NLRX1 Inhibits Glial Inflammation and Neurodegeneration in Experimental Models of Multiple Sclerosis

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Presentation Time: 11:30 AM - 12:45 PM
Poster Board Number: B629
Abstract ID: 4727

Presenting Author:
Marjan Gharagozloo , Assistant Professor at Johns Hopkins Univ. Sch. of Med.

Abstract:

Chronic innate immune activation in the central nervous system (CNS) significantly contributes to neurodegeneration in progressive multiple sclerosis (MS). This study aimed to explore the potential of the innate immune sensor NLRX1 in protecting neurons of the anterior visual pathway using experimental autoimmune encephalomyelitis (EAE), a mouse model of MS. We utilized multiple EAE models to investigate the impact of NLRX1 on inflammatory neurodegeneration in the optic nerves and retina. We assessed retinal ganglion cell (RGC) density, optic nerve axonal degeneration, gliosis, and T-cell infiltration in Nlrx1^-/- and wild-type (WT) EAE mice using immunohistochemistry. Our results indicate that Nlrx1^-/- mice exhibit significantly increased RGC loss and axonal injury compared to WT mice, despite no significant difference in EAE clinical scores and T cell infiltration into the CNS. Adoptive transfer experiment using lymphocyte-deficient Rag^-/- mice revealed more severe microgliosis and astrogliosis in the optic nerve of Nlrx1^-/-Rag^-/- mice compared to Rag^-/- mice, suggesting a regulatory role of NLRX1 in innate immune compartments. Transcriptome analysis in primary astrocytes demonstrated that NLRX1 negatively regulates TLR-mediated NF-κB activation. These findings highlight NLRX1 as a promising target for neuroprotection in progressive MS. Currently, we are investigating novel pharmacologic targeting of NLRX1 to prevent neurodegeneration in EAE and other relevant models