|Year : 2016 | Volume
| Issue : 3 | Page : 155-160
Depression and inflammation: Pathophysiology and therapeutic implications
Department of Physiology, Lady Hardinge Medical College and Associated Hospitals, New Delhi, India
|Date of Web Publication||9-Jun-2016|
C/O Mr. Pankaj Pangtey, C 2/11, Flat No. 3, First Floor, IGNOU Road, Saidula Jaib Ext, New Delhi - 110 030
Source of Support: None, Conflict of Interest: None
Depression may result in far reaching adverse health outcomes in addition to impaired sociooccupational or quality of life. Depression is commonly associated with greater cardiovascular morbidity and mortality. Dysregulated inflammation has been suggested as one of the plausible underlying mechanism relating the two. Several studies have reported elevated levels of proinflammatory cytokines and acute phase proteins in depression patients. The proinflammatory cytokines have been shown to alter various signaling pathway relevant to depression such as neurotransmitter metabolism, neuroendocrine dysfunction, and synaptic plasticity after reaching the brain. Potential pathways which have been implicated in mediating the depression and inflammation include the tryptophan-kynurenine pathway, hypothalamic-pituitary-adrenal axis dysregulation, and neuronal plasticity. Inflammation appears to play a pivotal role in the pathophysiology of depression but only in subset of depressive patients. It may prove to be an effective target to develop several treatment modalities and thus open avenues for development of potential therapeutic strategies in vulnerable at risk depressive patients.
Keywords: Cardiovascular disease, depression, inflammation
|How to cite this article:|
Jangpangi D. Depression and inflammation: Pathophysiology and therapeutic implications. CHRISMED J Health Res 2016;3:155-60
|How to cite this URL:|
Jangpangi D. Depression and inflammation: Pathophysiology and therapeutic implications. CHRISMED J Health Res [serial online] 2016 [cited 2021 Jun 24];3:155-60. Available from: https://www.cjhr.org/text.asp?2016/3/3/155/183728
| Introduction|| |
Major depressive disorder (MDD) is a psychiatric illness of major public health importance. The implications of MDD extends from having a decreased quality of life and altered sociooccupational functioning to increased cardiovascular morbidity and mortality risk, which have been found to be associated with depression. , Moreover, depression has been listed as the third leading cause of disease burden worldwide which further adds to its paramount importance as an illness. 
For several decades depletion or imbalance of monoaminergic neurotransmission has been accepted as an etiology of Depressive disorder and majority of current treatment modalities focus on targeting the monoamines relevant to depression.  However, current therapeutic approaches in a form of conventional antidepressants have not been able to achieve remission in the minority of patients.  Therefore, there is a current and pressing need to look further into the role of other neurobiological mechanisms that contributes to depression which may help in developing novel and effective therapeutic strategies by targeting them. 
There are accumulating evidence indicating an association of inflammation and depression. Several studies have revealed an increase in inflammatory markers in patients of depression.  In the current review, we will discuss the potential mechanisms linking inflammation and depression and further its therapeutic implications.
| Research methodology|| |
Electronic databases of MEDLINE (PubMed) and Google Scholar search engines were searched for relevant studies and reviews published from 1990 to 2015. The keywords used were "major depression," "inflammation," "innate immune response," "proinflammatory cytokines," "Pathophysiology," and "cardiovascular disease." In addition, the reference list of relevant recently published articles and reviews were also screened. Titles, abstracts, and full-texts of peer-reviewed articles about related topics published in English were included.
