TRIM5 drives lung–brain inflammatory priming to exacerbate traumatic brain injury

Traumatic brain injury (TBI) outcomes are strongly influenced by secondary neuroinflammatory responses; however, the contribution of pre-existing peripheral inflammatory conditions to post-traumatic brain pathology remains incompletely understood. Low-grade pulmonary inflammation is a common clinical condition associated with chronic respiratory disorders, environmental exposure, and recurrent infections, yet its impact on TBI susceptibility has not been well characterized. This study investigated whether subclinical pulmonary inflammatory priming exacerbates TBI outcomes and explored the underlying molecular mechanisms. Mice were subjected to repeated low-dose intratracheal lipopolysaccharide (LPS) administration to induce low-grade pulmonary inflammatory priming prior to controlled cortical impact (CCI)-induced TBI. Behavioral, histological, transcriptomic, and molecular analyses were performed to evaluate neurological outcomes and neuroinflammatory responses. Trim5 knockout mice, Cx3cr1 promoter-driven AAV-mediated TRIM5 overexpression, bulk RNA sequencing, and pharmacological inhibition of the NLRP3 inflammasome were utilized to investigate the underlying mechanisms. Repeated low-dose pulmonary inflammatory priming significantly aggravated neurological dysfunction, cognitive deficits, microglial activation, and neuronal injury following TBI despite the absence of overt lung injury or systemic sickness behavior. Transcriptomic analyses identified persistent Trim5 upregulation and enrichment of inflammasome-associated pathways in the brain following pulmonary inflammatory priming and TBI. TRIM5 was predominantly expressed in microglia and promoted a primed inflammatory state characterized by heightened responsiveness to secondary injury. Global genetic deletion of Trim5 markedly attenuated pulmonary inflammation-induced exacerbation of TBI pathology, whereas Cx3cr1 promoter-driven TRIM5 overexpression recapitulated these pathological phenotypes in the absence of prior pulmonary inflammation. Mechanistically, comparative transcriptomic and histological analyses identified exaggerated NLRP3 inflammasome activation as a major downstream pathway regulated by TRIM5. Pharmacological inhibition of the NLRP3 inflammasome using MCC950 significantly alleviated TRIM5-mediated neuroinflammatory injury and behavioral impairments following TBI. Our findings identify low-grade pulmonary inflammation as a previously underrecognized factor capable of increasing vulnerability to secondary neuroinflammatory damage after traumatic brain injury. Our study further establishes the TRIM5–NLRP3 signaling axis as a critical molecular mechanism underlying this pathological lung–brain interaction and highlights its potential as a therapeutic target for limiting inflammation-associated susceptibility to TBI.