FPR-1 mediates monocyte-driven cytokine dysregulation in sepsis via mitochondrial ROS-dependent signaling pathways.

Sepsis is a life-threatening condition driven by dysregulated immune responses to infection, characterized by excessive inflammatory cytokine release that frequently culminates in cytokine storm and multi-organ failure, yet the molecular mechanisms governing cytokine regulation of monocytes in sepsis remain poorly understood. In this study, we retrieved RNA-sequencing (RNA-seq) datasets regarding cytokine storm-related diseases from the Gene Expression Omnibus (GEO) and performed comparative analysis of gene expression profiles among patients with sepsis, severe COVID-19, macrophage activation syndrome, and healthy controls to identify critical cytokine regulatory genes. We identified 109 shared differentially expressed genes across these cytokine storm-related diseases and pinpointed Formyl peptide receptor 1 (FPR-1) as a key gene significantly upregulated in sepsis monocytes via LPS/TLR4 pathway. Furthermore, we found that FPR-1 activation enhances LPS-induced IL-6 and TNF-α production through AKT and p38-MAPK signaling. Furthermore, FPR-1 modulates mitochondrial ROS levels, thereby amplifying pro-inflammatory cytokine expression in a mitochondrial ROS-dependent manner. These findings demonstrate that FPR-1 is a crucial modulator of monocyte-driven cytokine dysregulation in sepsis via key inflammatory signaling pathways and mtROS homeostasis, providing novel mechanistic insights and potential therapeutic targets for sepsis management.