FPR-1 drives monocyte cytokine storm in sepsis via AKT, p38-MAPK, and mitochondrial ROS pathways

Sepsis is a life-threatening condition characterized by a dysregulated immune response to infection, often leading to a cytokine storm and multi-organ failure. Despite its high mortality, the precise molecular mechanisms governing monocyte-driven cytokine release remain poorly understood, hindering effective therapeutic development. Current standard-of-care treatments often fall short in controlling the excessive inflammation and tissue damage, highlighting an urgent need for novel targets that can modulate the immune response without compromising host defense.

Researchers analyzed RNA-sequencing (RNA-seq) datasets from the Gene Expression Omnibus (GEO) comparing gene expression profiles across patients with sepsis, severe COVID-19, macrophage activation syndrome, and healthy controls. This comparative analysis aimed to identify critical cytokine regulatory genes shared across cytokine storm-related diseases. Subsequent in vitro experiments investigated the role of FPR-1 activation on LPS-induced cytokine production in monocytes, assessing its impact on AKT and p38-MAPK signaling, as well as mitochondrial reactive oxygen species (ROS) levels.

Comparative RNA-seq analysis identified 109 shared differentially expressed genes across cytokine storm-related diseases. Crucially, Formyl peptide receptor 1 (FPR-1) was pinpointed as a key gene significantly upregulated in sepsis monocytes, primarily via the LPS/TLR4 pathway. Further in vitro studies confirmed that FPR-1 activation substantially enhanced LPS-induced IL-6 and TNF-α production. This amplification was mediated through the activation of both AKT and p38-MAPK signaling pathways. The study also revealed a critical role for mitochondrial ROS: > FPR-1 modulates mitochondrial ROS levels, thereby amplifying pro-inflammatory cytokine expression in a mitochondrial ROS-dependent manner. These findings demonstrate that FPR-1 acts as a central modulator of monocyte-driven cytokine dysregulation in sepsis by integrating key inflammatory signaling pathways and mitochondrial ROS homeostasis.