BY AUSTIN LAM
Inflammation in Depression
‘The complex of melancholia behaves like an open wound’ – Sigmund Freud[69]
‘Sickness behavior’ is a term which reflects immune activation and is often associated with depression. However, the criteria required for depression diagnosis often coincides with sickness behavior symptomology due to systemic inflammation ranging from lethargy, decreased appetite, reduced social behavior and mobility, loss of libido, anorexia, cognitive impairment, and lastly depressed affect[70].
Inflammation in depression has been well researched. In major depressive disorder (MDD), the key features of a classic inflammatory response exist, involving an increase in proinflammatory cytokine expression which can trigger neuroinflammation. Elevated levels of systemic inflammatory markers, importantly interleukin (IL)-6, tumor necrosis factor- α (TNF-α), and C reactive protein have been observed for those with MDD compared with controls[71],[72], many of which, along with IL-1β, function as reliable biomarkers of inflammation in depressed patients. IL-6 is also a promising predictor of depression chronicity as high severity also predicted higher levels[73]. Therefore, the low-grade inflammatory process is related to depression development. The initial proposition that the etiology of depression was related to an increased immune response date back to 1991 from Smith’s ’macrophage theory of depression’[74].
Cytokine blockade of TNF or of components of the inflammatory signaling pathway, such as the precursor of prostacyclin, cyclooxygenase 2, proves to reduce depression in those with chronic disease, from MDD to rheumatoid arthritis[75]. This suggests that the role of inflammation in the context of treatment response is crucial, and inflammatory profiles should always be accounted for in antidepressants, under the assumption that they generally lean towards an anti-inflammatory response. Whether in vitro or ex vivo, they decrease pro-inflammatory cytokine production and increase anti-inflammatory cytokines such as IL-10[76].
Moreover, the fact that a lack of response with antidepressant treatment has association with inflammation, and evidence that peripheral cytokine levels can alter antidepressant treatment outcome, suggests that inflammatory profiling may be a useful prerequisite prior to a personalized antidepressant prescription.
Taking the angle of rare post-mortem data in the context of teenage suicide, it was found that both mRNA as well as protein expression levels of IL-1β, IL-6, and TNF-α had a notable increase in the Brodmann area 10 (Ba-10)[77]. Similarly, suicide has associations with elevation of microglial density in both depression and schizophrenia, with regions of the anterior cingulate cortex from suicide completers reporting a higher density of QUIN reactive microglia[78].
The line of evidence that is easiest to follow is the co-occurrence of inflammation related disorders and depression. Reports of co-morbid depression in Rheumatoid Arthritis[79], to neurodegenerative disorders allude to neuroinflammatory roles[80].
Endotoxin infusions trigger cytokine release, leading to depressive symptoms[81]. Exogenous cytokine administration alters behavior and provides classic depressive symptoms, as interferon (IFN)-alpha is often utilized as a treatment measure for both cancer and viral infection. In the case of hepatitis C, one in every 4 patients who have undergone interferon treatment have fallen victim to emergent major depression[82]. IFN-α-induced depression is uncannily like that of major depression. From the common choice of an inflammation-related model bacterial endotoxin LPS to Salmonella typhi[83] administrations, these immune challenges induce depressive symptoms through microglial activation.
Pro-inflammatory cytokines from systemic LPS administration induces sickness behavior characterized by aforementioned symptoms. Sickness as an adaptive response is reversible upon pathogen elimination, unlike depression. Sickness behavior peaks anywhere from two to six hours after intraperitoneal injection of LPS before stabilizing. Interestingly depression-like behavior persists after sickness behavior wanes exemplified through increased immobility in the tail-suspension test along with the forced-swim test[84]. 34 hours Post-LPS administration, both depression-like behavior and ubiquitous indoleamine 2,3-dioxygenase (IDO) reach their peaks, and notably pro-inflammatory cytokines enhance IDO activation. This activation leads to decreased tryptophan (TRP) levels, increased kynurenine (KYN) production, and other tryptophan-derived metabolites. Pre-treatment with minocycline, however, can mitigate sickness and depression-like behavior. Contrastingly, an IDO competitive inhibitor, 1-methyl tryptophan (1-MT) can also block solely depression-like behavior induced by LPS when administered.
