Pioglitazone Reverses Alcohol-Induced Alveolar Macrophage Phagocytic Dysfunction

Alcohol use disorders (AUD) increase susceptibility to respiratory infections by 2- to 4-fold in part because of impaired alveolar macrophage (AM) immune function. Alcohol causes AM oxidative stress, diminishing AM phagocytic capacity and clearance of microbes from the alveolar space. Alcohol increases AM NADPH oxidases (Noxes), primary sources of AM oxidative stress, and reduces peroxisome proliferator-activated receptor gamma (PPAR gamma) expression, a critical regulator of AM immune function. To investigate the underlying mechanisms of these alcohol-induced AM derangements, we hypothesized that alcohol stimulates CCAAT/enhancer-binding protein beta (C/EBP beta) to suppress Nox-related microRNAs (miRs), thereby enhancing AM Nox expression, oxidative stress, and phagocytic dysfunction. Furthermore, we postulated that pharmacologic PPAR gamma activation with pioglitazone would inhibit C/EBP beta and attenuate alcohol-induced AM dysfunction. AM isolated from human AUD subjects or otherwise healthy control subjects were examined. Compared with control AM, alcohol activated AM C/EBP beta, decreased Nox1-related miR-1264 and Nox2-related miR-107, and increased Nox1, Nox2, and Nox4 expression and activity. These alcohol-induced AM derangements were abrogated by inhibition of C/EBP beta, overexpression of miR-1264 or miR-107, or pioglitazone treatment. These findings define novel molecular mechanisms of alcohol-induced AM dysfunction mediated by C/EBP beta and Nox-related miRs that are amenable to therapeutic targeting with PPAR gamma ligands. These results demonstrate that PPAR gamma ligands provide a novel and rapidly translatable strategy to mitigate susceptibility to respiratory infections and related morbidity in individuals with AUD.

Automated summary

Alcohol use disorders impair alveolar macrophage immune function and increase susceptibility to respiratory infections. Alcohol induces oxidative stress in alveolar macrophages, affecting their phagocytic capacity. Pharmacologic activation of PPAR gamma can mitigate alcohol-induced dysfunction in alveolar macrophages.