P2X4 receptors on myeloid cells mediate tissue injury in a murine model of trauma and hemorrhagic shock

Trauma and hemorrhagic shock (T/HS) trigger systemic inflammation and multiorgan injury, yet the molecular mediators of this response remain incompletely defined. Purinergic receptors, including P2X4 and P2X7, are key regulators of innate immune signaling and may contribute to post-trauma organ dysfunction. Here, we assessed the roles of P2X4 and P2X7 in T/HS-induced injury across multiple organs using genetic and pharmacologic approaches in murine models. Global P2X4 knockout (KO) mice exhibited significantly reduced injury in the lung as reflected by improved histopathology, decreased myeloperoxidase activity, and preserved tissue architecture. Additionally, P2X4 KO reduced liver and kidney injury, as indicated by plasma liver enzymes and blood urea nitrogen levels. Myeloid-specific P2X4 deficiency recapitulated these protective effects, suggesting a central role for myeloid cell–mediated P2X4 signaling in multiorgan injury. Bulk RNA sequencing of lung tissue from P2X4 KO mice revealed altered expression of immune response genes, including downregulation of P2X7. Pharmacological inhibition of P2X7 reduced injury in the lung, liver, and kidney. Both P2X4 and P2X7 expression were downregulated in affected organs following T/HS and in LPS-stimulated macrophages in vitro. These findings identify P2X4, particularly in myeloid cells, as a key driver of multiorgan injury following T/HS, and support further investigation of P2 receptor modulation as a therapeutic strategy in trauma-induced organ injury.