Neuroimmune mechanisms of cytokine-induced depression: current theories and novel treatment strategies

Abstract

The relationships between immune and neural function are an increasingly important area of study for neuropsychiatric disorders, in particular depression. This is exemplified by the growing number of publications on cytokines and depression during the last 10 years, as compared to earlier decades. This review summarizes the current theories and novel treatment strategies for depression, with a focus on cytokine-induced depression. Neuroimmune mechanisms are now viewed as central to the development of depressive symptoms and emerging evidence is beginning to identify the neural circuits involved in cytokine-induced depression. The current diagnostic categories for depression, as defined by the Diagnostic and Statistical Manual of Mental Disorders, however, are not etiologically or biologically derived, and it has been proposed that "depression", likely reflects multiple pathogeneses leading to varying symptom constellations. As we move toward a better biological understanding of depression-related symptom constellations or syndromes, the term "depression" may prove inadequately broad, and an integration of interdisciplinary literatures will increase in importance. Future research should aim to characterize these depression-related symptom constellations or syndromes better with the goal of optimizing treatment strategies.

Fig. 1

The dramatic increase in research on the topic of cytokine-induced depression is illustrated by the significantly higher number of original and review articles, rapid communications, letters to the editor and case reports published in the last 9 years, as compared to earlier decades. PubMed was searched from 1980 to present with “cytokines and major depression” used as the search terms. It is noteworthy that from 2000 to present, of the 616 articles published, 29% were review articles, highlighting the importance of this topic yet the need for more original research.

Fig. 2

Immune and central nervous systems interact and contribute to the etiology and pathophysiology of cytokine-induced depression. Text boxes summarize the putative factors contributing to the development of depressive symptoms as well as the accompanying alterations in peripheral and central neuroimmune modulators. Current theory proposes that years of cumulative risk factors (e.g., genetic polymorphisms, repeated brain injuries or vascular insults, exposure to stress and toxins, or oxidative stress) combine to activate danger associated molecular pattern detectors (DAMPs) within the innate immune system, in turn modifying microglial receptors [e.g., toll-like receptors (TLRs), receptors for highly glycosylated end products (RAGEs)], resulting in the chronic overproduction of proinflammatory cytokines such as TNF-α, IL-1β, and IL-6 (Maccioni et al., 2009). Related immune mechanisms activating pathogen associated molecular pattern molecules (PAMPs) are also speculated to contribute to the etiology of depressive symptoms and may be especially relevant for depression accompanying specific medical conditions. 2a. IDO pathway and its role in mediating cytokine-induced depression. Cytokines, such as IFN-γ, can induce the enzyme indoleamine 2,3-dioxygenase (IDO) or tryptophan 2,3-dioxygenase (TDO; an analogous enzyme located in the liver), which induces the metabolism of tryptophan. Activation of IDO decreases the amount of tryptophan for conversion to serotonin and increases the possibility of oxidative stress. Specifically, kynurenine, a metabolite of tryptophan, can be transported across the blood–brain barrier into the brain where it is further metabolized in macrophages, microglia and astrocytes leading to the generation of potentially neurotoxic compounds: 3-hydroxykynurenine (3-HK) and quinolinic acid (QA). Taken together, these studies provide support for the hypothesis that alterations in the regulation of certain cytokines such as IL-1, IL-6, and TNF-α released during an immune response activate the hepatic synthesis of CRP and components of the HPA axis, alter neurotransmitter networks activity, and induce fatigue, loss of appetite, anhedonia, and other depressive symptoms.