Azithromycin inhibits IL-1 secretion and non-canonical inflammasome activation

Abstract

Deregulation of inflammasome activation was recently identified to be involved in the pathogenesis of various inflammatory diseases. Although macrolide antibiotics display well described immunomodulatory properties, presumably involved in their clinical effects, their impact on inflammasome activation has not been investigated. We compared the influence of macrolides on cytokine induction in human monocytes. The role of intracellular azithromycin-accumulation was examined by interference with Ca++-dependent uptake. We have also analysed the signalling cascades involved in inflammasome activation, and substantiated the findings in a murine sepsis model. Azithromycin, but not clarithromycin or roxithromycin, specifically inhibited IL-1α and IL-1β secretion upon LPS stimulation. Interference with Ca++-dependent uptake abolished the cytokine-modulatory effect, suggesting a role of intracellular azithromycin accumulation in the modulatory role of this macrolide. Azithromycin’s inhibiting effects were observed upon LPS, but not upon flagellin, stimulation. Consistent with this observation, we found impaired induction of the LPS-sensing caspase-4 whereas NF-κB signalling was unaffected. Furthermore, azithromycin specifically affected IL-1β levels in a murine endotoxin sepsis model. We provide the first evidence of a differential impact of macrolides on the inflammasome/IL-1β axis, which may be of relevance in inflammasome-driven diseases such as chronic obstructive pulmonary disease or asthma.

Idiopathic chronic productive cough and response to open‐label macrolide therapy: An observational study

“…Azithromycin treatment resulted in no change in sputum concentration of IL‐8, IL‐17A or TNF‐α, whereas IL‐1β levels decreased significantly. IL‐1β is a potent pro‐inflammatory cytokine which induces pulmonary neutrophil airway inflammation and airway damage in mice, and the reduction in IL‐1β with azithromycin is consistent with findings from murine studies and suggests a mechanism for decreased neutrophilic inflammation.…”

Differential inhibition of activity, activation and gene expression of MMP-9 in THP-1 cells by azithromycin and minocycline versus bortezomib: A comparative study

“…However, we showed that (at a 6 μM concentration) the reduction in MMP-9 levels upon treatment with minocycline and azithromycin was independent of NFκB. Specifically, NF-κB-independent reduction of LPS-induced IL-1β secretion was previously described for azithromycin [40] Moreover, treatment of human monocytes with azithromycin had an impaired induction of caspase-4 which was recently described as a new intracellular LPS sensor [47, 48]. Indeed, pharmacokinetics of macrolide antibiotics such as azithromycin show a predominant accumulation in white blood cells [49].…”

“…At a concentration of 6 μM neither minocycline nor azithromycin affected NF- κB phosphorylation in comparison to cells only stimulated with LPS (Fig 7A). Among cytokines which can induce MMP-9 expression [39], IL-1β was previously reported to be reduced by azithromycin, independently of NF- κB [40]. Therefore, we next evaluated the presence of IL-1 β in cell supernatants.…”

Autoinflammatory disease in the lung

“…The drug is widely used in vitro as an inhibitor of NLRP3 inflammasome. The introduction of other macrolides including erythromycin, clarithromycin and azithromycin appears to have similar anti‐inflammatory and immunomodulatory properties .…”

“…The introduction of other macrolides including erythromycin, clarithromycin and azithromycin appears to have similar anti‐inflammatory and immunomodulatory properties . The macrolide azithromycin has also been shown to have anti‐inflammatory effects in bronchiectasis, as it enhances the clearance of apoptotic cells, such as neutrophils, by improved macrophage phagocytic function .…”