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Moore, Nicholas; Jarrahi, Abbas; Lu, Yujiao; Khodadadi, Hesam; Jones, Earl Dane; Kaoutzani, Lydia; Vale, Fernando L.; Vender, John R.; Baban, Babak; Dhandapani, Krishnan
Neurosurgery, 04/2024, Letnik: 70, Številka: Supplement_1Journal Article
INTRODUCTION: Traumatic brain injury (TBI) induces immediate mechanical injury, including diffuse axonal shearing and myelin degradation. Epidemiological studies suggest a single, severe TBI initiates progressive neurodegeneration, including extensive white matter injury and culminating in long-term cognitive decline. While underlying mechanisms remain undefined, the degree of chronic inflammation correlates with delayed white matter tract damage after TBI. METHODS: Immune cell infiltration and activation was measured using preparative and analytical flow cytometry after controlled cortical impact, a pre-clinical model of focal penetrating injury, in adult mice. To assess T cell priming, APCs pulsed with myelin or isolated after experimental TBI were co-cultured with naÏve splenic T cells. Progressive neurodegeneration was assessed by histology and magnetic resonance imaging at eight weeks post-injury. RESULTS: Peripheral macrophages predominated as APCs within the CNS parenchyma after severe TBI. Myelin-pulsed APCs or APCs isolated after experimental TBI efficiently primed naÏve T cells ex vivo, generating myelin-reactive Th1/Th17 cells. Activity of the master metabolic regulator AMPK, previously shown to promote counter-inflammatory immune polarization, was decreased in myeloid cells after injury. Treatment with metformin, an AMPK activator, restored myeloid AMPK activity and attenuated neurodegenerative changes at eight weeks post-TBI. CONCLUSIONS: TBI-induced immunometabolic dysregulation allows generation of auto-reactive T cells that may contribute to chronic inflammation and progressive neurodegeneration. Metabolic reprogramming of myeloid cells via metformin restores AMPK activity and reduces progressive white matter loss after TBI, representing a potential therapeutic intervention to mitigate long-term consequences of TBI.
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JCR | SNIP | JCR | SNIP | JCR | SNIP | JCR | SNIP |
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