FAM19A4 enhances neutrophil respiratory burst via p38 MAPK in lethal sepsis

Sepsis causes high mortality and resource strain, with neutrophil-derived reactive oxygen species (ROS) contributing to excessive inflammation. The secretory protein FAM19A4 modulates ROS release, but its role in sepsis is unclear. In this study, we find elevated FAM19A4 levels in septic patients and cecal ligation and puncture (CLP) mice, which correlate with increased mortality. <i>Fam19a4</i> ^{<i>-</i>/ <i>-</i>} mice subjected to CLP show significantly improved survival and attenuated multiorgan injury without impaired peritoneal bacterial clearance or altered circulating neutrophil counts. FAM19A4 deficiency reduces the cell counts of neutrophils (Ly6G ⁺) and macrophages (F4/80 ⁺) in the lungs and liver, diminishes systemic ROS production tracked by bioluminescence, and decreases neutrophil extracellular trap (NET) formation in serum and lung tissue. <i>In vitro</i>, FAM19A4 enhances neutrophil phagocytosis and ROS generation but does not affect lipopolysaccharide-induced chemotaxis. Mechanistically, FAM19A4 drives neutrophil ROS release specifically through p38 MAPK signaling activation, as revealed by bulk RNA sequencing, western blot analysis, and treatment with p38 inhibitor SB203580. These results indicate that FAM19A4 is upregulated during sepsis and exacerbates outcomes by enhancing neutrophil ROS production via p38 MAPK, representing a promising therapeutic target for this condition.