P2X7R-mediated IL-1β release by human brain tissue: the impact of CNS-penetrant potential therapeutics
Cowley, Jamie Harrison, Neale Pegg, Ashley Chan, Hujo Li, Zhi Kaur, Arshpreet Welsh, Emma Brewin, Alex Carlos Yam-Puc, Juan Fensome, Grace
Cowley, Jamie
Harrison, Neale
Pegg, Ashley
Chan, Hujo
Li, Zhi
Kaur, Arshpreet
Welsh, Emma
Brewin, Alex
Carlos Yam-Puc, Juan
Fensome, Grace
Abstract
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.
Affiliations
Date
2026-02-19
Type
Article
Subject
Collections
Citation
Cowley J, Harrison N, Pegg A, Chan H, Li Z, Kaur A, Welsh E, Brewin A, Carlos Yam-Puc J, Fensome G, Broome E, Morano IM, Jinks E, Grafton G, Cooper AJ, Ahmed Z, Stevens AR, Anderson FG, Wykes V, Chelvarajah R, Tsermoulas G, Ughratdar I, Zisakis A, O'Halloran PJ, Davies DJ, Land T, Chowdhury YA, Sher Z, Yakoub KM, Bergin C, Galloway L, Upthegrove R, Brady CA, Gordon J, Qureshi O, Belli A, Barnes NM. P2X7R-mediated IL-1β release by human brain tissue: the impact of CNS-penetrant potential therapeutics. Brain. 2026 Feb 19:awag068. doi: 10.1093/brain/awag068. Epub ahead of print.