The concept of depression as a dysfunction of the immune system

Abstract

Chronic stress, by initiating changes in the hypothalamic-pituitary-adrenal axis and the immune system, acts as a trigger for anxiety and depression. Both experimental and clinical evidence shows that a rise in the concentrations of proinflammatory cytokines and glucocorticoids, as occurs in chronically stressful situations and in depression, contribute to the behavioural changes associated with depression.A defect in serotonergic function is associated with hypercortisolaemia and the increase in proinflammatory cytokines that accompany depression. Glucocorticoids and proinflammatory cytokines enhance the conversion of tryptophan to kynurenine. In addition to the resulting decrease in the synthesis of brain serotonin, this leads to the formation of neurotoxins such as the glutamate agonist quinolinic acid and contributes to the increase in apoptosis of astrocytes, oligodendroglia and neurons.The importance of the inflammation hypothesis of depression lies in raising the possibility that psychotropic drugs that have a central anti-inflammatory action might provide a new generation of antidepressants.

Figure 1

Stress causes the activation of the corticotrophin releasing factor (CRF) in the corticolimbic regions of the brain. CRF activates the hypothalamic-pituitary-adrenal axis resulting in an elevation in circulating glucocorticoids. In addition, CRF activates the locus coeruleus which results in an increase in central and peripheral sympathetic activity. Stress increases the release of pro-inflammatory cytokines from microglia in the brain and from macrophages in the blood. In addition noradrenaline and adrenaline, from the sympathetic system, also activate the macrophages and microglia thereby contributing to the inflammatory response. Chronic hypercortisolaemia that results from the lowered stress threshold in depression, combined with the activation of the anterior pituitary by the pro-inflammatory cytokine interleukin-6, desensitizes the glucocorticoid type 2 receptors on immune cells, and in the pituitary, hypothalamus and on neurons. This causes glucocorticoid resistance. The increase in the mobilization of fat by the glucocorticoids contributes to the increased deposition of visceral fat. Visceral fat acts as an extra-endocrine organ and liberates pro-inflammatory cytokines together with the peptides leptin and resistin. Leptin contributes to the activation of the HPA axis while resistin, together with the increased glucocorticoids, contributes to insulin resistance.

Figure 2

In depression, tryptophan is preferentially metabolized through the kynurenine pathway. The two key enzymes that convert tryptophan to kynurenine are indoleamine 2,3 dioxygenase (IDO) and tryptophan dioxygenase (TDO). IDO, that is quite widely distributed in the peripheral tissues and the brain, is induced by pro-inflammatory cytokines while TDO, which is confined to the liver, is induced by glucocorticoids. In depression, kynurenine is further metabolized to 3-hydroxykynurenine by kynurenine 3 mono-oxygenase, an enzyme that is also induced by pro-inflammatory cytokines. The most important end product of this inflammatory pathway is the neurotoxin quinolinic acid which activates N-methyl-D-aspartate glutamate receptor on neurons leading to neuronal apoptosis. Activated microglia synthesise quinolinic acid in the brain while astrocytes can metabolise the toxin to nicotinamide-adenine dinucleotide (NAD) when present in low concentrations. High concentrations of quinolinic acid, thought to occur in chronic depression, cause apoptosis of astrocytes thereby increasing the vulnerability of the neurons to neurotoxic damage.