The inflammatory-antigen presenting macrophage polarization defect contributes to sepsis-induced cardiomyopathy by...

As one of the severe sepsis complications that can usually cause mortality, sepsis-induced cardiomyopathy (SIC) is typically characterized by reversible myocardial dysfunction, yet its pathogenesis is insufficiently understood. Here, by collecting a mouse scRNA-seq dataset (GSE190856) along with three integrated bulk RNA-seq datasets, including GSE267388, GSE171546, and GSE229925, a distinct M1-type Skil⁺Mac2 macrophage subpopulation was identified through multiple bioinformatic techniques. It was indicated that the Skil⁺Mac2 subpopulation was strongly proinflammatory by activating key pathways, such as TNFα-NFκB signaling, TGF-β signaling, IL6-JAK-STAT3 signaling, and other inflammatory responses. By pseudotemporal trajectories, the Skil⁺Mac2 was indicated to reside in the early stage of differentiation, possessing strong phenotypic plasticity. Antigen-presenting genes of Skil⁺Mac2 were significantly downregulated during SIC, which was consistent with BulkRNA-seq differential analysis. By Cell communication analysis, it was revealed that the TGF-β pathway of the Skil⁺Mac2 subpopulation was greatly downregulated in SIC. During the acute phase of SIC, as demonstrated by CLP3d, the Skil+Mac2 subpopulation showed significantly lower M2 polarization scores, indicating impaired M2 polarization ability. Conclusively, a key proinflammatory Skil⁺Mac2 macrophage subset was identified in SIC, characterized by impaired polarization abilities by downregulating the TGF-β signaling pathway, thereby causing persistent inflammation and myocardial tissue damage. Through this study, a new insight into understanding the SIC pathogenesis was uncovered, providing a potential approach by targeting the polarization of Skil⁺Mac2 subpopulation for SIC treatment.