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.