From stress to inflammation and major depressive disorder - Slavich, Irwin, 2014 - Article

Summary with the article: From stress to inflammation and major depressive disorder - Slavich, Irwin, 2014

Depression is the most common psychiatric disorder. One in every four women and one in every six men experience a depression during their life. Besides this, many people never get the diagnosis depression or don’t receive treatment. Only 30 to 35% recover from a depression through treatment. Depression is a huge social and economic burden. The best predictors are major stressful life events. However, there is not much known about the biological processes influencing stress, that may lead to depression.

Inflammatory processes of the immune system might play a role in the development of a depression. When experiencing stress this can trigger inflammatory activity, which might lead to behavioural changes. One of those changes being depressive symptoms. The present review shows how life stress can cause inflammation and how this can lead to a bigger risk for depression.

The immune system

The immune system reacts to physical injuries and infections to avoid illness or death. The first line of defence against tissue damage and microbes is the innate immunity. Immune cells in the body use their receptors to detect pathogens. This leads to a cascade of inflammatory processes to contain the infection and promote recovery. Innate immunity is nonspecific and doesn’t lead to long-lasting protection. If the innate immunity lacks efficiency, the adaptive immunity starts. This involves the proliferation of microbe-specific white blood cells that destroy the microbes, because they have an immunological memory, since they responded to this specific pathogen in the past. The innate immunity is very fast. However, the adaptive immunity response takes days to develop.

Innate immunity

The first defence by the innate immunity is called the acute-phase response. It leads to an increase in inflammatory activity locally and systematically. The innate immune response starts when the immune cells recognize microbes or pathogen-associated molecular patterns (PAMPs). This recognition strategy is called pattern recognition and the innate immune receptors are called pattern recognition receptors.

Toll-like receptors (TLRs) are present on macrophages, neutrophils and dendritic cells. TRLs can recognize the microbes, leading to inflammation and antimicrobial innate immune responses. With the activation of the TLRs a cascade is activated. This leads to the activation of two intracellular transcription factors: (1) nuclear factor-κB and interferon regulatory factors. These lead to the expression of pro-inflammatory immune response genes, which secrete These lead to the expression of pro-inflammatory immune response genes, which secrete cytokines.

Cytokines

Functions of cytokines include the coordination of cell-to-cell communication and alteration of neurochemical and neuroendocrine processes. They are released from immune cells and mediate physiological responses, relying on receptor-ligand interactions. They also have self (autocrine), local (paracrine) and distal (endocrine) effects. Cytokines increasing or upregulating inflammation are called pro-inflammatory. Cytokines downregulating inflammation are called anti-inflammatory.

Some example pro-inflammatory cytokines are IL-1, interleukin-6 (IL-6) and TNF-α. Inflammatory cytokines promote increased vascular permeability and cellular adhesion, leading to immune cells leaving the blood vessels to got to issues to eliminate the pathogens. This process is aided by chemokines, which are activated by the pro-inflammatory cytokines. They screen the body for pathogens in immunosurveillance. When a pathogen is detected, the chemokines act as chemoattractans to recruit other immune cells to the infection site.

Cytokines can lead to redness, heat, swelling and pain at infection sites. They can induce generation of acute-phase protein C-reactive protein, which increases body temperature, heart rate, respiratory rate and fever. This way wound healing is facilitated and the spread of the infection is constrained. It also leads to social-behavioural withdrawal, through which the organism can recover without spreading it to the surroundings.

Inflammation

Altered or prolonged activation of the inflammatory response might cause more damage to the host than the pathogen. It plays a role in major diseases. A factor than can prolong this inflammation is stress.

Systemic inflammation

Genomic regulation

The inflammatory response is mostly regulated by genomic intracellular processes. Depending on the type of threat, a specific pathway is involved. When exposed to an extracellular pathogen, the intracellular transcription factors NF-κB and activator protein 1 (AP-1) are activated. They start the pro-inflammatory immune response leading to increased generation of pro-inflammatory cytokines. An intracellular pathogen activates transcription factors such as IFN regulatory factors, inducing antiviral immune response genes. By translating IFN signal transducer and activator of transcription-1 are activated, through which pro-inflammatory cytokines are produced.

