Cytokine, sickness behavior, and depression

Abstract

Sufficient evidence is now available to accept the concept that the brain recognizes cytokines as molecular signals of sickness. Clarifying the way the brain processes information generated by the innate immune system is accompanied by a progressive elucidation of the cellular and molecular components of the intricate system that mediates cytokine-induced sickness behavior. We are still far, however, from understanding the whole. Among the hundreds of genes that proinflammatory cytokines can induce in their cellular targets, only a handful has been examined functionally. In addition, a dynamic view of the cellular interactions that occur at the brain sites of cytokine production and action is missing, together with a clarification of the mechanisms that favor the transition toward pathology.

Fig. 1

Mechanisms of brain actions of cytokines. Proinflammatory cytokines are released by activated innate immune cells at the periphery in response to PAMP. PAMP and circulating cytokines act on TLRs on macrophage-like cells in the CVOs and choroid plexus, leading to the production of brain cytokines that diffuse by volume propagation into the brain parenchyma. The action of peripheral proinflammatory cytokines also can be relayed to the brain by afferent nerves, resulting in the production of brain proinflammatory cytokines by microglial cells. In both cases, the action of brain proinflammatory cytokines can be mediated by prostaglandins that diffuse to brain targets or by activation of neural pathways within the brain, which enables the immune message to be transported far away from its site of origin. Prostaglandins can be synthesized only by endothelial cells of brain venules in response to circulating cytokines. Dotted arrows represent instances of neural transmission of the immune message from the periphery to the brain or within the brain itself.

Fig. 2

Motivational model of sickness. Like fear, sickness has motivational properties in the sense that it organizes the organism's functioning at three levels—subjective, behavioral, and visceral—so as to cope with the threat to which the organism is exposed.

Fig. 3

The two-hit model of cytokine-induced depression. Production of proinflammatory cytokines induces sickness behavior that usually is terminated by endogenous anti-inflammatory molecules. Sustained production of proinflammatory cytokines in the context of insufficient production of anti-inflammatory molecules can lead to depression in vulnerable individuals. Many factors, acquired or genetic, can contribute to vulnerability.

Fig. 4

Mechanisms of the depressing effects of cytokines on mood. Activation of the innate immune system is triggered by cytokine immunotherapy or psychosocial stressors (via a β2adrenergic receptor). It results in the overproduction of proinflammatory cytokines. The same condition occurs during chronic inflammation. Cytokines, such as TNF-α and IFN-γ, increase activity of the enzyme, IDO, that degrades tryptophan along the kynurenine/quinolinic acid metabolic pathway, resulting in a decrease in tryptophan and an increase in kynurenine. The decreased tryptophan bioavailability leads to decreased serotoninergic neurotransmission and depressed mood. Depression itself can be accompanied by altered immunity, including activation of the innate immune system, further increasing the proinflammatory cytokine load.