Inflammation: The Common Pathway of Stress-Related Diseases

Liu, Yun-Zi; Wang, Yunxia; Jiang, Chun‐Lei

doi:10.3389/fnhum.2017.00316

Cited by 500 publications

(367 citation statements)

References 115 publications

(133 reference statements)

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“…Thus, our data highlight that para-inflammation appears to be a common mechanism in the three brain regions investigated, and is part of the protective adaptive response to chronic stress which is in line with a recent framework emphasizing that inflammatory signals contribute to restore homeostasis (58). This observation agrees well with the emerging view that chronic stress and stress-related diseases, such as major depression, share inflammation as a common mediator (59,60).…”

Section: Close Association Between Rems Enhancement and The Corticostsupporting

confidence: 91%

REM sleep: unique associations with behavior, corticosterone regulation and apoptotic pathways in chronic stress in mice

Nollet

Hicks

McCarthy

et al. 2018

Preprint

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2 AbstractOne of sleep's putative functions is mediation of adaptation to waking experiences. Chronic stress is a common waking experience, however, which specific aspect of sleep is most responsive, and how sleep changes relate to behavioral disturbances and molecular correlates remain unknown. We quantified sleep, physical, endocrine and behavioral variables and the brain and blood transcriptome in mice exposed to nine weeks of unpredictable chronic mild stress (UCMS). Comparing 46 phenotypical variables revealed that rapid-eye-movement sleep (REMS), corticosterone regulation and coat state were most responsive to UCMS. REMS theta oscillations were enhanced whereas delta oscillations in non-REMS were unaffected. Transcripts affected by UCMS in the prefrontal cortex, hippocampus, hypothalamus and blood were associated with inflammatory and immune responses. A machine learning approach controlling for unspecific UCMS effects identified transcriptomic predictors for specific phenotypes and their overlap. Transcriptomic predictor sets for the inter-individual variation in REMS continuity and theta activity shared many pathways with corticosterone regulation and in particular pathways implicated in apoptosis, including mitochondrial pathways. Predictor sets for REMS and anhedonia, one of the behavioral changes following UCMS, shared pathways involved in oxidative stress, cell proliferation and apoptosis. RNA predictor sets for non-NREMS parameters showed no overlap with other phenotypes. These novel data identify REMS as a core and early element of the response to chronic stress, and identify apoptotic pathways as a putative mechanism by which REMS mediates adaptation to stressful waking experiences. Significance Statement 3 Significance StatementSleep is responsive to experiences during wakefulness and is altered in stress-related disorders. Whether sleep changes primarily concern rapid-eye-movement sleep (REMS) or non-REM sleep, and how they correlate with stress hormones, behavioral and transcriptomic responses remained unknown. We demonstrate using unpredictable chronic (9-weeks) mild stress that REMS is the most responsive of all the measured sleep characteristics, and correlates with deficiency in corticosterone regulation. An unbiased machine learning, controlling for unspecific effects of stress, revealed that REMS correlated with RNA predictor sets enriched in apoptosis including mitochondrial pathways. Several pathways were shared with predictors of corticosterone and behavioral responses. This unbiased approach point to apoptosis as a molecular mechanism by which REMS mediates adaptation to an ecologically relevant waking experience.

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Section: Close Association Between Rems Enhancement and The Corticostsupporting

confidence: 91%

REM sleep: unique associations with behavior, corticosterone regulation and apoptotic pathways in chronic stress in mice

Nollet

Hicks

McCarthy

et al. 2018

Preprint

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“…The pro-inflammatory trans-signalling pathway is the principal pathway activated by IL-6 in the central nervous system 48 . Of note, evidence suggests that acute stress causes an inflammatory response which could explain why several disorders where stress is a risk factor are associated with the same immune alterations 46,49 . Another mechanism to explain the increased risk with IL-6 is linked to the hypothalamus-pituitary-adrenal (HPA) axis.…”

Section: Discussionmentioning

confidence: 99%

Disentangling causal relationships between inflammatory markers and depression: a bidirectional Mendelian randomization analysis