Central regulation

More distal regulation in the brain prepares the body for physical wounding or injury before the assault leads to pathogen-related infection. This is called pathogen host defence response. In order to do this innate immune cells are redistributed and trafficked to the infection sites. It leads to better wound healing and recovery after the injury.the pathogen host defence response starts because immune response genes ‘listen’ for chemical signals that indicate an enhanced risk for infection. The innate immunity responses when we are exposed to adverse conditions, such as social conflict, evaluation, rejection, isolation or exclusion.

Which type of innate immunity response is activated, depends on the nature of the experience. There is an upregulation of pro-inflammatory immune response genes with contemporary social stressors to fight off bacteria and other extracellular pathogens. Antiviral immune response genes are downregulated to target intracellular pathogens, such as viruses. This is called basal transcriptome and it is useful when encountering physical threat. However, when it is activated by nonphysical social, symbolic, anticipated or imagined threats, it can raise the risk for viral infection and inflammation-related disease.

The sympathetic nervous system (SNS) and the hypothalamic-pituitary-adrenal (HPA) axis convert social-environmental adversity into pro-inflammatory transcriptional programs. The parasympathetic nervous system prevents excessive inflammation, by modulating immune responses at regional level through the efferent and afferent fibers of the vagus nerve.

Sympathetic nervous system

The SNS releases norepinephrine into peripheral tissues, lymphoid organs and other organ systems, which regulates the production of pro-inflammatory cytokines. Norepinephrine modulates the immune response gene transcription by stimulating the β-adrenergic receptors. The transcription of antiviral type I IFN genes are thereby suppressed and the transcription of pro-inflammatory immune response genes upregulated. Therefore systemic inflammatory activity increases.

Hypothalamic-pituitary-adrenal axis

Normally the HPA axis suppresses the transcription of pro-inflammatory and antiviral immune response genes by stimulating the release of cortisol from the adrenal cortex. This is done through several mechanisms:

• glucocorticoid receptor binding to gene promotor sequences;

• glucocorticoid receptor activation leading to transcriptional induction of anti-inflammatory genes;

• pro-inflammatory transcription factors antagonize gene transcription via protein-protein interactions.

This glucocorticoid feedback inhibition is very important to protect against diseases of excessive inflammation. There might however be HPA axis-related increases in inflammation, which is called glucocorticoid resistance or glucocorticoid insensitivity. Glucocorticoids can no longer compensate for the persistent secretion of immune cells. Under frequent or chronic social-environmental threat it is adaptive to have cortisol and pro-inflammatory cytokines increase in concert with each other. This is also true for acute stress with increased social threat or physical danger. Cortisol gives energy to respond and pro-inflammatory cytokines promote wound healing and limit the infection.

When glucocorticoid resistance occurs the ‘fight or flight’ responses of the HPA axis become altered and promote excessive inflammation. This can have implications for mental as well as physical health. In depression people have higher cortisol levels, which might be explained by the levels of glucocorticoid sensitivity. Glucocorticoid signalling influences the maintenance or progression of many disorders, such as anxiety, PTSD and asthma.

Stress

The question is whether social stress is associated with depression, and whether inflammatory processes mediate this relationship. Indeed stressful life events increase the risk of developing a major depressive disorder. This is particularly the case for major life events that cause cognitive upheaval and that disrupt the goals, plans and aspirations of the person. Depressed people have 2,5 times more chance of having experienced a major life event before they developed depression than non-depressed people. This makes major life stress the strongest risk factor for depression, especially in women.

Interpersonal loss

The effects on depression differ depending on the core features and social-psychological characteristics of the life event. The greatest predictor of depression is interpersonal loss. This disrupts important social bonds, which may evoke intense distress. The risk for depression is greatest when interpersonal loss is coupled with social rejection, which might signal a loss of social status, value and regard. Its strong association with depression is not driven by differences in severity than other stressors, because even when comparing interpersonal loss to other stressors of the same severity, interpersonal loss causes depression more often.

