FPR1-dependent Pro-inflammatory Ccl4(high) monocytes/macrophages drive and predict sepsis-induced acute lung injury.

The elusive pathogenesis of sepsis-induced acute lung injury (ALI) combined with the absence of reliable diagnostic biomarkers, significantly hinders the development of targeted therapies and precision medicine approaches for affected patients. In this study, we employed scRNA-seq to profile the transcriptional landscape of the lungs in well-established murine models of sepsis-induced ALI. These findings were further validated experimentally leading to the identification of tri-lineage candidate biomarkers for sepsis-associated ALI: SCGB3A2 (in epithelial cells), AKAP12 (in endothelial cells), and CCL4 (in monocytes/macrophages, Mo/Mφ). In pulmonary immune microenvironment of sepsis-induced ALI, Mo/Mφ were identified as the dominant contributors to pulmonary immune heterogeneity during the acute inflammatory phase of sepsis-induced ALI. Among these, the Ccl4(high) Mo/Mφ subpopulation exhibited disease-specific lung infiltration and a distinct proinflammatory phenotype. Mechanistically, FPR1 was up-regulated in hyperinflammatory cluster of Ccl4(high) Mo/Mφ. Pharmacological inhibition of FPR1 in vivo selectively reduced pulmonary infiltration of Ccl4(high) Mo/Mφ and attenuated sepsis-induced ALI. Furthermore, we established a peripheral blood-based five-gene panel (CCL4, NFKBIA, IL1B, BATF, and XBP1) derived from signatures of Ccl4(high) Mo/Mφ, which robustly predicted sepsis-induced ALI in clinical cohorts. Collectively, our work delineates the transcriptional alterations of lungs in sepsis-induced ALI, identifies candidate biomarkers for sepsis-induced ALI, and establishes a clinically applicable diagnostic model for early detection. These findings enhance our understanding of the underlying mechanisms of sepsis-induced ALI and offer new targets for its precision diagnosis and therapeutic intervention. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12931-025-03385-5.