| Depression, Immune System, and Inflammation|| |
Immune system is crucial for host survival as it helps in initiating and coordinating the host defense mechanisms against microbial invasion or tissue injury by generating an inflammatory response. Immune system comprises two components first is innate immunity and second adaptive immunity. Innate immune response is one of ancient first line defense mechanism which acts rapidly when encountered with pathogens or tissue damage.  Cells of innate immune response such as neutrophils, macrophages, and dendritic cells expressed a germ-line encoded receptors referred as pattern recognition receptors (PRRs). One of the important families of PRR is Toll-like receptors. These receptors which are expressed by cells of innate immune response play a major role in recognition of conserved molecular components known as pathogen-associated molecular patterns (PAMPs) which are commonly found in the majority of pathogens, but not normally found in the host.  After recognition of microbes, toll-like receptors binds with PAMP and initiate a cascade of inflammatory signaling pathway resulting in activation of transcription factors such as nuclear factor-kappa B (NF-κB), mitogen-activated protein kinase (MAPK), and interferon regulatory factor 1 (IRF-1). These transcription factors further induce the production of proinflammatory cytokines such as interleukin-6 (IL-6), IL-1, tumor necrosis factor-alpha (TNF-α). , These cytokines then enters the blood and activates the acute phase response in the liver, leading to the production of several acute-phase proteins such as C-reactive protein (CRP). 
Moreover, innate immunity on activation if not sufficient to eliminate pathogens also leads to activation of microbial-specific adaptive immunity which is mediated by antigen-specific T and B lymphocytes. Cytokines are the soluble proteins that play a pivotal role in mediating immune and subsequently an inflammatory response. , The cytokines that up-regulate an immune-inflammatory response are referred as proinflammatory such as IL-6, IL-1, TNF-α and help enhance inflammation and induce changes in infected tissues including redness, heat, swelling, and pain commonly known as signs of inflammation.  Besides these, they also orchestrate sociobehavioral changes such as fatigue, social withdrawal, altered sleep and anorexia called as sickness behavior which is strikingly similar to occur in depressive disorders. These behavioral changes in a way aid in containment of infection and recovery.  Once the inflammatory response system have succeeded in containing the infection the overall response shifts to anti-inflammatory signals which take over and bring about resolution of inflammation and normal homeostasis.  Inflammation is a tightly regulated response to infection or tissue injury which must be regulated precisely as if it is insufficient or in excess may lead to infection, considerable morbidity, and even mortality. 
In the current scenario, studies relating the altered innate immune response, inflammation and depression dominates the literature, although there have been studies which have also tried to ascertain the role played by the altered adaptive immune response in depression. In accordance with earlier studies, a recent meta-analytic review has shown the association of depression and stress with a decrease in the percentage of lymphocytes. 
There are many observations consistently provided by several studies which have emphasized the role of inflammation in the pathophysiology of depression. Patients of depressive disorder have been found to be having elevated concentrations of several proinflammatory cytokines including IL-1, IL-6, and TNF-α along with acute phase protein CRP not only in peripheral blood but also in cerebrospinal fluid (CSF).  A meta-analysis performed by Howren et al., have found each inflammatory marker IL-6, IL-1, CRP was positively associated with depression, with the strongest association found in clinically depressed patients groups.  In an another recent study also reveal elevated inflammatory markers IL-6 and TNF-α in MDD patients.  Elevated inflammatory cytokines which are found to be present in patients of depression, there levels were found to reduce the following treatment.  Although, there are some studies which showed inconclusive and conflicting results since they were unable to find any association. For instance, Kagaya et al. compared depressed patients with age- and sex-matched healthy controls and levels of IL-6, TNF-α, and IL-1 showed no significant differences between the two groups.  Similarly, a study by Pan et al. reported no association between depressive symptoms and CRP levels.  These observations may be attributed to heterogeneity of disease and methodological differences in studies but also reflect that altered inflammatory response might contribute to etiology of depression only in subpopulation of vulnerable depressive patients. 
The other observation which provides insight being the co-occurrence of several inflammatory illnesses with depression prominently being cardiovascular diseases, diabetes, and some autoimmune diseases.  Inflammation has been suggested as one of the plausible mechanisms as the common underlying biologic process of low-grade inflammation is present in both of them. 
The other finding which is notable in examining the relationship is on exposure of cytokines such as interferon-alpha (IFN-α) and IL-2 which are used for treatment in chronic hepatitis C and cancer have resulted in occurrence of depression in those individuals. Moreover, depressive symptoms which were induced by IFN-α were associated with changes in serum cytokines levels. 
