From stress to inflammation and major depressive disorder: A social signal transduction theory of depression.

Abstract

Major life stressors, especially those involving interpersonal stress and social rejection, are among the strongest proximal risk factors for depression. In this review, we propose a biologically plausible, multilevel theory that describes neural, physiologic, molecular, and genomic mechanisms that link experiences of social-environmental stress with internal biological processes that drive depression pathogenesis. Central to this social signal transduction theory of depression is the hypothesis that experiences of social threat and adversity up-regulate components of the immune system involved in inflammation. The key mediators of this response, called proinflammatory cytokines, can in turn elicit profound changes in behavior, which include the initiation of depressive symptoms such as sad mood, anhedonia, fatigue, psychomotor retardation, and social-behavioral withdrawal. This highly conserved biological response to adversity is critical for survival during times of actual physical threat or injury. However, this response can also be activated by modern-day social, symbolic, or imagined threats, leading to an increasingly proinflammatory phenotype that may be a key phenomenon driving depression pathogenesis and recurrence, as well as the overlap of depression with several somatic conditions including asthma, rheumatoid arthritis, chronic pain, metabolic syndrome, cardiovascular disease, obesity, and neurodegeneration. Insights from this theory may thus shed light on several important questions including how depression develops, why it frequently recurs, why it is strongly predicted by early life stress, and why it often co-occurs with symptoms of anxiety and with certain physical disease conditions. This work may also suggest new opportunities for preventing and treating depression by targeting inflammation.

In Sickness and in Health: The Co-Regulation of Inflammation and Social Behavior

“…A more detailed account of the specific mechanisms whereby social factors regulate immune system responses is presented elsewhere (Irwin and Cole, 2011;Slavich and Cole, 2013;Slavich and Irwin, 2014). Here, we summarize research that highlights several of the consequences of having an immune system that is sensitive to features of the social environment.…”

Danger Signals and Inflammasomes: Stress-Evoked Sterile Inflammation in Mood Disorders

“…Compelling clinical research has established that repeated, chronic and excessive stressor exposure increases inflammatory state and is associated with increased risk and severity of a variety of mood disorders (for reviews see Kiecolt-Glaser et al, 2010Segerstrom and Miller, 2004;Slavich and Irwin, 2014). For example, exposure to repeated life stressors or laboratory stressors involving social conflict, threat, isolation, and rejection increases inflammatory markers including C-reactive protein (CRP), interleukin-6 (IL-6), interleukin-1β (IL-1β) and soluble tumor necrosis factor-α receptor (TNFsr) in the blood (Aschbacher et al, 2012;Denson et al, 2009;Dickerson et al, 2009;Steptoe et al, 2007) and NF-κB mRNA (a transcription factor for inflammatory proteins) in leukocytes (Murphy et al, 2013;Pace et al, 2012).…”

Post-menopausal Women Exhibit Greater Interleukin-6 Responses to Mental Stress Than Older Men

“…Psychosocial stress is a risk factor for cardiovascular disease (CVD) and depressive disorders [1,2]. Mechanisms mediating the adverse effect of stress on CVD risk include exaggerated or dysregulated immune activation in response to psychosocial stress [1,3].…”

“…Mechanisms mediating the adverse effect of stress on CVD risk include exaggerated or dysregulated immune activation in response to psychosocial stress [1,3]. Acute mental stress elicited using behavioral or cognitive tasks is known to up-regulate pro-inflammatory gene expression in peripheral mononuclear blood cells resulting in the synthesis and release of inflammatory cytokines [4,5].…”