System xC− is a mediator of microglial function and its deletion slows symptoms in amyotrophic lateral sclerosis mice

Abstract

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.

Glioblastoma cells induce differential glutamatergic gene expressions in human tumor-associated microglia/macrophages and monocyte-derived macrophages

“…Pro-and anti-inflammatory molecules have been reported to alter expression of EAAT1, EAAT2 and xCT. A proinflammatory milieu appears to lead to increased expression of EAAT and xCT, 19,20,21 but so do anti-inflammatory molecules. 15,22 It is worth noting that, in our study, this is an immunosuppressive, anti-inflammatory milieu that led to alterations in gene expression of glutamate receptor and transporters as well as GS that were found to differ between TAMs and MDMs.…”

“…The decrease in xCT gene expression was observed to be statistically significant in MDMs after co-culture with glioblastoma cells compared to MDMs after co-culture with NHA. A low xCT expression has been reported to be linked to a more anti-inflammatory and neuroprotective phenotype, 15,20,21 which is a typical phenotype of TAMs. The decreased xCT gene expression might account for the fTAMs and MDMs response to reduce additional release of glutamate into the extracellular matrix.…”

Inflammation, Glutamate, and Glia: A Trio of Trouble in Mood Disorders

“…Probably owing to their spatial proximity, glutamate released by the xC-system has preferential access to extrasynaptic NMDA receptors in a paracrine manner leading to neuronal toxicity as described earlier (Camacho and Massieu, 2006;Hardingham and Bading, 2010). Inflammatory cytokines including TNF and LPS administration upregulate the xC-system and induce glutamate release from cultured and primary microglia (Figuera-Losada et al, 2014;Mesci et al, 2015;Piani and Fontana, 1994). Similarly, IL-1β has been implicated in increasing the xC-system expression on the surface of astrocytes (but not on microglia or macrophages)-an effect that is mediated through the activation of nuclear factor kappa B (NF-kB) signaling (Jackman et al, 2010).…”

Astrocytic transporters in Alzheimer's disease

“…To date, however, there are no studies characterising changes in CT, 4F2hc levels or xc-activity in AD or animal models of AD disease. Nonetheless, neuroprotective properties of ceftriaxone in an animal model of motor neuron disease have been attributed to its ability to induce XCT (190) but, paradoxically, deletion of XCT reduces symptoms in a transgenic mouse model of motor neuron disease (191). Therefore, it remains to be demonstrated if system xc-is a worthwhile target in the search for novel AD therapeutics.…”