Organ-specific inflammatory profiles during sepsis: divergent macrophage polarization and oxidative stress response in lung and liver in mouse model of caecal ligation and puncture

Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection. Although systemic, sepsis mechanisms vary between organs. Macrophage activation or inhibition within specific organs is thought to drive disease progression. Identifying organ-specific biomarkers could improve understanding of individual organ failure. This study compared the systemic inflammatory response in lung and liver, exploring macrophage involvement in compartmentalized responses using a murine polymicrobial sepsis model induced by cecal ligation and puncture (CLP). Moderate sepsis was induced in male C57BL/6 mice divided into seven groups: Basal, Control (1 and 5 days), Sham (1 and 5 days), and CLP (1 and 5 days). Analyses included histology, lung and liver function (assessed via the ratio of arterial oxygen partial pressure to fractional inspired oxygen (PaO2/FiO2), bilirubin, and hepatic enzymes), and the measurement of cytokines and chemokines in blood, liver, and lung. We further analyzed oxidative stress markers—specifically Superoxide Dismutase (SOD) and Catalase (CAT) gens expression—macrophage activation states (using Cluster of Differentiation 86 (CD86) and 206 (CD206)), and Programmed Death-Ligand 1 (PD-L1) expression via immunohistochemistry. Tissue remodeling was assessed through Matrix Metalloproteinase (MMP) and Tissue Inhibitor of Metalloproteinase (TIMP) gene expression. Respiratory and liver dysfunction were evident at day 5 post-CLP by histology, decreased PaO2/FiO2, and increased bilirubin. Plasma TNF-α, IL-6, IL-10, and CCL2 peaked within 24 h and decreased by day 5, while cytokine profiles in organs differed from systemic levels. The lung showed elevated Ccl2, Ccr2, and Cx3cr1 expression compared to the liver, whereas the liver had a more pronounced oxidative imbalance. Lung tissue remodeling featured higher MMP expression with relatively lower inhibitors compared to the liver. Both organs showed increased CD86 and CD206 macrophage activation at day 5, but CD86-positive cells were three times more numerous in the liver, and CD206-positive cells were twice as high in the lung. Additionally, PD-L1 expression increased markedly in lung but not liver macrophages after CLP, affecting CD206⁺ subsets and suggesting lung-specific late immunosuppression. These findings support inflammatory compartmentalization in sepsis, with macrophages central to organ-specific immune regulation. Differential monocyte recruitment (CCL2/CCR2), oxidative stress, MMP/TIMP profiles and distinct CD86/CD206 distributions PD-L1 upregulation was restricted to CD206⁺ lung macrophages, reflecting late lung-specific immunosuppression. This emphasizes the potential of organ-targeted therapies and macrophage-related.