NeuroImmune Transmitters: Glutamate

A common contributing cause of increased excitatory stimulation is elevated glutamate as a result of an overly active immune system. Glutamate is highly excitatory and is described as “excitotoxic” because elevated levels can damage neurons.  Elevated glutamate could be a root cause behind calming neurotransmitter (serotonin and GABA) imbalances and a consequence of imbalances in the immune system. Glutamate is highly influenced by the presence of both acute and chronic inflammatory responses. Glutamate is released upon over-activation of the kynurenine pathway by quinolinic acid (Figure 1) and from dendritic cells binding to antigens or dendritic cell maturation.  Glutamate binds directly to receptors on T cells and at concentration dependent doses affects their function to either enhance cytokine secretion (at mid to high glutamate concentration) or decrease cytokine secretion (at very high glutamate concentration).  Below, examples of glutamate’s association with the immune system will be explored

  • Figure 1. A peripheral inflammatory response is suggested to increase quinolinic acid from microglial cells, which is associated with increased glutamate release and decreased glutamate reuptake. (Image from Miller et al. 2009)

    Muller, et al., in 2007, described an integrated view of depression.  Activation of the kynurenine pathway by IL-2, IFN-γ, or TNF-α causes increases in indoleamine 2,3-dioxygenase (IDO) activation.  IDO is the enzyme responsible for the conversion of tryptophan to N-formylkynurenine, the start of the kynurenine pathway.  This increase in IDO activation leads to an increase of quinolinic acid in microglial cells, which can then overproduce glutamate in people with impaired astrocyte response to immune challenge causing an inflammatory response reaction.

  • Steiner, et al. (2011) found that severe depression is associated with increased microglial quiolinic acid in subregions of the anterior cingulate gyrus and hypothesized that this could be evidence for immune-modulated glutamatergic neurotransmission.
  • Franco, et al., (2007) describes the role of glutamate in T cell mediated immunity.  There are a number of glutamate receptors on resting T cells, including the ionotropic glutamate receptor 3 (iGlu3R) and metabotropic glutamate receptor 5 (mGlu5R).  Stimulation of iGlu3R promotes a pattern of adhesion and migration towards certain chemokines, and stimulation of mGlu5R impairs T cell activation.  Mature, glutamate-releasing dendritic cells in lymph nodes encounter patrolling naïve T cells and can promote T cell activation; however mGlu5R prevents excessive activation when dendritic cell signaling is not strong enough to promote activation.  When T cells become activated, the granzyme B they release degrades iGlu3R.  T cells also express metabotropic glutamate receptor 1 (mGlu1R), which promotes T cell activation partly by bypassing the mGlu5R-mediated inhibitory signal to potentiate T cell proliferation and enhancing the secretion of TNF-α, IFN-γ, and IL-6.  In this way, depending on the activation state of a T cell, glutamate can have an inhibitory or stimulating role on immune function.

Glutamate, in addition to acting as an excitatory neurotransmitter, also plays a role in immune function and modulation.  Increased glutamate is released in response to over-activation of the kynurenine pathway and quinolinic acid, which suggests evidence for immune-modulated glutamatergic neurotransmission.  Glutamate can also bind directly to T cell receptors to enhance or decrease cytokine secretion leading to immune modulation. When reviewing urinary neurotransmitter test results, it is important to keep in mind the immune system’s connection to glutamate. If patients are found to have elevated glutamate levels, root causes to immune system imbalances may need to be factored into differentials and further testing considerations.

References
Franco, R., et al. (2007). The emergence of neurotransmitters as immune modulators. Trends in immunology, 28(9):400-7.
Miller, A.H., Maletic, V., Raison, C.L. (2009). Inflammation and its discontents: the role of cytokines in the pathophysiology of major depression. Biol Psychiatry, 65(9):732-41.
Muller, N., Schwarz, M.J. (2007). The immune-mediated alteration of serotonin and glutamate: Towards and integrated view of depression. Molecular Psychiatry, 12(11):988-1000.
Steiner, J., et al. (2011). Severe depression is associated with increased microglial quiolinic acid in subregions of the anterior cingulate gyrus: Evidence for an immune-modulated glutamatergic neurotransmission?. Journal of Neuroinflammation, 8:94.
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