810 Aberrant Immune Activation Drives Chronic White Matter Loss After Experimental Traumatic Brain Injury. (1st April 2022)

• Record Type: Journal Article
• Authors: Jarrahi, Abbas; Braun, Molly; Ahluwalia, Meenakshi; Ahluwalia, Pankaj; Lu, Yujiao; Khodadadi, Hesam; Salles, Evila Lopes; Vaibhav, Kumar; Vender, John R.; Baban, Babak; Vale, Fernando L.; Dhandapani, Krishnan
• Is Part Of: Neurosurgery. Volume 68(2022)Supplement 1
• Page Start: 135
• Page End: 135
• Publication Date: 2022-04-01
• Subjects: Nervous system -- Surgery -- Periodicals; 617.48005
• DOI: 10.1227/NEU.0000000000001880_810
• Languages: English
• ISSNs: 0148-396X

Abstract

Abstract : INTRODUCTION: Epidemiological studies suggest a single traumatic brain injury (TBI) initiates progressive neurodegeneration, including extensive white matter (WM) injury; yet, the majority of demyelination and WM atrophy occurs in the years following TBI in both rodents and humans. Chronic immune activation correlates with neurological dysfunction after TBI, but the underlying mechanisms remain undefined. METHODS: To define the molecular changes associated with focal TBI, unbiased Nanostring arrays were utilized after controlled cortical impact, a pre-clinical model of focal TBI, in adult mice. Immune activation was monitored using flow cytometry and neurodegeneration was assessed at 8 weeks post-TBI, by histology, electron microscopy, and magnetic resonance imaging. RESULTS: Genomic profiling revealed acute upregulation of gene classes associated with leukocyte activation, phagocytosis, antigen presentation, lymphocyte activation, and metabolism whereas genes associated with axon/dendrite structure and neural connectivity were downregulated. Infiltrating macrophages, which phagocytosed myelin debris, represented the predominant antigen presenting cells (APCs) within the CNS after TBI. Similarly, a time dependent increase in the number of myelin containing macrophages was observed within cerebrospinal fluid of severe TBI patients. Functionally, APCs stimulated with myelin ex vivo or isolated after TBI increased T-helper (TH) cell proliferation and enhanced pro-inflammatory TH1/TH17 polarization. Myeloid-selective activation of the key metabolic regulator, 5'-adenosine monophosphate-activated protein kinase (AMPK), suppressed myelin reactive T-cells, and reduced neurodegeneration after TBI. CONCLUSIONS: The infiltrating myeloid cells after TBI undergo metabolic dysfunction following phagocytosis of myelin debris and orchestrate the generation of myelin autoreactive T-cells resulting in progressive neurodegeneration.