Neutrophil-derived Il1r2 modulates inflammation and alleviates acute lung injury by promoting M2 macrophage polarization.

Acute Lung Injury (ALI) and Acute Respiratory Distress Syndrome (ARDS) are severe inflammatory conditions with high morbidity and mortality. Understanding the molecular mechanisms underlying these diseases is crucial for developing effective treatments. To investigate the molecular mechanisms underlying ALI, we established a lipopolysaccharide (LPS)-induced mouse model. Bioinformatics and machine learning techniques were utilized to identify key genes and construct gene co-expression networks. Single-cell RNA sequencing was performed to analyze Il1r2 expression specifically in neutrophils. CellChat and hdWGCNA were employed to explore gene co-expression modules and cell-cell communication networks, respectively. Experimental validations included qRT-PCR for gene expression quantification, and western blotting, immunohistochemistry, and immunofluorescence for protein-level confirmation. Four key genes-Cebpd, Hspa12b, Pim1, and Il1r2-were identified as potential biomarkers and therapeutic targets. Il1r2 was identified as a key regulator of inflammation, predominantly expressed in neutrophils. Immune cell infiltration analysis revealed increased neutrophils, monocytes, and dendritic cells in ALI samples. CellChat and hdWGCNA highlighted the significant role of Il1r2 in neutrophil-macrophage signaling in immune regulation. Furthermore, overexpression of Il1r2 in neutrophils reduced lung inflammation and promoted M2 macrophage polarization in vivo. This indicated that Il1r2 alleviates ALI by modulating the immune response, particularly through interactions with macrophages. Neutrophil-derived Il1r2 plays a critical role in modulating inflammation in ALI by promoting M2 macrophage polarization. These findings suggest that targeting Il1r2 may offer a novel therapeutic approach to control the immune response in ALI and other inflammatory diseases.