Azithromycin inhibits IL-1 secretion and non-canonical inflammasome activation (VAC9P.1110)

Abstract

Deregulation of inflammasome activation was recently identified to be involved in the pathogenesis of various inflammatory diseases. Although macrolide antibiotics have well-established immunomodulatory properties probably involved in their clinical effects, studies on their impact on this pathway are missing. Comparing the influence of macrolides on cytokine induction in human monocytes, we found that azithromycin, but not clarithromycin or roxithromycin, specifically inhibited IL-1β secretion upon LPS stimulation whereas no effects were observed after flagellin stimulation. Blockage of azithromycin’s transmembrane transport abolished the cytokine-modulatory effect, indicating intracellular azithromycin accumulation to be causative for diverging effects. Consistent with IL-1β inhibition restricted to LPS stimulation, we found impaired induction of the intracellular LPS-sensing caspase-4 whereas NF-κB signalling was unaffected. Substantiating our in vitro data, azithromycin specifically dampened IL-1β levels and enhanced survival in a murine endotoxin sepsis model. Overall, we provide first evidence of a differential impact of macrolides on the inflammasome/IL-1β axis, which might be of relevance in inflammasome driven diseases like COPD or asthma.