NLRX1 inhibits the early stages of CNS inflammation and prevents the onset of spontaneous autoimmunity.

Marjan Gharagozloo,Subburaj Ilangumaran,Peter A Calabresi,Samir Jarjoura,Denis Gris,Albert Lamontagne,Matthew D Smith,Diwakar Bobbala,Louis Gendron,Jenny P Ting,Jean-Bernard Denault,Kenzo Yamamoto,Shaimaa Mahmoud,Carles Vilariño-Güell,Abdelaziz Amrani,A Dessa Sadovnick,Véronique Blais,Camille Simard

doi:10.1371/journal.pbio.3000451

Abstract

Nucleotide-binding, leucine-rich repeat containing X1 (NLRX1) is a mitochondria-located innate immune sensor that inhibits major pro-inflammatory pathways such as type I interferon and nuclear factor-κB signaling. We generated a novel, spontaneous, and rapidly progressing mouse model of multiple sclerosis (MS) by crossing myelin-specific T-cell receptor (TCR) transgenic mice with Nlrx1−/− mice. About half of the resulting progeny developed spontaneous experimental autoimmune encephalomyelitis (spEAE), which was associated with severe demyelination and inflammation in the central nervous system (CNS). Using lymphocyte-deficient mice and a series of adoptive transfer experiments, we demonstrate that genetic susceptibility to EAE lies within the innate immune compartment. We show that NLRX1 inhibits the subclinical stages of microglial activation and prevents the generation of neurotoxic astrocytes that induce neuronal and oligodendrocyte death in vitro. Moreover, we discovered several mutations within NLRX1 that run in MS-affected families. In summary, our findings highlight the importance of NLRX1 in controlling the early stages of CNS inflammation and preventing the onset of spontaneous autoimmunity.

Highlights

Multiple sclerosis (MS) is a neurological disease that affects young adults, leading to long-term disabilities with a staggering societal cost [1]
To study what role NLRX1 plays in the initiation of central nervous system (CNS) inflammation, we crossed T-cell receptor (TCR) transgenic 2D2 mice to Nlrx1−/− mice and measured the incidence of spontaneous experimental autoimmune encephalomyelitis (spEAE) in 2D2 and Nlrx1−/− 2D2 mice housed under the same pathogen-free conditions
When we assessed the presence of inflammation in the CNS of Nlrx1−/− 2D2 spEAE mice, we found that the lack of NLRX1 did not affect the expression of glial fibrillary acidic protein (GFAP), ionized calcium binding adaptor molecule 1(Iba1), and myelin basic protein (MBP) in the spinal cords of healthy Nlrx1−/− 2D2 mice (S1A Fig)

Summary

Introduction

Multiple sclerosis (MS) is a neurological disease that affects young adults, leading to long-term disabilities with a staggering societal cost [1]. It is associated with inflammation-driven demyelination and neurodegeneration within the central nervous system (CNS) [1,2]. The inside-out model presents the idea that MS is primarily initiated by neurodegenerative processes in which oligodendrocyte and/ or neuronal injury or death triggers the CNS inflammation in the absence of a direct immune attack [4,6,7] This inflammation leads to the drainage of CNS antigens into secondary lymphoid organs and consequent activation of autoreactive T and B cells [6]

Methods

Results

Conclusion