The brain-bone marrow axis: Implications for chronic traumatic brain injury and age-related neurodegeneration.

Introduction: It is well established that traumatic brain injury (TBI) causes acute and chronic alterations in systemic immune function and that systemic immune changes contribute to posttraumatic neuroinflammation and neurodegeneration. However, how TBI affects bone marrow (BM) hematopoietic stem cells/progenitors chronically and to what extent such changes may negatively impact innate immunity and neurological function has not been examined. Methods: To further understand the role of BM cell derivatives on TBI outcome, we generated BM chimeric mice by transplanting BM from chronically injured or sham (i.e., 90 days post-surgery) congenic donor mice into otherwise healthy, age-matched, irradiated hosts. Immune changes were evaluated by flow cytometry, multiplex ELISA, and NanoString technology. Moderate-to-severe TBI was induced by controlled cortical impact injury and neurological function was measured using a battery of behavioral tests. Results: TBI induced chronic alterations in the transcriptome of BM lineage-c-Kit+Sca1+ (LSK+) cells in wild type (WT) mice, including modified epigenetic and senescence pathways. After 8 weeks of reconstitution, no changes in BM or blood leukocyte number or composition were observed in TBI→WT chimeric mice compared to either SH→WT or non-irradiated WT control mice, suggesting normal engraftment. However, peripheral myeloid cells from TBI→WT mice showed significantly higher oxidative stress levels and reduced phagocytic activity, consistent with previous findings in WT TBI mice. TBI→WT mice also showed higher plasma concentrations of chemokines and displayed significant deficits in neurological function. At eight months after reconstitution, TBI→WT chimeric mice were leukopenic, with continued altered phagocytosis and oxidative stress responses, as well as persistent neurological deficits. NanoString gene expression analysis revealed BM-driven changes in neuroinflammation and neuropathology after 8 weeks and 8 months of reconstitution, respectively. Chimeric mice subjected to TBI at 8 weeks and 8 months post-reconstitution showed that longer reconstitution periods (i.e., time post-injury) were associated with increased microgliosis and leukocyte infiltration. Pre-treatment with a senolytic agent, ABT-263, significantly improved behavioral performance of aged mice at baseline, although it did not attenuate neuroinflammation in the acutely injured brain. Conclusion: TBI causes chronic activation and progressive dysfunction of the BM stem/progenitor cell pool, which drives long-term deficits in hematopoiesis, innate immunity, neurological function, as well as altered sensitivity to subsequent brain injury.