Stress possesses the ability to cause inflammatory changes within both the brain and peripheral immune system. Various forms of stress exposure, especially psychosocial stressors, increase vulnerability to depression. Psychosocial stressors such as learned helplessness, chronic mild stress and social isolation are able to increase pro-inflammatory cytokine levels. The isolated microglia of stressed mice exhibited higher levels of IL-1β, IL-6, and TNF-α[85]. Hodes et al[86] found that after repeated social defeat stress (RSDS), a causal relationship could be drawn between baseline IL-6 levels as well as stress-susceptible mice. Elevated circulating IL-6 levels made mice more susceptible to depressive-like behavioral phenotypes, whilst IL-6 knockout mice proved to be resilient. In humans, Maes et al[87] initially introduced the idea of stress-induced anxiety producing a T-helper-1-like response, with higher production of IFN-γ and lower IL-10 as a response to psychological stress. Chronic stress is also a popular choice for depression models, activating inflammatory cytokines from evaluation after a 4-week period[88].
Psychosocial stressors and their role in immunoregulatory cytokine modulation suggest that inflammation has a key role in stress-related diseases, such as depression. Therefore, it is no mystery why such stressors occur prior to depression onset. Altogether, we can infer that IDO acts as a main player and mediator of the depressive-like phenotype caused by inflammation.
Inflammation-induced BDNF suppression in Depression
Extensive evidence has associated chronic low-grade inflammation with depression as increased levels of circulating pro-inflammatory cytokines have been proved. Altered BDNF expression has been studied in vivo delineating the effect of inflammation, and a negative correlation between that neuroinflammation and BDNF can be posited. According to the purported respective antidepressant and depressive-like effect of BDNF signaling and cytokine action, pro-inflammatory cytokines can be said to suppress BDNF expression in cortical regions related to mood regulation. Intraperitoneal injection of LPS or recombinant IL-1β gave a significant decrease in BDNF mRNA levels within the rat hippocampus and cortex, a result replicated by bacterial mimetics such as Poly:IC,[90]. Moreover, when rats were presented with acute E.coli treatment, suppression of BDNF exons I, II, and IV were reduced in the CA1 and dentate gyrus of the hippocampus. From this we can conclude that immune challenge and inflammation can partake in isoform-specific transcriptional repression due to selective impairment of isoform transcription rather than a universal change in expression[91]. This downregulation of BDNF is mediated through cytokine-induced activation of intra-cellular signaling molecules, such as p38 mitogen-activated protein kinase (MAPK) and NF-κB pathways. Tong et al.[92] discovered that facilitation of LTP by BDNF was disrupted from IL-1β application in rat hippocampal slice cultures, though its negative effect was cancelled through a p38 signaling inhibitor.
Clinically, IFN-α treatment can trigger iatrogenic depression in about 30% of non-depressed patients, hence cytokine-induced repression of BDNF has a role in depressive behavior[93]. During IFN-α therapy for treatment of Hepatitis C, pro-inflammatory cytokine levels predicted lower subsequent BDNF levels, both of which were independently associated with depressive symptom development[94]. The mechanistic role in which depression is triggered by inflammation – especially in individuals with an elevated baseline IL-6 level and originally low BDNF levels as vulnerability factors[95]. Despite elevated levels of both BDNF and IL-1β suggesting inflammation can impair BDNF signaling, it could simply be a compensatory response from chronic antidepressant use[96]. The BDNF Val66Met polymorphism has associations with greater risk of IFN-α induced depression as well as suicide ideation because of BDNF release in an activity-dependent manner.
Sex differences may well underlie said vulnerabilities, considering women are much more likely to develop depression, with higher basal levels of peripheral inflammation, greater IL-6 sensitivity to endotoxin exposure, and fluctuation in mood[97]. Moreover, more intense depressive behavior following an attenuated anti-depressant response exists in female BDNF conditional knockout mice compared to male BDNF conditional knockout mice[98]. Alternatively, estrogen deficiency in rodent models increases IDO hippocampus expression, along with kynurenine metabolite presence, pro-inflammatory cytokine expression, suggestive of a regulatory role in depressive development[99]. The relationship between sex, BDNF and inflammation deserves further research.
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