The Potential of NLRX1 in Immune Regulation and Neuroprotection for Inflammatory Neurodegenerative Disorders: Marjan Gharagozloo, PhD

WATCH TIME: 5 minutes

"This is a very interesting question; how is inflammation regulated in the CNS (central nervous system)? We are focusing on understanding the innate immune regulatory pathways that control chronic inflammation within the CNS, so that we can therapeutically enhance them to limit inflammation and neurodegeneration. This approach could potentially have huge implications for treating neurodegenerative diseases, including multiple sclerosis (MS)."

NLRX1 is an innate immune regulator that is located in mitochondria and inhibits major proinflammatory pathways including type I interferon and nuclear factor-κB signaling. Prior research shows that NLRX1 inhibits subclinical stages of microglial activation and prevents generation of neurotoxic astrocytes that induce neuronal and oligodendrocyte death in vitro, according to a study published in PLOS Biology.¹ Thus, these findings highlight the importance of NLRX1 in managing the early stages of central nervous system (CNS) inflammation and preventing the onset of spontaneous autoimmunity in neurodegenerative disease like multiple sclerosis (MS).

Presented at the 2024 Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) Forum, February 29 to March 2, in West Palm Beach, Florida, a recent preclinical study showed NLRX1 inhibited inflammatory neurodegeneration in experimental models of MS.² In the study, investigators used experimental autoimmune encephalomyelitis (EAE) models to assess the impact of NLRX1 on inflammatory neurodegeneration in the anterior visual pathway. Conducted by senior author Marjan Gharagozloo, PhD, and colleagues, the findings demonstrated significantly worse retinal ganglion cell loss and reduced neurofilament light chain expression in the optic nerves of Nlrx1-/- mice compared with wild-type mice among both active and spontaneous EAE models. These results suggest NLRX1 plays a neuroprotective role in inflammatory neurodegeneration, which at least in part may occur through downregulation of inflammatory-reactive microglia and astrocytes.

At the forum, Gharagozloo, an assistant professor of neurology at Johns Hopkins Medicine, sat down with NeurologyLive® in an interview to further discuss how innate immune cells regulate inflammation in the CNS. She also spoke about the potential therapeutic implications her preclinical research may hold for inflammatory neurodegenerative diseases including MS. In addition, Gharagozloo explained how animal models, particularly those mimicking MS, are utilized in studying the role of innate immune regulator NLRX1 in neurodegeneration.

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REFERENCES
1. Gharagozloo M, Mahmoud S, Simard C, et al. NLRX1 inhibits the early stages of CNS inflammation and prevents the onset of spontaneous autoimmunity. PLoS Biol. 2019;17(9):e3000451. Published 2019 Sep 16. doi:10.1371/journal.pbio.3000451
2. Gill J, Garton T, Smith MD, et al. Innate Immune Regulator NLRX1 Protects the Anterior Visual Pathway Against Inflammatory Neurodegeneration. Presented at ACTRIMS Forum 2024; February 29 to March 2; West Palm Beach, Florida. CE1.2.