• Repetitive head impacts induce optic tract –specific white matter pathology. • Blood Brain Barrier (BBB) disruption at the optic nerve facilitates peripheral immune cell entry. • Infiltrating peripheral F4/80 + macrophages, CD4 + and CD8 + T-cells also accumulate in the optic tract alongside activated microglia. • Elevated pro-inflammatory cytokines TNFα and IL-1β, together with complement C3 and chemoattractants Ccl2, Ccl5, Cxcl3, and Cxcl10, suggest synergistic interactions between innate and peripheral inflammatory cascades. • DTI and fMRI detect progressive structural and functional tract damage with clinical relevance. Chronic white matter inflammation is a feature of traumatic brain injury (TBI), persisting for years in humans and consistently observed in rodent models of repetitive mild TBI. Here, we use a high-frequency head impact (HFHI, 5 impacts per day, over 6 consecutive days) model to investigate neuroimmune responses in the optic tract, a white matter region particularly vulnerable to primary injury-induced degeneration. To capture a comprehensive view of pathology, we integrated immunohistochemistry, digital spatial proteomics, transcriptomic profiling, and BBB assessments with non-invasive imaging modalities, including diffusion tensor imaging (DTI) and functional MRI (fMRI). HFHI elicited a robust and sustained inflammatory response specifically within the optic tract, marked by elevated IBA1 + and CD68 + expression detectable from the acute phase and persisting for at least 3 m post-injury. Characterization of these IBA1 + cells revealed a strong F4/80 + phenotype, indicative of infiltrating peripheral macrophages. Concurrent with this, a transient blood brain barrier (BBB) disruption was observed at the optic nerve, potentially facilitating acute peripheral immune cell entry. We identified the recruitment of CD4 + and CD8 + T cells to the optic tract, with digital spatial proteomic signatures revealing Granzyme B and CTLA4 expression, indicative of both regulatory and cytotoxic immune activity. Transcriptomic analyses further suggest polarization toward CD4 + Th1 and CD8 + Tc1 subsets, as evidenced by increased expression of T-bet and IFNγ. Chronic elevations of pro-inflammatory cytokines TNFα and IL-1β, complement component C3, and the chemoattractants Ccl2, Ccl5, Cxcl3, and Cxcl10 further suggest that synergistic interactions between innate and peripheral inflammatory cascades contribute to white matter degeneration after repetitive head impact. Diffusion tensor imaging and fMRI reveal reductions in fractional anisotropy and disrupted optic tract–visual cortex connectivity, indicating functional consequences of this tract-specific immune activation. Importantly, DTI and fMRI provide sensitive, translational readouts of this neuroimmune pathology, with potential relevance to traumatic optic neuropathy and visual dysfunction in clinical populations. These findings support the potential of targeted immune modulation within the optic tract as a therapeutic approach to target this white matter specific injury.
Main et al. (Sun,) studied this question.