Elsevier

Brain, Behavior, and Immunity

Volume 31, July 2013, Pages 105-114
Brain, Behavior, and Immunity

The inflammasome: Pathways linking psychological stress, depression, and systemic illnesses

https://doi.org/10.1016/j.bbi.2012.12.008Get rights and content

Abstract

Stress is a common occurrence in everyday life and repeated or traumatic stress can be a precipitating factor for illnesses of the central nervous system, as well as peripheral organ systems. For example, severe or long-term psychological stress can not only induce depression, a leading illness worldwide, but can also cause psychosomatic diseases such as asthma and rheumatoid arthritis. Related key questions include how psychological stress influences both brain and peripheral systems, and what detection mechanisms underlie these effects? A clue is provided by the discovery of the pathways underlying the responses to host “danger” substances that cause systemic diseases, but can also contribute to depression. The inflammasome is a protein complex that can detect diverse danger signals and produce the accompanying immune-inflammatory reactions. Interestingly, the inflammasome can detect not only pathogen-associated molecules, but also cell damage-associated molecules such as ATP. Here, we propose a new inflammasome hypothesis of depression and related comorbid systemic illnesses. According to this hypothesis, the inflammasome is a central mediator by which psychological and physical stressors can contribute to the development of depression, and as well as a bridge to systemic diseases. This hypothesis includes an explanation for how psychological stress can influence systemic diseases, and conversely how systemic diseases can lead to psychiatric illnesses. The evidence suggests that the inflammasome may be a new target for the development of treatments for depression, as well as psychosomatic and somato-psycho diseases.

Highlight

► The inflammasome is a broad range sensor of danger signals and mediator of psychological and physical stressors that can lead to depression and comorbid illnesses.

Introduction

Major depressive disorder (MDD) is characterized by depressed mood, low self-esteem, anhedonia, and disrupted sleeping, eating, and cognition, and has now been recognized to have an overall impact on global illness that is projected to be second only to ischemic heart disease in social and economical burden by 2020 (Greden, 2001, Murray and Lopez, 1997). In the United States, about 14 million people, or about 10% of the population, suffer from depression at any point in time (Kessler et al., 2003). Because approximately one third of MDD patients do not respond to traditional pharmacological medications such as monoamine reuptake inhibitors, there is a major unmet need for the development of novel, more efficacious therapeutic agents.

Although it is clear that genetic factors are involved [heritability estimates from twin studies are reported to be 37%–38% (Kendler et al., 2006, Sullivan et al., 2000)], environmental factors such as stress are strongly implicated in the pathology of depression (Kessler, 1997). Levels of stress have increased with growing social and economic demands in recent decades, resulting in a rapid rise in the prevalence of depression (Kessler et al., 2003). Here, we discuss evidence that psychological, as well as physical stressors can activate immune and inflammation processes and lead to increased cytokine levels, contributing to structural and functional alterations of neurons and the development of MDD.

A role for inflammation and related cytokines in MDD was first suggested in the 1980’s and since then evidence has accumulated in support of this hypothesis (Ader and Cohen, 1993, Maes, 1995, Maier et al., 1994, Tecoma and Huey, 1985). There have been several excellent reviews of this work, but the current paper examines a novel aspect of the immune-inflammation process in the response to stress and depression: that interkeukin-1β (IL-1β) and its regulator, “the Nod-like receptor (NLR) family, pyrin domain-containing 3 (NLRP3) inflammasome”, are a bridge between psychological stress and depression. Related to this hypothesis is the possibility that the inflammasome provides a bidirectional pathway between depression and comorbid systemic illnesses, suggesting novel strategies for treating depression.

Section snippets

Comorbidity of mood disorders and systemic/peripheral diseases

Psychosocial stress and systemic disease can both affect the onset of depression. For example, the comorbidity of depression in patients with diabetes, cancer, or cardiac disease is 17%–29%, much higher than that of the general population (10.3%) (% comorbidity of depression with specific systemic illnesses is shown in Table 1) (Evans et al., 2005). Moreover, chronic inflammation is implicated in the pathology of these diseases, and the possible mechanisms by which the NLRP3 inflammasome may

Innate immune response mechanisms

Host survival requires defense mechanisms against external danger substances, including the ability to discriminate “nonself” from “self” and to eliminate or neutralize danger molecules. The mechanisms by which the immune system detects diverse danger signals were only recently elucidated with the discovery of Toll-like receptors (TLRs). TLRs are pattern recognition receptors (PRRs) on the cell-surface of immune cells, characterized by extracellular leucine-rich repeats (LRRs) and an

NLRP3 inflammasome and pattern recognition

The PRR danger signal receptors are divided into two major types membrane-associated and cytosolic, based on cellular localization (Bryant and Fitzgerald, 2009) (Fig 1). Membrane-associated PRRs include TLRs and C-type lectin receptors (CLR), and cytosolic PRRs include nucleotide-binding oligomerization domain (NOD)-like receptors (NLR), retinoic acid-inducible gene (RIG)-like RNA helicases (RIR), and DNA sensor (absent in melanoma 2: AIM2 etc.). Activation of TLRs leads to increased

Inflammasome is a key mediator of stress, depression and comorbid illnesses

This review focuses on the role of the inflammasome and IL-1β in depression for several reasons. First, inflammatory cytokines such as IL-1β are elevated in depression, and second, activate the HPA axis, which is dysregulated in depressed patients. Third, chronic inflammatory diseases like rheumatoid arthritis and diabetes that have high rates of comorbidity with depression also activate the NLRP3 inflammasome complex (Evans et al., 2005, Mason et al., 2012). Fourth, we have found that blockade

Effects of anti-inflammatory drugs on depression

Activation of the inflammasome and elevated cytokines in stress and depression suggests that suppression of the inflammatory response could ameliorate depressive symptoms. Interestingly, tricyclic antidepressants (TCA) and SSRIs normalize serum levels of inflammatory cytokines in depressed patients, as well as increase the production of anti-inflammatory cytokines such as IL-10 (Kenis and Maes, 2002, Raedler, 2011). In addition, co-treatment of antidepressants with non-steroidal

Regulation of IL-1β expression, release, and signaling

We have previously demonstrated that administration of an IL-1β antagonist blocks the inhibitory effects of stress on neurogenesis, as well as the expression of depressive behaviors (Koo and Duman, 2008). In addition, IL-1R null mice are resistant to the development of depressive behaviors, including anhedonia, caused by chronic stress exposure (Koo and Duman, 2009). These studies indicate that blockade of IL-1R, or the production and release of IL-1β would produce antidepressant effects. We

An inflammasome hypothesis of depression: bidirectional pathways between depression and comorbid systemic illnesses

Here we suggest a new hypothesis for depression and comorbid illnesses based on evidence of bidirectional pathways between psychological stress and systemic diseases, and danger substances and depression (Fig. 4). As previously discussed, psychological stress can activate the NLRP3 inflammasome, leading to the release of IL-1β, which can contribute to the pathophysiology of systemic illnesses such as diabetes, cardiovascular, and inflammatory diseases. In addition, danger substances such as

Acknowledgments

The authors would like to thank Dr. F. Sakaue for helpful discussion and making illustrations in this paper.

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