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

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

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Article numbere3000451
JournalPLoS biology
Volume17
Issue number9
DOIs
StatePublished - Jan 1 2019

Fingerprint

autoimmunity
Neurology
Autoimmunity
Leucine
leucine
central nervous system
Nucleotides
Central Nervous System
inflammation
nucleotides
Inflammation
sclerosis
Multiple Sclerosis
mice
Interferon Type I
Mitochondria
Autoimmune Experimental Encephalomyelitis
Lymphocytes
Adoptive Transfer
myelin sheath

ASJC Scopus subject areas

  • Neuroscience(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Gharagozloo, M., Mahmoud, S., Simard, C., Yamamoto, K., Bobbala, D., Ilangumaran, S., ... Gris, D. (2019). NLRX1 inhibits the early stages of CNS inflammation and prevents the onset of spontaneous autoimmunity. PLoS biology, 17(9), [e3000451]. https://doi.org/10.1371/journal.pbio.3000451

NLRX1 inhibits the early stages of CNS inflammation and prevents the onset of spontaneous autoimmunity. / Gharagozloo, Marjan; Mahmoud, Shaimaa; Simard, Camille; Yamamoto, Kenzo; Bobbala, Diwakar; Ilangumaran, Subburaj; Smith, Matthew D.; Lamontagne, Albert; Jarjoura, Samir; Denault, Jean Bernard; Blais, Véronique; Gendron, Louis; Vilariño-Güell, Carles; Dessa Sadovnick, A.; Ting, Jenny P.; Calabresi, Peter; Amrani, Abdelaziz; Gris, Denis.

In: PLoS biology, Vol. 17, No. 9, e3000451, 01.01.2019.

Research output: Contribution to journalArticle

Gharagozloo, M, Mahmoud, S, Simard, C, Yamamoto, K, Bobbala, D, Ilangumaran, S, Smith, MD, Lamontagne, A, Jarjoura, S, Denault, JB, Blais, V, Gendron, L, Vilariño-Güell, C, Dessa Sadovnick, A, Ting, JP, Calabresi, P, Amrani, A & Gris, D 2019, 'NLRX1 inhibits the early stages of CNS inflammation and prevents the onset of spontaneous autoimmunity', PLoS biology, vol. 17, no. 9, e3000451. https://doi.org/10.1371/journal.pbio.3000451
Gharagozloo M, Mahmoud S, Simard C, Yamamoto K, Bobbala D, Ilangumaran S et al. NLRX1 inhibits the early stages of CNS inflammation and prevents the onset of spontaneous autoimmunity. PLoS biology. 2019 Jan 1;17(9). e3000451. https://doi.org/10.1371/journal.pbio.3000451
Gharagozloo, Marjan ; Mahmoud, Shaimaa ; Simard, Camille ; Yamamoto, Kenzo ; Bobbala, Diwakar ; Ilangumaran, Subburaj ; Smith, Matthew D. ; Lamontagne, Albert ; Jarjoura, Samir ; Denault, Jean Bernard ; Blais, Véronique ; Gendron, Louis ; Vilariño-Güell, Carles ; Dessa Sadovnick, A. ; Ting, Jenny P. ; Calabresi, Peter ; Amrani, Abdelaziz ; Gris, Denis. / NLRX1 inhibits the early stages of CNS inflammation and prevents the onset of spontaneous autoimmunity. In: PLoS biology. 2019 ; Vol. 17, No. 9.
@article{7d242b122e6042bd9ee1a032f19506da,
title = "NLRX1 inhibits the early stages of CNS inflammation and prevents the onset of spontaneous autoimmunity",
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.",
author = "Marjan Gharagozloo and Shaimaa Mahmoud and Camille Simard and Kenzo Yamamoto and Diwakar Bobbala and Subburaj Ilangumaran and Smith, {Matthew D.} and Albert Lamontagne and Samir Jarjoura and Denault, {Jean Bernard} and V{\'e}ronique Blais and Louis Gendron and Carles Vilari{\~n}o-G{\"u}ell and {Dessa Sadovnick}, A. and Ting, {Jenny P.} and Peter Calabresi and Abdelaziz Amrani and Denis Gris",
year = "2019",
month = "1",
day = "1",
doi = "10.1371/journal.pbio.3000451",
language = "English (US)",
volume = "17",
journal = "PLoS Biology",
issn = "1544-9173",
publisher = "Public Library of Science",
number = "9",

}

TY - JOUR

T1 - NLRX1 inhibits the early stages of CNS inflammation and prevents the onset of spontaneous autoimmunity

AU - Gharagozloo, Marjan

AU - Mahmoud, Shaimaa

AU - Simard, Camille

AU - Yamamoto, Kenzo

AU - Bobbala, Diwakar

AU - Ilangumaran, Subburaj

AU - Smith, Matthew D.

AU - Lamontagne, Albert

AU - Jarjoura, Samir

AU - Denault, Jean Bernard

AU - Blais, Véronique

AU - Gendron, Louis

AU - Vilariño-Güell, Carles

AU - Dessa Sadovnick, A.

AU - Ting, Jenny P.

AU - Calabresi, Peter

AU - Amrani, Abdelaziz

AU - Gris, Denis

PY - 2019/1/1

Y1 - 2019/1/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85072716458&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85072716458&partnerID=8YFLogxK

U2 - 10.1371/journal.pbio.3000451

DO - 10.1371/journal.pbio.3000451

M3 - Article

C2 - 31525189

AN - SCOPUS:85072716458

VL - 17

JO - PLoS Biology

JF - PLoS Biology

SN - 1544-9173

IS - 9

M1 - e3000451

ER -