Metabotropic glutamate receptor 5 deficiency inhibits neutrophil infiltration after traumatic brain injury in mice

Traumatic brain injury (TBI) triggers a complex cascade of secondary damage fueled by inflammation, where both resident glial cells and peripheral white blood cells—notably neutrophils—play critical roles. Neutrophils are among the first immune cells to infiltrate the brain parenchyma following injury, and while they are part of the initial immune response, their excessive accumulation exacerbates tissue damage and neurological dysfunction. This study investigates the role of metabotropic glutamate receptor 5 (mGluR5) in regulating this infiltration process during the acute phase of TBI.

The researchers utilized a controlled cortical impact (CCI) model to induce moderate TBI in both wild-type (WT) and mGluR5 knockout (KO) mice. They performed behavioral assessments, including the modified neurological severity score and the foot-fault test, to evaluate functional recovery. The team analyzed brain sections to quantify neutrophil infiltration and tight junction integrity (specifically claudin-5), while using both in vivo mouse models and in vitro blood-brain barrier (BBB) assays to observe the mechanism by which mGluR5 influences the passage of neutrophils into the brain.

Global mGluR5 deficiency was found to be protective against TBI. KO mice exhibited improved motor and sensory performance compared to WT littermates. The underlying mechanism involves a dual protective effect: first, mGluR5 deficiency significantly preserved BBB integrity, limiting the physical breach required for neutrophil entry. Second, the absence of mGluR5 led to a marked reduction in the expression of neutrophil-associated chemokines (such as CXCL1, CXCL2, and various CCL proteins). The study further established that the protein kinase C (PKC) signaling pathway is a key downstream mediator, as PKC blockade effectively mimicked the inhibitory effects of mGluR5 deficiency on chemokine production.