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.

Figures

Figure 1

Conserved transcriptional response to adversity (CTRA). The innate immune system developed to counter physical threats from predatory animals and hostile conspecifics that dominated our ancestral environment. Exposure to these threats activates a CTRA that involves up-regulation of proinflammatory immune response genes, which combat extracellular pathogens and wound-related bacterial infections, and down-regulation of antiviral immune response genes, which target intracellular pathogens such as viruses. This redeployment of the leukocyte basal transcriptome is adaptive in the context of actual physical threat because it enhances wound healing and recovery from injury and infection. The CTRA can also be activated by modern-day social, symbolic, anticipated, and imagined threats, however, leading to increased risk for several inflammation-related conditions, including depression (see Antoni et al., 2012; S. W. Cole et al., 2012; Fredrickson et al., 2013; Irwin & Cole, 2011; Powell et al., 2013; Slavich & Cole, 2013). Saber-toothed cat image copyright 2013 by Dorling Kindersley; chimpanzee image copyright 2013 by Ronald van der Beek; pointing man image copyright 2013 by Craig Wactor; all other images copyright 2013 by Getty Images. All images reprinted with permission.

Figure 2

Cortisol and proinflammatory cytokine responses to social cues indicating possible danger. The hypothalamic–pituitary–adrenal (HPA) axis and inflammatory system coordinate to keep an individual physically safe and biologically healthy. Increases in HPA axis activity and the associated release of cortisol prepare an individual for “fight-or-flight” when he or she is exposed to cues indicating the presence of socially threatening conspecifics. This initial cortisol response has a strong anti-inflammatory effect, which allows the organism to react to the impending threat without being hampered by the onset of sickness behaviors, such as fatigue and social-behavioral withdrawal. As cues of the social threat wane, the body up-regulates the inflammatory response to accelerate wound healing and limit infection caused by possible injury. Glucocorticoid resistance allows for elevations in systemic inflammation to occur together with, or closely after, increases in cortisol. Although these dynamics are adaptive during actual, intermittent physical threat, prolonged activation of the HPA axis and inflammatory response caused by persistent actual or perceived threat is biologically costly and can increase a person’s risk for several inflammation-related conditions including asthma, rheumatoid arthritis, cardiovascular disease, chronic pain, metabolic syndrome, and (possibly) certain cancers.

Figure 3

Neuro-inflammatory sensitization to adversity. Bidirectional links between the brain and periphery allow the brain to regulate inflammatory activity, and inflammatory activity to in turn influence neural processes in the brain. This dynamic is initiated by experiences of early life stress or chronic adversity, which promote a proinflammatory skewing of the leukocyte basal transcriptome (i.e., the conserved transcriptional response to adversity [CTRA]) that feeds back on pain-related neural systems to perpetuate subjective perceptions of threat. Brain regions involved in this process include the anterior insula (AI) and dorsal anterior cingulate cortex (dACC, shown in the insert). As a result of this physiologic recursion, experiences of social-environmental adversity can become biologically embedded and sustain perceptions of threat for months or years after the original social-environmental impetus has passed. The consequences of these dynamics are multifold and start with increased hypervigilance, chronic anticipation of adversity, sensitivity to pain, and symptoms of social anxiety. As activation of the CTRA persists, somatic and affective symptoms of depression may develop. Finally, after years of sustained engagement, these dynamics may confer increased risk for inflammation-related disorders, infection, accelerated biological aging, and early mortality (see Eisenberger & Cole, 2012; G. E. Miller, Chen, & Parker, 2011; G. E. Miller & Cole, 2012; Slavich & Cole, 2013). IL-1β = interleukin-1β; IL-6 = interleukin-6; TNF-α = tumor necrosis factor-α.

