Exosomal miR-155-5p drives widespread macrophage M1 polarization in hypervirulent Klebsiella pneumoniae-induced acute lung injury via the MSK1/p38-MAPK axis

Abstract

Background Hypervirulent Klebsiella pneumoniae (hvKp) infection-induced sepsis-associated acute lung injury (ALI) has emerged as a significant clinical challenge. Increasing evidence suggests that activated inflammatory macrophages contribute to tissue damage in sepsis. However, the underlying causes of widespread macrophage activation remain unclear. Methods BALB/c mice were intravenously injected with inactivated hvKp (iHvKp) to observe lung tissue damage, inflammation, and M1 macrophage polarization. In vitro, activated RAW264.7 macrophage-derived exosomes (iHvKp-exo) were isolated and their role in ALI formation was investigated. RT-PCR was conducted to identify changes in exosomal miRNA. Bioinformatics analysis and dual-luciferase reporter assays were performed to validate MSK1 as a direct target of miR-155-5p. Further in vivo and in vitro experiments were conducted to explore the specific mechanisms involved. Results iHvKp successfully induced ALI in vivo and upregulated the expression of miR-155-5p. In vivo, injection of iHvKp-exo induced inflammatory tissue damage and macrophage M1 polarization. In vitro, iHvKp-exo was found to promote macrophage inflammatory response and M1 polarization through the activation of the p38-MAPK pathway. RT-PCR revealed exposure time-dependent increased levels of miR-155-5p in iHvKp-exo. Dual-luciferase reporter assays confirmed the functional role of miR-155-5p in mediating iHvKp-exo effects by targeting MSK1. Additionally, inhibition of miR-155-5p reduced M1 polarization of lung macrophages in vivo, resulting in decreased lung injury and inflammation induced by iHvKp-exo or iHvKp. Conclusions The aforementioned results indicate that exosomal miR-155-5p drives widespread macrophage inflammation and M1 polarization in hvKp-induced ALI through the MSK1/p38-MAPK Axis. Graphical Abstract

Obesity-induced downregulation of miR-192 exacerbates lipopolysaccharide-induced acute lung injury by promoting macrophage activation

“…1 F). Macrophages primarily activate into pro-inflammatory M1 type and anti-inflammatory M2 type [ 10 ]. RT-qPCR findings revealed that the mRNA levels of M1 macrophage markers, iNOS and CD86, increased significantly during obesity, while the levels of M2 macrophage markers, Arg-1 and CD206, showed an opposite trend.…”

“…Research has revealed that obesity can alter the lung’s inflammatory environment and immune cell populations, subsequently influencing susceptibility to lung injury [ 9 ]. Within the lungs, macrophages are the predominant immune cells, and their activation plays a pivotal role in the progression of ALI [ 10 ]. Effectively interrupting the lung inflammation cascade and alleviating lung injury can be achieved by inhibiting the pro-inflammatory M1 polarization of macrophage [ 11 ].…”

Airway epithelial‐derived exosomes induce acute asthma exacerbation after respiratory syncytial virus infection

“…Previous studies have also shown that exosomal hsa‐miR‐155‐5p drives widespread macrophage inflammation in acute lung injury through MSK1/p38–MAPK Axis. 46 It has also found that hsa‐miR‐155‐3p is functionally relevant in the immune context as a proinflammatory regulator in multiple immune cells, including dendritic cells, macrophages, T cells, and astrocytes. 47 hsa‐miR‐210 is one of the important molecules that involved in the growth and metastasis of tumor cells.…”