Glia in the cytokine-mediated onset of depression: fine tuning the immune response

Abstract

Major depressive disorder (MDD) is a mood disorder of multifactorial origin affecting millions of people worldwide. The alarming estimated rates of prevalence and relapse make it a global public health concern. Moreover, the current setback of available antidepressants in the clinical setting is discouraging. Therefore, efforts to eradicate depression should be directed towards understanding the pathomechanisms involved in the hope of finding cost-effective treatment alternatives. The pathophysiology of MDD comprises the breakdown of different pathways, including the hypothalamus-pituitary-adrenal (HPA) axis, the glutamatergic system, and monoaminergic neurotransmission, affecting cognition and emotional behavior. Inflammatory cytokines have been postulated to be the possible link and culprit in the disruption of these systems. In addition, evidence from different studies suggests that impairment of glial functions appears to be a major contributor as well. Thus, the intricate role between glia, namely microglia and astrocytes, and the central nervous system's (CNSs) immune response is briefly discussed, highlighting the kynurenine pathway as a pivotal player. Moreover, evaluations of different treatment strategies targeting the inflammatory response are considered. The immuno-modulatory properties of vitamin D receptor (VDR) suggest that vitamin D is an attractive and plausible candidate in spite of controversial findings. Further research investigating the role of VDR in mood disorders is warranted.

Keywords: KYN pathway; VDR; depression; glia; inflammation; vitamin D.

Figure 1

Vitamin D and its receptor (VDR) in the cytokine-mediated onset of depression. (A) Stress and/or infection activate the inflammatory response resulting in inflammatory cytokines production. These cytokines can trigger the kynurenine (KYN) pathway by stimulating indoleamine 2, 3-dioxygenase (IDO). Therefore, tryptophan enters the KYN pathway instead of the serotonergic pathway, resulting in the depletion of monoamines. Once the KYN pathway is triggered, kynurenic acid (KA) in astrocytes and quinolinic acid (QUIN) in microglia are synthesized. QUIN contributes to the activation of N-methyl-D-aspartate receptor (NMDAr) itself and by inhibiting glutamate re-uptake, resulting in excessive extracellular glutamate, inducing further NMDAr agonism. Excessive NMDAr activation leads to the disruption of the glutamatergic system, a key pathological feature in mood disorders. (B) The binding of vitamin D to VDR in a number of immune cells (e.g., macrophages, neutrophils, dendritic cells, B cells, T cells, astrocytes and microglia) leads to attenuation of the inflammatory response and stimulation of anti-microbial peptides production, potentially ameliorating symptoms of mood disorders. However, certain pathogens can also block or modulate epigenetic VDR activity.