The Immune Regulator NLRX1 Limits Inflammatory Neurodegeneration in the Anterior Visual Pathway
Year: 2024
Type: article
Abstract: Objective To determine the neuroprotective role of NLRX1 and define the efficacy NLRX1 agonists to limit neurodegeneration in experimental autoimmune encephalomyelitis (EAE). Background Chronic innate immune activation within the CNS is believed to be a significant contributor to neurodegeneration in progressive MS. Understanding the mechanisms that control reactive and inflammatory glial responses is of paramount importance for developing innovative neuroprotective strategies for progressive MS. NLRX1 is an innate immune sensor that negatively regulates several inflammatory pathways, including NF-κB. Design/Methods Active, spontaneous, and adoptive transfer EAE models were used to evaluate the impact of NLRX1. Retinal ganglion cell (RGC) count, optic nerve axonal degeneration, gliosis, and T-cell infiltration were assessed by immunohistochemistry (IHC). Adoptive transfer experiments transferred MOG-specific T-cells into Rag -/- and Nlrx1 -/- Rag -/- mice. Lastly, LPS-stimulated mixed-glial cultures and EAE mice were treated with novel NLRX1 agonists. Results This study revealed significantly worse RGC loss and decreased optic nerve neurofilament light chain expression in Nlrx1 -/- mice compared to WT mice in both active and spontaneous EAE, despite no change in the infiltration of peripheral T-cells. Adoptive transfer EAE experiments showed that Nlrx1 -/- Rag -/- mice had increased Iba1 and GFAP expression in their optic nerves compared to compared to Rag -/- mice. Two novel NLRX1 agonists, NX-13 and LABP-66, were able to decrease NF-κB inflammatory gene expression in LPS-simulated mixed glia in an NLRX1-dependent manner. Oral treatment with LABP-66 in active EAE mice after disease onset resulted in significantly higher RGC density (less RGC loss) compared to vehicle-treated mice. Conclusions These findings collectively suggest that NLRX1 plays a neuroprotective role in inflammatory neurodegeneration and protection may occur, at least in part, through downregulation of reactive microglia and astrocytes. NLRX1 and other innate immune system regulators of inflammatory glia should continue to be studied to aid in the development of novel therapeutic strategies for progressive MS.
Source: Neurology
Language: English
Subfield: Pathology and Forensic Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W4403206400