Clinical and central outcomes of peripheral inflammation: what is the role of system xc-?

A variety of pathological stimuli is able to induce systemic inflammation. When systemic inflammation occurs, soluble mediators released from peripheral immune cells are able to reach the central nervous system (CNS) leading to defective brain homeostasis and activation of central immune cells, further exacerbating brain inflammation. Moreover, peripheral inflammation also leads to acute and chronic effects on cognition and behavior. System xc-, with xCT as specific subunit, exchanges intracellular glutamate for extracellular cystine and is the main source of extracellular glutamate in mouse hippocampus and striatum. In vitro, it has been shown that several pro-inflammatory stimuli increase the expression of xCT. Besides leading to excessive release of glutamate, increased expression and/or activity of system xc- can directly influence microglia phenotypes towards a pro-inflammatory/neurotoxic state. Modulation of system xc- could therefore be beneficial in inflammation-related disorders in two ways: attenuate the glial release of toxic amounts of glutamate and directly influence microglial polarization towards a protective phenotype. In this study we induced peripheral inflammation via a single injection of 5 mg/kg bacterial lipopolysaccharide (LPS) i.p. and we sought to: i) investigate the consequences of peripheral inflammation on glutamate transporters, ii) unveil the central effects of peripheral inflammation in xCT+/+ and xCT-/- mice and iii) evaluate if deletion of xCT dampens acute clinical implications induced by peripheral inflammation. We demonstrated that LPS strongly impairs glutamate homeostasis in vivo leading to significant changes in xCT and GLT1 glutamate transporter protein expression levels in the hippocampus 1 week p.i. Those changes may potentially trigger enhanced hyperexcitability and neuronal death due to toxic extracellular levels of glutamate. We observed that in xCT-/- mice several LPS-induced clinical implications, such as hypothermia, depressive-like behavior in the forced swim and tail suspension tests and increased seizure susceptibility in the pentylenetetrazole model, were significantly attenuated. Our results highlight the importance of system xc- under inflammatory conditions and bring us one step closer in better understanding its potential relevance in neurological disorders characterized by neuroinflammation.