Novel Treatment Targets Based on Insights in the Etiology of Depression: Role of IL-6 Trans-Signaling and Stress-Induced Elevation of Glutamate and ATP

Abstract

Inflammation and psychological stress are risk factors for major depression and suicide. Both increase central glutamate levels and activate the hypothalamic-pituitary-adrenal axis and the sympathetic nervous system. Both factors also affect the function of the chloride transporters, Na-K-Cl-cotransporter-1 (NKCC1) and K-Cl-cotransporter-2 (KCC2), and provoke interleukin-6 (IL-6) trans-signaling. This leads to measurable increases in circulating corticosteroids, catecholamines, anxiety, somatic and psychological symptoms, and a decline in cognitive functions. Recognition of the sequence of pathological events allows the prediction of novel targets for therapeutic intervention. Amongst others, these include blockade of the big-K potassium channel, blockade of the P2X4 channel, TYK2-kinase inhibition, noradrenaline α2B-receptor antagonism, nicotinic α7-receptor stimulation, and the Sgp130Fc antibody. A better understanding of downstream processes evoked by inflammation and stress also allows suggestions for tentatively better biomarkers (e.g., SERPINA3N, MARCKS, or ¹³C-tryptophan metabolism).

Keywords: inflammasome; ketamine; major depressive disorder; suicide; vagus nerve.

Figure 1

This scheme is based upon data published by [44,58]. Stress activates a sequence of events that involves neuron-derived glutamate, astrocyte-derived ATP, and microglia-derived brain-derived neurotrophic factor (BDNF), and ultimately results in higher network excitability. Since stress induces dendritic atrophy, the elevated network excitability might serve a repair function. Legend: GR, glucocorticoid receptor; NMDA, N-methyl-D-aspartate; TrkB, tropomyosin receptor kinase-B; KCC2, K-Cl-cotransporter-2.

Figure 2

This scheme is based upon data published by [143]. It assumes that inflammation causes interleukin-6 (IL6)-release and shedding of sIL6R from microglia. Trans-activation of astrocytes would lead to the ‘neurotoxic-reactive’ phenotype that may cause damage to neurons. Activation of the glucocorticoid receptor would limit the inflammation-induced sequence of events. Legend: sIL6R, soluble IL-6-receptor.

Figure 3

A graphical summary of the biological effects induced by stress and inflammation. As reviewed in Section 2 and Section 3 of this manuscript, inflammation and psychological stress activate the hypothalamic-pituitary-adrenal (HPA) axis, the sympathetic nervous system, and increase glutamate, while the inhibitory effect of gamma-aminobutyric acid (GABA) is diminished. This leads to measurable increases in circulating corticosteroids, catecholamines, anxiety, somatic and psychopathological symptoms, and a decline in cognitive functions. Both stress and inflammation affect the function of the chloride transporters, Na-K-Cl-cotransporter-1 (NKCC1) and K-Cl-cotransporter-2 (KCC2), and provoke IL-6 trans-signaling. Although there is a large qualitative overlap, it may be that stress and inflammation lead to quantitative differences in the severity of the individual effects. Legend: BP = blood pressure, CS = corticosterone, HR = heart rate, NA = noradrenaline, ns = nervous system, PKC = protein kinase C, sIL6R = soluble IL6 receptor.