Intracerebral hemorrhage‐induced brain injury in mice: The role of peroxiredoxin 2‐Toll‐like receptor 4 inflammatory axis

Abstract

AbstractBackgroundPeroxiredoxin 2 (Prx2), an intracellular protein that regulates redox reactions, released from red blood cells is involved in inflammatory brain injury after intracerebral hemorrhage (ICH). Toll‐like receptor 4 (TLR4) may be crucial in this process. This study investigated the role of the Prx2‐TLR4 inflammatory axis in brain injury following experimental ICH in mice.MethodsFirst, C57BL/6 mice received an intracaudate injection of autologous arterial blood or saline and their brains were harvested on day 1 to measure Prx2 levels. Second, mice received an intracaudate injection of either recombinant mouse Prx2 or saline. Third, the mice were co‐injected with autologous arterial blood and conoidin A, a Prx2 inhibitor, or vehicle. Fourth, the mice received a Prx2 injection and were treated with TAK‐242, a TLR4 antagonist, or saline (intraperitoneally). Behavioral tests, magnetic resonance imaging, western blot, immunohistochemistry/immunofluorescence staining, and RNA sequencing (RNA‐seq) were performed.ResultsBrain Prx2 levels were elevated after autologous arterial blood injection. Intracaudate injection of Prx2 caused brain swelling, microglial activation, neutrophil infiltration, neuronal death, and neurological deficits. Co‐injection of conoidin A attenuated autologous arterial blood‐induced brain injury. TLR4 was expressed on the surface of microglia/macrophages and neutrophils and participated in Prx2‐induced inflammation. TAK‐242 treatment attenuated Prx2‐induced inflammation and neurological deficits.ConclusionsPrx2 can cause brain injury following ICH through the TLR4 pathway, revealing the Prx2‐TLR4 inflammatory axis as a potential therapeutic target.