Microglial GLUL loss worsens TBI outcomes by amplifying the arginine-citrulline pathway.

Abstract

Microglial hyperactivation-induced neuroinflammation is a central driver of neurological dysfunction after traumatic brain injury (TBI). Metabolic reprogramming is essential for microglial activation, but the specific metabolic alterations following TBI and their causal relationship with activation remain poorly defined. This study investigated the role and underlying mechanisms of glutamate-ammonia ligase (GLUL) in regulating microglial activation after TBI. A murine TBI model was established using a controlled cortical impact device, and brain injury severity, neuroinflammation, and behavioral outcomes were compared between wild-type and microglia-specific GLUL knockout mice. The inflammatory cytokine expression and amino acid metabolic fluxes assessed in GLUL-deficient microglia during activation in vivo and in vitro. Results showed that post-TBI microglia downregulate the GLUL expression, redirecting glutamate metabolism toward the pro-inflammatory arginine-citrulline cycle. This metabolic shift exacerbated microglial hyperactivation and aggravated neurological dysfunction following TBI. Conversely, inhibition of arginine-citrulline cycle attenuated microglial activation and suppressed pro-inflammatory cytokine release. Collectively, these findings identify a novel pathological mechanism linking metabolic alterations to microglial activation after TBI and suggest a metabolism-targeted strategy for anti-inflammatory therapy.