The Dual Role of Neuroinflammation in Short-Term Recovery versus Long-Term Cognitive Deficits in Pediatric TBI Patients

Naeema Z, Wajahat MM, Senami H, Lorena F, David G and Naeem H

Published on: 2026-01-02

Abstract

Neuroinflammation subsequent to pediatric traumatic brain injury (TBI) demonstrates a dual role, promoting acute tissue repair whereas instigating to chronic neurodegeneration when persistent. This comprehensive review integrates preclinical and clinical evidence on the biphasic characteristics of neuroinflammatory responses in the developing brain. In the acute phase, blood-brain barrier disruption, reactive astrogliosis, and microglial polarization toward reparative (M2) phenotypes to expedite the productive clearance of debris, cytokine-mediated repair (e.g., IL-6, IL-1β surges), and recruitment of peripheral immune cells to limit secondary injury. But inability to achieve resolution results in persistent pro-inflammatory (M1-dominated) activation, sustained cytokine release (e.g., TNF-α, IL-8), oxidative stress, excessive synaptic pruning, impaired hippocampal neurogenesis, progressive white matter degeneration, and hippocampal atrophy eventuating in long-term cognitive, behavioural, and executive function deficiency, with increased risk for neurodegenerative pathologies. Modulating factors, including APOE ε4 genotype, age at injury, sex (female’s often showing greater vulnerability), sleep disturbances, and injury severity, and exert a profound impact on the developmental course from adaptive to maladaptive inflammation. Preclinical data substantiate narrow clinical approaches for interventions like minocycline (microglial suppression) and omega-3 supplementation (resolution promotion), though pediatric clinical trials are limited, and non-specific anti-inflammatories (e.g., corticosteroids) have proven deleterious. Substantial gaps remain understanding in microglial phenotype transitions, age- and sex-specific mechanisms, systemic-central immune crosstalk, and transcriptomic pathways associating chronic inflammation to axonal/myelin loss in immature brains. Prospective research necessitates extended, diverse pediatric cohorts integrating multimodal imaging, serial fluid biomarkers (e.g., cytokines, inflammasome proteins), single-cell omics, and stratified designs to allow identification of risk stratification and targeted, developmentally customized immunomodulatory therapies that preserve protective effects whilst mitigating chronic sequelae.