When experiencing interpersonal loss that is self-initiated, the risk of developing depression is 10,2 times higher. However, when interpersonal loss is initiated by another person, the risk of developing depression is even 21,6 times higher. So the risk for depression doubles when taking into account social rejection. When this social rejection is directed at one person to actively try to sever the relational ties, which is called targeted rejection, depression is developed three times faster. These stressors are not only implicated in the development, onset, exacerbation or progression of depression, but also of other diseases, such as asthma, chronic pain and cancer. These conditions are probably mediated by inflammation.

Inflammation

There are strong associations between stress and inflammation for stressors with the presence of possible physical or social threat. In particular early life stress increases inflammatory activity, such as a childhood environment with a lot of unpredictability and interpersonal stress or a socially tumultuous early environment. Low socioeconomic status in childhood also leads to higher levels of cytokines and the shifting of leukocyte basal transcriptome toward a pro-inflammatory phenotype. This is caused by an increased expression of genes coding for TLR4, that activates the innate immunity response, and decreased expression of genes coding for glucocorticoid receptor, that downregulates inflammation in response to cortisol.

There is also an association between early life stress and inflammation in the context of depression. Adolescents that have experienced more early life stress, had greater increases in inflammatory activity when becoming depressed than their peers that didn’t experience much early life stress. We also see that the elevations in CRP persist when the depression has disappeared in adolescents with a history of early life stress, but that CRP levels reduce when depression abates in adolescents that have no history of early life stress.

Also acute and chronic social stressors in adolescence and adulthood are associated with enhanced inflammation. This is particularly strong for social stressors that involve conflict, threat, isolation and rejection. Examples of these social stressors are lower socioeconomic status in adulthood and negative social interactions with friends, peers, teachers or family members. It might be that only one major life event is even sufficient for enhancing inflammatory activity when it involves interpersonal loss or social rejection. The death of a spouse increases inflammation largely, but this may in part be because they have a flatter diurnal cortisol slope across the day.

Glucocorticoid dynamic may also play a role in the effect of social rejection on inflammatory activity. Experiencing one major life event namely predicts greater glucocorticoid resistance. This may link social rejection with enhanced inflammation and risk for depression. We know that the stronger social bonds lead to a decreased risk for mortality.

Also in a laboratory setting we see that social stressors trigger systemic inflammation. The strongest inflammatory responses are evoked by social conflict, rejection or exclusion. Examples are writing about traumatic experiences involving self-blame, shame and hostility. Many laboratory studies use the Trier Social Stress Test (TSST), in which participants are asked to prepare and give an impromptu speech and a difficult mental arithmetic for a nonresponsive and socially rejecting rater panel. In the people who complete the TSST we see a greater glucocorticoid resistance, greater increases in TNF-α production and increases in cortisol. Stressors with low controllability and high social-evaluative threat trigger the greatest cortisol responses and the slowest recovery of cortisol to baseline.

There are, however, a lot of individual differences in the inflammatory responses to social stress. It depends on the stress-related appraisals and reactions. For instance, individuals experiencing more fear to TSST show greater increases in pro-inflammatory marker sTNF-RII, greater levels of IL-1β and greater increases in IL-6. The increase in IL-1β might predict the depressive symptoms over the following year.

Moderating factors of the relationship between reactions on the TSST and inflammatory activity might be having experienced early life stress, having more feelings of the trait loneliness and being depressed. Depressed participants had higher increases in markers of SNS and HPA activity, in plasma levels of pro-inflammatory cytokines TNF-α and IL-6 and in inflammatory marker CRP after the TSST, than non-depressed participants. The elevations in CRP persisted after the TSST. Risk factors for depression are associated with this persistently high level of CRP and might contribute to these effects, for instance a sedentary lifestyle, high body mass index and being female.

Neural mechanisms

Being socially rejected activates the bilateral anterior insula and dorsal anterior cingulate cortex (dACC). When these brain regions were more activated, this was related to greater sTNF-RII responses to the TSST. This means that people that are more neutrally sensitive to social rejection exhibit greater inflammatory responses to acute social stress. The anterior insula and dACC are important regions in a network that is engaged in physical pain experiences.