Another link which might explain the association of depression and altered inflammatory response in medically healthy individual is stress which is considered as a major risk factor for depression has been observed to activate inflammatory signaling pathways both in the periphery and in central nervous system (CNS).  Experimental studies carried out in animals have reported that psychological stressors increase proinflammatory cytokines levels including IL-1β and TNF-α in the brain as well as in periphery.  The sympathetic nervous system may also provide a link between stress and depression as stress-induced activation of the sympathetic nervous system has been found to be associated with proinflammatory cytokines activation in the periphery. , Recent meta-analysis has drawn special attention to the role of a short (s) allele polymorphic variant in the promoter region of the serotonin transporter (SERT) gene (5-HTTLPR) in the propensity to depression in the presence of stressor. Those subjects who were carrying this less functional short allele polymorphic variant have reduced uptake of neurotransmitter serotonin into the presynaptic neurons of the brain and showed greater sensitivity to stress. 
Most studies conducted are cross-sectional in nature studying the association between inflammatory markers and depression does not tell about the causal direction of the association. Whether depression is resulting in inflammatory pathways activation or inflammatory illness/stress is culminating in depressive symptoms or whether there is a bidirectional relationship is still unclear. There are some prospective studies which have addressed the directionality of association. Stewart et al. reported baseline beck depression inventory-II (BDI-II) which is used to assess depressive symptoms was a predictor of 6-year change in IL-6 but baseline IL-6 did not predict 6 year change in BDI-II.  While Gimeno et al. studied both directions of association and reported baseline IL-6 and CRP were predictive of 12-year change in cognitive symptoms of depression. Thus, it can be said that depression-inflammation relationship is bidirectional and complex. 
| Potential pathways mediating depression and inflammation|| |
The different routes by which peripheral cytokines signal the brain has been proposed  are firstly through the leaky areas of the blood-brain barrier (BBB) like a circumventricular organ. Second, by directly across the BBB via binding with their specific transporters present in BBB. Another mechanism by which cytokines can reach the brain is along the afferent vagal fibers. Finally, an endothelial cell present in BBB gets activated by peripheral cytokines which then result in increased release of cytokines.
As we know that depression exhibits increased levels of cytokines in the peripheral blood. A bidirectional relationship seems to exist between peripheral and central neuronal pathways since peripheral cytokines once reaching the brain bring about changes by modulating several signaling pathways which are relevant to depression including neurotransmitter metabolism, neuroendocrine function, neuronal plasticity, and excitotoxicity.  Microglia astrocytes which are cells of the neuronal system have receptors and are capable of producing cytokines in the brain following signaling by peripheral cytokines. 
| Depression and Tryptophan-Kynurenine Pathway|| |
Serotonin is a major neurotransmitter in the brain whose dysregulation plays a major etiological role in depression. Inflammatory cytokines by the modulating serotonergic system may mediate depressive symptoms. 
Tryptophan is an essential amino acid required as a substrate for serotonin (5-HT) synthesis with the help of enzyme tryptophan hydroxylase. Proinflammatory cytokines like IFN-γ, TNF-α have been implicated in upregulation of indoleamine 2,3 dioxygenase (IDO) which is a rate limiting enzyme in the tryptophan-kynurenine pathway, by activation of several signaling pathways such as signal transducer and activator of transcription 1α, IRF-1, p38 MAPK, and NF-κB. IFNs are most notable inducer of IDO. 
IDO leads to increased formation of kynurenine from tryptophan resulting in decrease availability of tryptophan as a substrate for serotonin synthesis in neurons. Cytokines induce IDO expression in several immune cells including macrophages and microglia.  Moreover, the role of kynurenine metabolites has also been proposed in the development of depression. Kynurenine further metabolized to 3 hydroxy kynurenine and quinolinic acid in astrocytes and glia. These kynurenine metabolites have neurotoxic properties due to their ability to generate reactive oxygen species.  Quinolinic acid being a N-methyl-D-aspartate (NMDA) agonist stimulate increased glutamate release further resulting in CNS excitotoxicity. One of the metabolites referred as kynurenic acid being NMDA antagonist has been termed neuroprotective.  Moreover, it has also been shown that cytokines by inducing the neuronal SERT activity decrease the availability of serotonin for serotonergic neurotransmission.  Besides serotonin, researches in animal studies suggest the role of cytokines in decreasing the concentration of dopamine by stimulating nitric oxide (NO) synthesis and thereby decreasing the availability of tetrahydrobiopterin (BH4) which acts as a cofactor for tyrosine hydroxylase which is a rate-limiting enzyme in dopamine synthesis. As BH4 also required for NO synthesis. 
