Dexamethasone-induced immunosuppression in Pneumocystis pneumonia reprograms neutrophil metabolism and impairs...

Dexamethasone (DEX) is a widely used immunosuppressant that predisposes hosts to opportunistic infections like Pneumocystis pneumonia (PCP). However, the precise immunological and metabolic mechanisms by which DEX alters pulmonary immunity against Pneumocystis remain poorly understood. Using single-cell RNA sequencing on lung tissues of PCP model of control and DEX-induced immunocompromised mouse (DEX-PCP), we found that DEX related immunosuppression reshaped the pulmonary cellular landscape. It increased neutrophil and monocyte proportions while diminishing lymphocytes. Notably, neutrophils, despite being expanded, their pro-inflammatory and antibacterial capabilities were impaired, including reduced ROS production and phagocytic pathways. Metabolic analysis revealed a specific and profound suppression of fatty acid oxidation (FAO) in DEX-PCP neutrophils. Further flow cytometry, RT-qPCR, bulk RNA-seq and metabolomics assays verified the down-regulation of the FAO pathway and key antibacterial mediators. In conclusion, our study demonstrates that DEX-induced immunosuppression in PCP subverts neutrophil function by reprogramming their metabolic state, specifically through the impairment of FAO.