Increases in IL-6 were also associated with greater neural activity in the anterior insula and dACC. Activity in these brain regions mediates the relationship between endotoxin-indcued increases in IL-6 and depression in females. The endotoxin-induced increases in IL-6 were also related to greater activity in neural regions that play a role in metalizing, or the process of thinking about the content of other people’s mind.

So there seems to be a bidirectional link between systemic inflammation and pain-related neural systems in the brain. This can be adaptive in dangerous environments to prepare the body for possible physical threat or injury. However, because the neural responses to social evaluation and rejection also upregulate the systemic inflammation, and because increases in inflammation promote neural sensitivity to social rejection, this can lead to a recursive loop that increase inflammation levels and the risk of developing depression.

Genetic and genomic mechanisms

A locus of interest in the moderation of inflammatory responding to social stress is the functionally active regulatory single-nucleotide polymorphism (SNP) in the human IL6 promoter. High levels of social-environmental stress were associated with increased mortality risk for rs1800795G homozygotes, while C allele carriers had no increase in mortality risk. The homozygotes for the G allele had 2,8 years shortened life span. This relationship between stress and mortality was completely mediated by inflammation. So genetic factors do interact with social-environmental conditions as well to predict systemic inflammation relevant for health and mortality.

Hundreds of genes can be differentially expressed because of social adversity. So whole gene programs or gene profiles can be activated by social adversity. Genome-wide transcriptional shifts can lead to asthma, ovarian cancer, breast cancer and PTSD. However, the relationship with depression has not yet been studied.

Cytokines and the brain

Pro-inflammatory cytokines communicate with the brain and can alter its neural activity through cellular, molecular and neural mechanisms. Cytokines are large proteins, and can therefore not cross the blood-brain barrier via passive transport. They do pass the blood-brain barrier at parts where it is incomplete or permeable, which involves macrophage-like cells; by binding to the cerebral vascular endothelium, where second messengers are activated and local cytokine activity is induced; and through active transport.

Neural pathways also link the immune system processes to the brain. Inflammatory signalling in the periphery can activate afferent nerves, which leads to the secretion of pro-inflammatory cytokines in the brain. So there is a bidirectional communication between the peripheral cytokine activity and the brain.

Effects on behaviour

To see the effect of inflammatory activity on behaviour, studies exposed animals to immunological challenges. This is relevant for the understanding of depression in humans, because these processes evoke a social-behavioural state in animals that resembles depression in humans.

With inflammatory signalling in the periphery, the brain cells begin secreting pro-inflammatory cytokines that bind to cytokine receptors in the brain. This leads to the secretion of neurotransmitters norepinephrine, dopamine and serotonin, which initiates neurochemical cascades that have an effect on behaviour. Possible changes are disturbances in sleep-wake activity, decreases in daytime activity, decreased interest in feeding, grooming, socialising and mating and hedonic behaviours. These are called sickness behaviours and they facilitate the recuperation and recovery from injury or infection. These behaviours are similar to the somatic and behavioural symptoms of depression, and therefore cytokines might be able to induce depression in humans.

When administering pro-inflammatory cytokines IL-β and TNF-α to rodents, it led to sickness behaviours, such as hypersomnia, fatigue, anorexia and psychomotor retardation. The injection of bacterial endotoxin inhibited their sexual behaviour and consumption of sweetened solutions. These symptoms were alleviated when treated with antidepressant medication or when giving pre-treatment with cytokine synthesis blockers or cytokine antagonists.

Depression

The development of major depressive disorder might be initiated by stress-induced increases in inflammation. Sickness behaviour is an adaptive response to infection, mediated by cytokines. However, the cytokines might act on the brain to develop depression, because depression is characterised by an activate innate immunity. The symptoms can be alleviated with antidepressant medications. What we also see, is that people with somatic or physical disorder that have an underlying inflammatory component have a higher likelihood of developing a depression. These disorders are asthma, rheumatoid arthritis, inflammatory bowel disease, metabolic syndrome, coronary heart disease and chronic pain.

Chronic pain leads to heightened inflammation, which drives hyperalgesia or enhanced sensitivity to pain. It seems that chronic pain is highly comorbid with depression and it is a strong predictor of the onset and duration of depressive symptoms.

