Extracellular vesicles from alveolar macrophages harboring phagocytosed methicillin-resistant Staphylococcus aureus induce necroptosis

Summary: Methicillin-resistant Staphylococcus aureus (MRSA) infection, a major cause of hospital- and community-acquired pneumonia, still has a high mortality rate. Extracellular vesicles (EVs), as crucial mediators of intercellular communication, have a significant impact on infectious diseases. However, the role of EVs from alveolar macrophages (AMs) in MRSA pneumonia remains unclear. We report that AMs phagocytose MRSA and release more EVs in mice with MRSA pneumonia. EVs from AMs harboring phagocytosed MRSA exhibit significant proinflammatory effects and induce necroptosis by delivering tumor necrosis factor α (TNF-α) and miR-146a-5p. Mechanically, the upregulated miR-146a-5p in these EVs enhances the phosphorylation of RIPK1, RIPK3, and MLKL by targeting TNF receptor-associated factor 6 (TRAF6), thereby promoting TNF-α-induced necroptosis. The combination of a TNF-α antagonist and an miR-146a-5p antagomir effectively improves the outcomes of mice with MRSA pneumonia. Overall, we reveal the pronecrotic effect of EVs from MRSA-infected AMs and provide a promising target for the prevention and treatment of MRSA pneumonia

Extracellular vesicles derived from M2‐like macrophages alleviate acute lung injury in a miR‐709‐mediated manner

Abstract Acute lung injury/acute respiratory distress syndrome (ALI/ARDS) is characterised by an uncontrolled inflammatory response, and current treatment strategies have limited efficacy. Although the protective effect of M2‐like macrophages (M2φ) and their extracellular vesicles (EVs) has been well‐documented in other inflammatory diseases, the role of M2φ‐derived EVs (M2φ‐EVs) in the pathogenesis of ALI/ARDS remains poorly understood. The present study utilised a mouse model of lipopolysaccharide‐induced ALI to first demonstrate a decrease in endogenous M2‐like alveolar macrophage‐derived EVs. And then, intratracheal instillation of exogenous M2φ‐EVs from the mouse alveolar macrophage cell line (MH‐S) primarily led to a take up by alveolar macrophages, resulting in reduced lung inflammation and injury. Mechanistically, the M2φ‐EVs effectively suppressed the pyroptosis of alveolar macrophages and inhibited the release of excessive cytokines such as IL‐6, TNF‐α and IL‐1β both in vivo and in vitro, which were closely related to NF‐κB/NLRP3 signalling pathway inhibition. Of note, the protective effect of M2φ‐EVs was partly mediated by miR‐709, as evidenced by the inhibition of miR‐709 expression in M2φ‐EVs mitigated their protective effect against lipopolysaccharide‐induced ALI in mice. In addition, we found that the expression of miR‐709 in EVs derived from bronchoalveolar lavage fluid was correlated negatively with disease severity in ARDS patients, indicating its potential as a marker for ARDS severity. Altogether, our study revealed that M2φ‐EVs played a protective role in the pathogenesis of ALI/ARDS, partly mediated by miR‐709, offering a potential strategy for assessing disease severity and treating ALI/ARDS