System xc− regulates microglia and macrophage glutamate excitotoxicity in vivo

Abstract

It is widely believed that microglia and monocyte-derived macrophages (collectively referred to as central nervous system (CNS) macrophages) cause excitotoxicity in the diseased or injured CNS. This view has evolved mostly from in vitro studies showing that neurotoxic concentrations of glutamate are released from CNS macrophages stimulated with lipopolysaccharide (LPS), a potent inflammogen. We hypothesized that excitotoxic killing by CNS macrophages is more rigorously controlled in vivo, requiring both the activation of the glutamate/cystine antiporter (system xc-) and an increase in extracellular cystine, the substrate that drives glutamate release. Here, we show that non-traumatic microinjection of low-dose LPS into spinal cord gray matter activates CNS macrophages but without causing overt neuropathology. In contrast, neurotoxic inflammation occurs when LPS and cystine are co-injected. Simultaneous injection of NBQX, an antagonist of AMPA glutamate receptors, reduces the neurotoxic effects of LPS+cystine, implicating glutamate as a mediator of neuronal cell death in this model. Surprisingly, neither LPS nor LPS+cystine adversely affects survival of oligodendrocytes or oligodendrocyte progenitor cells. Ex vivo analyses show that redox balance in microglia and macrophages is controlled by induction of system xc- and that high GSH:GSSG ratios predict the neurotoxic potential of these cells. Together, these data indicate that modulation of redox balance in CNS macrophages, perhaps through regulating system xc-, could be a novel approach for attenuating injurious neuroinflammatory cascades.

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

“…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). LPSinduced activation of TLR3 and 4 increases surface expression of the xC-system and thus co-administration of LPS and the xC-system stimulator cystine can potentially lead to enhanced glutamate toxicity (Kigerl et al, 2012). Increases in xC-system function have been implicated in multiple medical disorders (Massie et al, 2015), but more intriguingly is being actively targeted for new drug development for the treatment of substance dependence (Baker et al, 2003).…”

Redox Control of Microglial Function: Molecular Mechanisms and Functional Significance

“…It has been proposed that the modulation of thiol redox balance in microglia, possibly by targeting the X c -exchanger, could be an effective approach for attenuating injurious inflammatory cascades (126). Recent evidence shows that several flavonoid extracts from Rhus verniciflua were effective in preventing glutamate-mediated toxicity and oxidative stress in microglial cells in vitro (46).…”

Is there a role for glutamate-mediated excitotoxicity in inflammation-induced depression?

“…29,40 Tryptophan and kynurenine enter the brain via a sodium-independent large neutral amino-acid transporter known as System L (see Figure 2). 41,42 This transporter is composed of two subunits, a heavy glycoprotein chain, CD98, and one catalytic chain known as large neutral amino acid transporter, LAT-1. 41,42 Although it should be theoretically possible to block the entry of kynurenine into the brain by targeting LAT-1 during systemic inflammation to prevent inflammation-induced depression, this has not yet been tested.…”