Receptor P2X7R-mediado de liberación de IL-1β por tejido cerebral humano: el impacto de los productos terapéuticos...

Traumatic brain injury (TBI) is a major cause of death throughout the world and currently there are no approved drugs to treat this debilitating condition emphasising the clear unmet substantial clinical need. It is well recognised that microglial activation and the hostile neuroinflammatory response arising after the initial insult provides a therapeutic window for pharmacological intervention. The purinergic P2X7 receptor (P2X7R) is a key driver of neuroinflammation in a range of animal models of TBI. To generate translational evidence for the role of the P2X7R, we optimised two human inflammatory models; human cells (monocyte-derived microglia (hMDM)) in vitro and human brain tissue ex vivo, to test the impact of clinical-stage brain-penetrant P2X7R antagonists. Using lipopolysaccharide (LPS)-primed hMDM, the P2X7R agonist, BzATP, evoked a concentration-dependent increase in pro-inflammatory IL-1β and IL-18 release, which was antagonised in a concentration-dependent manner by selective P2X7R antagonists, and also inhibitors of either the NLRP3 complex or caspase-1, implicating a role for the inflammasome in P2X7R-mediated cytokine release. Using slices of human brain tissue, BzATP similarly evoked cytokine release in a concentration-dependent manner that was also antagonised by selective P2X7R antagonists at pharmacologically relevant concentrations. The present study demonstrates the ability of P2X7R antagonists to suppress the neuroinflammatory response from primed hMDM and human brain slices to offer direct translational data that central P2X7R antagonism may limit pathology-driven pro-inflammatory responses in the brain. This is predicted to improve the clinical outcomes for patients with TBI and other neuroinflammatory pathologies.