Dardani

Yarmolinsky

Robinson

et al. 2019

Preprint

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BackgroundThe inflammatory markers C-reactive protein (CRP), interleukin-1 receptor antagonist (IL1-Ra), and interleukin-6 (IL-6) have been associated with depression risk in observational studies. The causal nature of these associations is unclear as conventional observational designs are susceptible to reverse causation and residual confounding. Bidirectional Mendelian randomization (MR) analysis uses genetic variants to proxy for risk factors to help elucidate the presence, magnitude, and direction of causal relationships between traits.MethodsWe performed bidirectional two-sample MR to examine causal associations between circulating CRP, IL1-Ra, and IL-6 and major depressive disorder (MDD) in 135,458 cases and 344,901 controls in the Psychiatric Genetics Consortium. Genetic instruments to proxy inflammatory markers and liability to MDD were constructed by obtaining single-nucleotide polymorphisms (SNPs) associated with these phenotypes in genome-wide association study meta-analyses. Wald ratios and inverse-variance weighted random-effects models were employed to generate causal effect estimates and various sensitivity analyses were performed to examine violations of MR assumptions.ResultsThere was evidence supporting a causal effect of circulating IL-6 on risk of MDD (per natural-log increase: OR 0.85, 95% CI: 0.75-0.96, P=0.007). Higher circulating levels of IL-6 as influenced by variants in the IL6R gene region represent lower cellular binding of IL-6 to its receptor and therefore the present results suggest that IL-6 increases the risk of MDD. We found limited evidence supporting a causal effect of CRP (1.06, 95% CI 0.93-1.22; P=0.36) or IL1-Ra (OR 0.95, 95% CI: 0.87-1.03, P=0.20) on risk of MDD. Reverse direction MR analyses suggested limited evidence for a causal effect of genetic liability to MDD on any of the inflammatory markers examined.ConclusionsThese findings support a causal role of IL-6-related pathways in development of major depressive disorder and suggest the possible efficacy of interleukin-6 inhibition as a therapeutic target for depression.

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“…This is further demonstrated by the ability to transfer stress-prone phenotypes from one mouse to another via fecal transplantation (Collins, Kassam, & Bercik, 2013). Stress also activates an inflammatory response via the promotion of inflammatory cytokines (Liu, Wang, & Jiang, 2017). Given that inflammation is recognized as underlying many psychological and neurodegenerative disorders (Almond, 2013;Miller & Raison, 2016;Rea et al, 2016), stress then appears to play a role in both the etiology and maintenance of psychological illness via biological pathways, all of which are regulated by the GM.…”

Section: Stressmentioning

confidence: 99%

The role of the brain–gut–microbiota axis in psychology: The importance of considering gut microbiota in the development, perpetuation, and treatment of psychological disorders

Ganci

Suleyman

Butt³

et al. 2019

Brain and Behavior

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IntroductionThe prevalence of psychological disorders remains stable despite steady increases in pharmacological treatments suggesting the need for auxiliary treatment options. Consideration of the brain–gut–microbiota axis (BGMA) has made inroads into reconceptualizing psychological illness from a more holistic perspective. While our understanding of the precise role of gut microbiota (GM) in psychological illness is in its infancy, it represents an attractive target for novel interventions.MethodAn extensive review of relevant literature was undertaken.ResultsGut microbiota are proposed to directly and indirectly influence mood, cognition, and behavior which are key components of mental health. This paper outlines how GM may be implicated in psychological disorders from etiology through to treatment and prevention using the Four P model of case formulation.ConclusionMoving forward, integration of GM into the conceptualization and treatment of psychological illness will require the discipline of psychology to undergo a significant paradigm shift. While the importance of the GM in psychological well‐being must be respected, it is not proposed to be a panacea, but instead, an additional arm to a multidisciplinary approach to treatment and prevention.

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Inflammation: The Common Pathway of Stress-Related Diseases

Cited by 500 publications

References 115 publications

REM sleep: unique associations with behavior, corticosterone regulation and apoptotic pathways in chronic stress in mice

REM sleep: unique associations with behavior, corticosterone regulation and apoptotic pathways in chronic stress in mice

Disentangling causal relationships between inflammatory markers and depression: a bidirectional Mendelian randomization analysis

The role of the brain–gut–microbiota axis in psychology: The importance of considering gut microbiota in the development, perpetuation, and treatment of psychological disorders

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