Enhanced inflammatory activity

Depressed people have higher pro-inflammatory cytokine levels, including IL-1, IL-6 and TNF-α, and higher levels of the systemic inflammatory biomarker CRP, than non-depressed people. The concentrations of anti-inflammatory cytokine IL-10, however, are lower for depressed than non-depressed people. These increase in IL-6 and CRP can prospectively predict the development of depression. Depression can also predict increases in inflammation. So the inflammation-depression link might be bidirectional. Using antidepressant medication lowers the levels of pro-inflammatory cytokines IL-1β, IL-2 and IL-6.

Cytokines also reduce serotonin levels through the decrease of serotonin precursor tryptophan. Serotonin is important in the regulation of mood, motivation, and behaviour, and therefore the cytokine-related tryptophan depletion might play a role in the pathogenesis of depression. In depression also the cell-mediated immune activation heightens, which includes the macrophages, monocytes and T-lymphocytes. The cell-mediated immune activation might lead to tryptophan reductions, resulting in somatic and neurovegetative depressive symptoms.

Depression is also related to immune suppression, namely reductions in antiviral immunity. The SNS outflow in depression could suppress the transcription of antiviral immune response genes, which increases the susceptibility to viruses, but enhance the transcription of pro-inflammatory immune response genes, which increases systemic inflammatory activity.

Causal models

All described studies above are correlational, so we don’t know if cytokines cause depression of if they are secondary to the disorder. To examine the causal models, studies have looked at alterations in cognitive and behavioural functioning resulting from vaccination or immunotherapy with three models: IFN-α model, typhoid vaccination model and endotoxin model.

Administering IFN-α leads to anxiety, pain, depressed mood, anhedonia, fatigue, cognitive impairment, sleep disturbance, anger, hostility, loss of appetite and suicidal ideation. The development of depression after administration of IFN-α might develop because of increased TNF-α and IL-6 signalling, reduced HPA axis diurnal variation, increased glucocorticoid insensitivity, reduced plasma concentrations of brain-derived neurotrophic factor, reduced plasma concentrations of tryptophan, increased plasma and cerebrospinal fluid concentrations of kynurenine and quinolinic acid, and reduced slow-wave sleep and sleep continuity. The risk for developing depression after IFN-α treatment is also higher for people with a history of depression and for people carrying short-alleles of 5-HTTLPR (serotonin transporter gene).

Administering typhoid vaccination or bacterial endotoxin also induces negative mood, confusion, fatigue and anxiety. The increases in depressive symptoms after endotoxin administration are associated with changes in peripheral blood levels of pro-inflammatory cytokines IL-6 and TNF-α. The depressive symptoms reduce after treating it with antidepressant medications. Endotoxin administration also leads to feelings of social disconnection and the desire to be alone.

Neural systems

Immunological challenges upregulation inflammation change neural activity in the basal ganglia, cerebellum, anterior cingulate cortex (ACC) and ventral striatum. IFN-α treatment leads to greater dACC activity, an area that is involved in processing physical pain experiences and is active with inflammatory responses to social stress. Glucose metabolism in the basal ganglia and cerebellum also increased, both regions are involved in motor activity and motivation. The bilateral ventral striatum reduced in activity. It is involved in reward-related responding, and reduced activation leads to anhedonia, depression and fatigue.

Typhoid vaccination alters the activity in the substantia nigra, part of the basal ganglia involved in motor planning and reward seeking, and enhances the activity in the subgenual ACC, implicated in depression. Activity in the ventral striatum reduces after administering bacterial endotoxin and this has implications on the depressed mood.

Anti-inflammatory agents

Anti-inflammatory agents reduce cytokine activity and the severity of depression. Examples of anti-inflammatory agents are celecoxib, which is used to treat inflammation and pain; etanercept, used to treat rheumatoid arthritis and other inflammatory conditions; and TNF-α antagonist infliximab. These anti-inflammatory agents block the inflammation-related behavioural changes in animal models of depression. The question remains, if the anti-inflammatory agents can reduce depression in all people or only in a subgroup.