Figure 4

Social signal transduction theory of depression. Social signal transduction theory of depression describes mechanisms that convert, or transduce, experiences of the external social environment into the internal biological environment of depression pathogenesis. (1) Social-environmental experiences indicating possible social threat or adversity (e.g., social evaluation, rejection, isolation, or exclusion) are represented neurally, especially in brain systems that process experiences of social and physical pain. Key nodes in this neural network include the anterior insula (AI) and dorsal anterior cingulate cortex (dACC, shown in the insert). These regions project to lower level brain areas (e.g., hypothalamus, brainstem autonomic control nuclei) that have the ability to initiate and modulate inflammatory activity via three pathways that involve (2) the hypothalamic–pituitary–adrenal axis, (3) sympathetic nervous system (SNS), and (4) efferent vagus nerve. (5) Activation of these pathways leads to the production of glucocorticoids, epinephrine, norepinephrine (NE), and acetylcholine (ACh), which interact with receptors on cytokine-producing cells. Whereas glucocorticoids and acetylcholine have anti-inflammatory effects, epinephrine and norepinephrine activate intracellular transcription factors (e.g., nuclear factor-κB and activator protein 1) that bind to cis-regulatory DNA sequences to up-regulate inflammatory gene expression. When this occurs and immune response genes are expressed, DNA is transcribed into RNA and then translated into protein. The resulting change in cell function leads to the production of proinflammatory cytokines (e.g., interleukin-1β [IL-1β], interleukin-6 [IL-6], tumor necrosis factor-α [TNF-α]) that signal the brain to induce cognitive, emotional, and behavioral alterations that include several hallmark symptoms of depression (e.g., sad mood, anhedonia, fatigue, psychomotor retardation, altered appetite and sleep, and social-behavioral withdrawal). Cytokines can exert these effects on the central nervous system by (6) passing through leaky or incomplete regions of the blood–brain barrier (e.g., circumventricular organs, organum vasculosum of the lamina terminalis) and by (7) stimulating primary afferent nerve fibers in the vagus nerve, which relays information to brain systems that regulate mood, motor activity, motivation, sensitivity to social threat, and arousal. Although these neurocognitive and behavioral responses are adaptive during times of actual threat, as depicted in Figure 1, these social signal transduction pathways can also be initiated by purely symbolic, anticipated, or imagined threats—that is, situations that have not yet happened or that may never actually occur. Moreover, activation of these pathways can become self-promoting over time due to neuro-inflammatory sensitization and, as a result, remain engaged long after an actual threat has passed (see Figure 3). In such instances, these dynamics can increase risk for depression in the short-term and possibly promote physical disease, accelerate biological aging, and hasten mortality over the long run. ACTH = adrenocorticotropic hormone; mRNA = messenger ribonucleic acid.

Figure 5

Social threat hypothesis of anxiety, inflammation, and depression. Individuals’ perceptions of social threat and adversity are shaped by several influences including genetic factors (e.g., regulatory single nucleotide polymorphisms in the serotonin transporter or IL6 gene), personality traits (e.g., neuroticism, interpersonal and rejection sensitivity), and social-environmental conditions during childhood and adolescence (e.g., experiences of social stress, uncertainty, abuse, and neglect). Elevated levels of actual or perceived threat that result from these factors are hypothesized to increase feelings of anxiety and activate social signal transduction pathways that up-regulate inflammatory activity. Relatively mild, preclinical levels of inflammation may have limited effects on health in childhood and adolescence, especially for persons who are otherwise healthy. However, sustained engagement of these systems resulting from prolonged experiences of social threat or adversity may drive neuro-inflammatory sensitization, which could lead to both elevated levels of inflammation and exaggerated perceptions of social threat. Transcriptional changes that occur during this process may in turn foster an increasingly proinflammatory milieu that elevates risk for depression as an individual grows older. From this perspective, genetic, personality, and social-environmental factors early in life promote elevated perceptions of social threat, symptoms of anxiety, and preclinical levels of inflammation; then, at least for some individuals, anxiety symptoms become eclipsed by symptoms of depression that include sad mood, anhedonia, fatigue, altered appetite and sleep, and social-behavioral withdrawal.