Type II Alveolar Epithelial Cells Promote Sepsis‐Induced Immunosuppression in Alveolar Macrophages via Exosomal lncRNA Rmrp Release

Secondary pneumonia, a common complication of sepsis-induced immunosuppression (SII), is closely linked to alveolar macrophage (AM) dysfunction primarily due to impaired glycolytic activity. However, the underlying molecular mechanisms remain unclear. In this study, it is found that exosomal RNA component of the mitochondrial RNA processing endoribonuclease (Rmrp), derived from type II alveolar epithelial cells (AEC-IIs), drives glycolytic defects and immune tolerance in AMs following cecal ligation and puncture (CLP) sepsis. Targeted depletion of Rmrp in either AEC-IIs or AMs alleviated SII and secondary pneumonia induced by Pseudomonas aeruginosa infection 48 h post CLP. Mechanistically, Rmrp interacts with and inhibits the ubiquitination and degradation of the RNA-binding protein zinc finger protein 36 (ZFP36). This results in ZFP36 upregulation, subsequently accelerating the decay of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (Pfkfb3) mRNA by binding to its AU-rich elements in the 3' untranslated region. The degradation of Pfkfb3 mRNA leads to impaired glycolysis and suppresses immune responses in AMs after sepsis. Additionally, it is found that exosomal Rmrp levels are correlated with AM immune tolerance and the prognosis of patients with sepsis. These findings highlight the critical role of AEC-II-derived exosomal Rmrp in the pathogenesis of SII and secondary pneumonia. Importantly, the study suggests that exosomal Rmrp may serve as a biomarker for predicting and managing SII in clinical settings.