke (CS) to induce the model of COPD with comorbid depression, and pathological alterations in serum, hippocampus, lung, and bronchoalveolar lavage fluid were determined. Our results showed that the CS procedure induced the accumulation of inflammatory cells (macrophages, neutrophils, and lymphocytes), the production of cytokines, the activation of inflammasome components (NLRP3, ASC, caspase-1), depression-related behaviours, and the stimulation of GR signalling. Intriguingly, glucocorticoid resistance occurred in CS-exposed mice, with elevated serum corticosterone and suppressed hippocampal GR levels, which suggested a novel potential regulatory mechanism underlying COPD-induced depression comorbidity. Furthermore, chronic CS exposure decreased the pGR-S211/pGR-S226 ratio, increased the active nuclear GR, and impaired cytosolic GR binding capacity and GR transcriptional activity, which might be responsible for the activation of the inflammasome-induced inflammatory cascade. These alterations were reversed by chronic FLU treatment, indicating that FLU-mediated GR signalling was involved in the COPD induced inflammasome activation. Our research explored the underlying molecular mechanism of comorbid COPD/depression and provided in vivo evidence that glucocorticoid resistance occurred during CS-induced central nervous system inflammation, a potential mechanism underlying the cross talk between the lung and brain.