System xc− in microglia is a novel therapeutic target for post-septic neurological and psychiatric illness

Abstract

Post-septic neurological and psychiatric illness (PSNPI) including dementia and depression may be observed after sepsis. However, the etiology of PSNPI and therapeutic treatment of PSNPI are unclear. We show that glutamate produced from microglia through the activity of system x c − plays a role in PSNPI. We established a mouse model of PSNPI by lipopolysaccharide (LPS) treatment that shows a disturbance of short/working memory and depression-like hypoactivity. Glutamate receptor antagonists (MK801 and DNQX) reduced these phenotypes, and isolated microglia from LPS-treated mice released abundant glutamate. We identified system x c − as a source of the extracellular glutamate. xCT, a component of system x c − , was induced and expressed in microglia after LPS treatment. In xCT knockout mice, PSNPI were decreased compared to those in wildtype mice. Moreover, TNF-α and IL-1β expression in wildtype mice was increased after LPS treatment, but inhibited in xCT knockout mice. Thus, system x c − in microglia may be a therapeutic target for PSNPI. The administration of sulfasalazine, an inhibitor of xCT, in symptomatic and post-symptomatic mice improved PSNPI. Our results suggest that glutamate released from microglia through system x c − plays a critical role in the manifestations of PSNPI and that system x c − may be a therapeutic target for PSNPI.

Cystine–glutamate antiporter deletion accelerates motor recovery and improves histological outcomes following spinal cord injury in mice

“…As demonstrated by the double labeling, slc7a11 /xCT mRNA was not found in the satellite oligodendrocytes. Our results, although based on in situ gene expression, are partly in line with those showing xCT protein in meningeal cells 32 , 33 , in astrocyte subpopulations 23 , 34 , 35 and in microglia 17 – 19 , 27 , 32 , 35 – 37 , while questioning an expression by oligodendrocytes 20 – 22 , 34 or neuron subtypes described elsewhere 19 , 22 , 37 . Instead, slc7a11 /xCT ish signal was widely distributed in gray matter neuropil where numerous neuronal and glial processes interwove, with a high density throughout Rexed laminae I to III.…”

“…Several lines of evidence now support that System xc− regulates the way microglia and macrophages polarize or activate along their inflammatory response 27 , 35 . In our model of SCI, we showed an impact of xCT deletion on the degree of microglia/macrophage activation; within the first two weeks post-SCI, injured xCT−/− spinal cords had an increased number of resting “type A” microglia/macrophage at several distances around the epicenter.…”

“…These findings on pro-to-anti-inflamatory gene response have been described in a similar context when xCT−/− mice were crossed with mutant SOD1 G37R ALS mice and ALS disease course was slowed down 27 . Also, xCT-deficiency alleviates the release of pro-inflammatory cytokines in the cerebral cortex or hippocampus in a model of LPS-induced post-septic neurological psychiatric illness 23 , 35 .…”

Update on the Relationship Between Depression and Neuroendocrine Metabolism

“…Astrocytes use glutamine synthetase to convert glutamate to glutamine ( Martinez-Hernandez et al, 1977 ), which is then supplied to neurons. Neurons convert glutamine to glutamate via glutaminase ( Kvamme et al, 2000 ) and repackage it into synaptic vesicles ( Fremeau et al, 2004 ) activating microglia to release glutamate via cystine/glutamate antiporter ( Mesci et al, 2015 ; Kitagawa et al, 2019 ). At the same time, activated microglia also release pro-inflammatory cytokines, activate astrocytes ( Bezzi et al, 2001 ; Liddelow et al, 2017 ), induce glutamate release from astrocytes ( Casamenti et al, 1999 ; Bezzi et al, 2001 ), and interfere with glutamate uptake ( Hu et al, 2000 ; Mandolesi et al, 2013 ; Hyvärinen et al, 2019 ).…”

Duzhong Fang Attenuates the POMC-Derived Neuroinflammation in Parkinsonian Mice

“…46 Recent studies have shown that microglia adopts two different functional phenotypes, consisting of phenotypes of "classical" reactivity and "alternative" reactivity. 47,48 Although the dichotomy classical/alternative is now recognized as oversimplification, this classification is still useful for understanding the function of microglia in various brain diseases. 49 When activated as a classical reactivity, microglia produces large amounts of neurotoxic mediators (IL-1β, TNF-α, NO) and worsen long-term neurological deficits after damage.…”