Journal
JOURNAL OF IMMUNOLOGY
Volume 199, Issue 10, Pages 3547-3558Publisher
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.1700251
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Funding
- National Institute of Neurological Disease and Stroke Awards [NS096281, NS081623]
- National Institute of Allergy and Infectious Diseases Animal Model Research for Veterinarians Training Grant [T32-OD010430]
- Virginia Tech Initiative for Maximizing Student Development program [GM0727-09]
- Virginia Tech Post-Baccalaureate Research and Education Program [GM066534-14]
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Traumatic and nontraumatic brain injury results from severe disruptions in the cellular microenvironment leading to massive loss of neuronal populations and increased neuroinflammation. The progressive cascade of secondary events, including ischemia, inflammation, excitotoxicity, and free-radical release, contribute to neural tissue damage. NLRX1 is a member of the NLR family of pattern recognition receptors and is a potent negative regulator of several pathways that significantly modulate many of these events. Thus, we hypothesized that NLRX1 limits immune system signaling in the brain following trauma. To evaluate this hypothesis, we used Nlrx1(-/-) mice in a controlled cortical impact (CCI) injury murine model of traumatic brain injury (TBI). In this article, we show that Nlrx1(-/-) mice exhibited significantly larger brain lesions and increased motor deficits following CCI injury. Mechanistically, our data indicate that the NF-kappa B signaling cascade is significantly upregulated in Nlrx1(-/-) animals. This upregulation is associated with increased microglia and macrophage populations in the cortical lesion. Using a mouse neuroblastoma cell line (N2A), we also found that NLRX1 significantly reduced apoptosis under hypoxic conditions. In human patients, we identify 15 NLRs that are significantly dysregulated, including significant downregulation of NLRX1 in brain injury following aneurysm. We further demonstrate a concurrent increase in NF-kappa B signaling that is correlated with aneurysm severity in these human subjects. Together, our data extend the function of NLRX1 beyond its currently characterized role in host-pathogen defense and identify this highly novel NLR as a significant modulator of brain injury progression.
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