System xC- is a mediator of microglial function and its deletion slows symptoms in amyotrophic lateral sclerosis mice.
Amyotrophic lateral sclerosis is the most common adult-onset motor neuron disease and evidence from mice expressing amyotrophic lateral sclerosis-causing SOD1 mutations suggest that neurodegeneration is a non-cell autonomous process where microglial cells influence disease progression. However, microglial-derived neurotoxic factors still remain largely unidentified in amyotrophic lateral sclerosis. With excitotoxicity being a major mechanism proposed to cause motor neuron death in amyotrophic lateral sclerosis, our hypothesis was that excessive glutamate release by activated microglia through their system [Formula: see text] (a cystine/glutamate antiporter with the specific subunit xCT/Slc7a11) could contribute to neurodegeneration. Here we show that xCT expression is enriched in microglia compared to total mouse spinal cord and absent from motor neurons. Activated microglia induced xCT expression and during disease, xCT levels were increased in both spinal cord and isolated microglia from mutant SOD1 amyotrophic lateral sclerosis mice. Expression of xCT was also detectable in spinal cord post-mortem tissues of patients with amyotrophic lateral sclerosis and correlated with increased inflammation. Genetic deletion of xCT in mice demonstrated that activated microglia released glutamate mainly through system [Formula: see text]. Interestingly, xCT deletion also led to decreased production of specific microglial pro-inflammatory/neurotoxic factors including nitric oxide, TNFa and IL6, whereas expression of anti-inflammatory/neuroprotective markers such as Ym1/Chil3 were increased, indicating that xCT regulates microglial functions. In amyotrophic lateral sclerosis mice, xCT deletion surprisingly led to earlier symptom onset but, importantly, this was followed by a significantly slowed progressive disease phase, which resulted in more surviving motor neurons. These results are consistent with a deleterious contribution of microglial-derived glutamate during symptomatic disease. Therefore, we show that system [Formula: see text] participates in microglial reactivity and modulates amyotrophic lateral sclerosis motor neuron degeneration, revealing system [Formula: see text] inactivation, as a potential approach to slow amyotrophic lateral sclerosis disease progression after onset of clinical symptoms.
1 Inserm U 1127, CNRS UMR 7225, Sorbonne Universités, UPMC Univ Paris 06 UMR S 1127, Institut du Cerveau et de la Moelle épinière, ICM, F-75013, Paris, France.
Pinar
P
Mesci
1 Inserm U 1127, CNRS UMR 7225, Sorbonne Universités, UPMC Univ Paris 06 UMR S 1127, Institut du Cerveau et de la Moelle épinière, ICM, F-75013, Paris, France.
Sakina
S
Zaïdi
1 Inserm U 1127, CNRS UMR 7225, Sorbonne Universités, UPMC Univ Paris 06 UMR S 1127, Institut du Cerveau et de la Moelle épinière, ICM, F-75013, Paris, France.
Christian S
CS
Lobsiger
1 Inserm U 1127, CNRS UMR 7225, Sorbonne Universités, UPMC Univ Paris 06 UMR S 1127, Institut du Cerveau et de la Moelle épinière, ICM, F-75013, Paris, France.
Stéphanie
S
Millecamps
2 CEA, DSV, I2BM, MIRCen and CNRS URA2210, Fontenay-aux-Roses, France.
Carole
C
Escartin
1 Inserm U 1127, CNRS UMR 7225, Sorbonne Universités, UPMC Univ Paris 06 UMR S 1127, Institut du Cerveau et de la Moelle épinière, ICM, F-75013, Paris, France.
Danielle
D
Seilhean
3 Department of Food and Applied Life Sciences, Faculty of Agriculture, Yamagata University, Tsuruoka, Yamagata, Japan.
Hideyo
H
Sato
1 Inserm U 1127, CNRS UMR 7225, Sorbonne Universités, UPMC Univ Paris 06 UMR S 1127, Institut du Cerveau et de la Moelle épinière, ICM, F-75013, Paris, France.
Michel
M
Mallat
1 Inserm U 1127, CNRS UMR 7225, Sorbonne Universités, UPMC Univ Paris 06 UMR S 1127, Institut du Cerveau et de la Moelle épinière, ICM, F-75013, Paris, France severine.boillee@upmc.fr.
Séverine
S
Boillée
D026962:Amino Acid Transport System ASC / Q000172:deficiency*; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics* / Q000401:mortality / Q000503:physiopathology*; D000818:Animals; D000831:Animals, Newborn; D002540:Cerebral Cortex / Q000166:cytology; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017628:Microglia / Q000187:drug effects / Q000378:metabolism*; D009046:Motor Neurons / Q000187:drug effects / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D009569:Nitric Oxide / Q000378:metabolism; D013482:Superoxide Dismutase / Q000235:genetics; D000072105:Superoxide Dismutase-1
D026962:Amino Acid Transport System ASC; D016207:Cytokines; D008070:Lipopolysaccharides; C000606290:SOD1 protein, human; D009569:Nitric Oxide; C470429:SOD1 G37R protein, mouse; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D005978:Glutathione
ALS; excitotoxicity; motoneuron; neuroinflammation; xCT