| Hypothalamic-Pituitary-Adrenal Axis Dysregulation in Depression|| |
Hypothalamic-pituitary-adrenal (HPA) axis is a central neuroendocrine system that regulates stress response in the body. Current researches have consistently emphasized the role of HPA axis dysfunction in the pathophysiology of depression.  Evidence suggest that cytokines can activate HPA axis and have been shown to stimulate the release of corticotropin-releasing hormone (CRH) in the brain. Patients of depression have been found to have elevated levels of cortisol in plasma, urine, and also increased levels of CRH in CSF.  When CRH has been administered in lab animals, it resulted in various behavioral alterations as those found in depression. 
Another mechanism by which cytokines may lead to HPA axis dysfunction is by inducing glucocorticoid resistance implying decreased responsiveness to glucocorticoids by impairing the functionality of glucocorticoid receptors (GRs) and also decreasing the expression of GRs.  Hyperactivity of CRH partly may have occurred due to altered glucocorticoid-mediated feedback inhibition of CRH production due to glucocorticoid resistance as demonstrated by nonsuppression of glucocorticoid cortisol to dexamethasone during dexamethasone suppression test.  Cytokines and their signaling pathways may affect GR function at several levels of glucocorticoid-mediated GR signaling. The expression of GR, GR-alpha isoform which is required for binding glucocorticoids during glucocorticoid signaling pathways is found to be reduced in patients of depression.  Cytokines have also been implicated in decreasing the function of GR by inducing various signaling proteins such as MAPK and interfering the cortisol-GR translocation from cytoplasm to the nucleus and also further preventing the GR complex binding to DNA thus impairing glucocorticoid signaling. ,
| Neuronal plasticity|| |
Neuronal plasticity is an ability of the brain to adapt itself against several environmental challenges. The proinflammatory cytokines when dysregulated in CNS either due to inflammation or environmental stimuli like stress have shown to decrease neurogenesis, inducing of apoptosis and also causing modulation of synaptic function through an increase in α-amino -3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA) receptors. , Brain-derived neurotrophic factor (BDNF) is a neurotrophic factor which is an important mediator of neurogenesis and neuron survival and found in brain regions involved in plasticity might provide a link between inflammation and neural plasticity. Animal studies have found decreased BDNF gene expression following the administration of proinflammatory cytokines or lypopolysacharide (LPS). 
| Therapeutic implications|| |
The role of inflammation in the pathophysiology of depression may provide a novel therapeutic strategy targeting inflammation in subset of patients exhibiting increased in inflammatory cytokines. The therapeutic treatment for depression targeting inflammation is still in the investigative stage, and several antidepressants have shown to decrease the inflammatory cytokines in patients of depression.  TNF-α antagonist infliximab has proved to be useful in improving depression in treatment-resistant depressive patients with increased inflammatory cytokines.  Agents like celecoxib which target inflammatory signaling are cyclooxygenase-2 inhibitors which if used along with antidepressant treatment have shown to increase the efficacy of antidepressant in depressive patients.  The inhibitor of IDO, 1 methyl tryptophan have also shown to inhibit LPS-induced depressive-like behavior in animal studies  and glutamate receptor antagonist such as NMDA antagonist ketamine have also proved to be useful. 
| Conclusion|| |
The review highlights the etiological role inflammation plays in the pathophysiology of depression. Depression being of multifactorial etiology resulting from the interaction of environmental and genetic factors, therefore not every depression patient will exhibit dysregulated inflammation but occur in subgroup of depression patients.  The inflammation could provide a potential therapeutic strategy in subset of depression patients exhibiting increased inflammation and treatment resistant to conventional antidepressants. The identification of potential inflammatory biomarkers further will not only aid in identifying vulnerable, at-risk patients but will also assist in preventing cardiovascular morbidity and mortality found to be associated with depressive disorder.
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