Genetic and Environmental Influences on Pro-Inflammatory Monocytes in Bipolar Disorder

Padmos, Roos C.; Baal, G. Caroline M. van; Vonk, Ronald; Wijkhuijs, Annemarie J.M.; Kahn, René S.; Nolen, Willem A.; Drexhage, Hemmo A.

doi:10.1001/archgenpsychiatry.2009.116

Cited by 51 publications

(30 citation statements)

References 44 publications

(51 reference statements)

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“…Apparently the inflammatory set point of monocytes is dependent on the (environmental or hormonal) state of the organism, an observation that is supported by twin studies in BD, showing that common endogenous or environmental factors play a prime role in the pro-inflammatory set point of the monocytes (35). In sum, only episodes of pro-inflammatory activation occur in circulating monocytes of individuals at risk to develop BD and in BD patients, and these episodes are probably environmentally and endogenously precipitated and only in part linked to the presence and activity of (manic) mood symptoms.…”

Section: Discussionmentioning

confidence: 89%

T Cell Deficits and Overexpression of Hepatocyte Growth Factor in Anti-inflammatory Circulating Monocytes of Middle-Aged Patients with Bipolar Disorder Characterized by a High Prevalence of the Metabolic Syndrome

et al. 2017

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BackgroundWe previously reported T cell deficits and pro-inflammatory gene activation in circulating monocytes of two cohorts of bipolar disorder (BD) patients, a cohort of postpartum psychosis patients and in bipolar offspring. Pro-inflammatory gene activation occurred in two clusters of mutually correlating genes, cluster 1 for inflammation-related cytokines/factors, cluster 2 for motility, chemotaxis, and metabolic factors.AimTo verify these cellular immune abnormalities in yet another cohort [the bipolar stress study (BiSS) cohort] of relative old (52 years, median) BD patients and to relate immune abnormalities to hair cortisol levels, measured in this cohort and representing long-term systemic cortisol levels, and to the presence of the metabolic syndrome (MetS), which was prevalent in 29% of the BiSS patients.MethodsMonocyte immune gene activation (quantitative polymerase chain reaction) and T cell deficits (fluorescence-activated cell sorting analysis) were determined in 97 well-controlled, largely euthymic BiSS BD patients. Monocyte genes included the cluster 1 and 2 genes, the genes for the glucocorticoid receptor (GR) α and GRβ, and the gene for hepatocyte growth factor [HGF, a marker of monocyte-derived circulating angiogenic cells (CACs)]. CACs serve vessel repair. Abnormal numbers are found in patients with MetS and vascular damage.ResultsAs compared to healthy controls: (1) the pro-inflammatory cluster 1 genes were downregulated, and the GRα and the HGF gene were upregulated in the monocytes of the BiSS patients and (2) T cell deficits were shown (reduced numbers of lymphocytes in particular of T cells). Within the reduced T cell population, a shift had taken place in the T-helper populations: T-helper 17 and T-helper 2 increased and T regulatory cells decreased. Correlations between hair cortisol, the MetS, monocyte gene activation, and T cell deficits were not found.ConclusionT cell deficits most likely are a trait phenomenon of BD, since they have also been found in the other cohorts of BD patients and in bipolar offspring. Monocytes of this cohort showed an anti-inflammatory set point, suggesting that pro- and anti-inflammation are state characteristics of BD. The monocyte gene profile indicated an increased CAC activity; the question arises whether this is due to putative vessel damage in these relatively old patients with a high prevalence of the MetS.

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Section: Discussionmentioning

confidence: 89%

T Cell Deficits and Overexpression of Hepatocyte Growth Factor in Anti-inflammatory Circulating Monocytes of Middle-Aged Patients with Bipolar Disorder Characterized by a High Prevalence of the Metabolic Syndrome

et al. 2017

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“…Inflammatory abnormalities in systemic circulation and in the central nervous system are increasingly reported in psychiatric diseases such as schizophrenia and bipolar disorder (Dickerson et al, 2013; Drexhage et al, 2010; Fillman et al, 2013; Gibney and Drexhage, 2013; Leonard et al, 2012; Miller et al, 2011; Miller et al, 2012; Muller et al, 2012a; Padmos et al, 2009; Severance et al, 2012b). The inflammation source is not known but may be inherent to the disease or may result from antipsychotic-related metabolic disturbances (Drexhage et al, 2010; Leonard et al, 2012; Miller et al, 2011; Miller et al, 2012; Muller et al, 2012a; Severance et al, 2012a; Severance et al, 2012b; Steiner et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

Discordant patterns of bacterial translocation markers and implications for innate immune imbalances in schizophrenia

Severance¹,

Gressitt²,

Stallings³

et al. 2013

Schizophrenia Research

206

146

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The origin of inflammation in psychiatric disorders is not well understood. The translocation of commensal microbiota across the gastrointestinal barrier can result in a persistent state of low-grade immune activation and/or inflammation. We measured serological surrogate markers of bacterial translocation (soluble CD14 (sCD14) and lipopolysaccharide binding protein (LBP)) in two psychiatric cohorts and compared these levels to C-reactive protein (CRP), body mass index (BMI), and food-related and autoimmune antibodies. The two cohorts were composed of the following: (1) n=141 schizophrenia, n=75 bipolar disorder, n=78 controls; (2) n=78 antipsychotic-naïve first-episode schizophrenia, n=38 medicated first-episode schizophrenia. sCD14 seropositivity conferred a 3.1-fold increased odds of association with schizophrenia (multivariate regressions, OR=3.09, p<0.0001) compared to controls. Case-control differences in sCD14 were not matched by LBP. Quantitative levels of LBP, but not sCD14, correlated with BMI in schizophrenia (R2=0.21, p<0.0001). sCD14 and LBP also exhibited some congruency in schizophrenia with both significantly correlated with CRP (R2=0.26-0.27, p<0.0001) and elevated in females compared to males (p<0.01). Antipsychotic treatment generally did not impact sCD14 or LBP levels except for significant correlations, especially sCD14, with gluten antibodies in antipsychotic-naïve schizophrenia (R2=0.27, p<0.0001). In bipolar disorder, sCD14 levels were significantly correlated with anti-tissue transglutaminase IgG (R2=0.37, p<0.001). In conclusion, these bacterial translocation markers produced discordant and complex patterns of activity, a finding that may reflect an imbalanced, activated innate immune state. Whereas both markers may upregulate following systemic exposure to Gram-negative bacteria, non-lipopolysaccharide-based monocyte activation, autoimmunity and metabolic dysfunction may also contribute to the observed marker profiles.

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“…A substantial fraction of the transcriptome is under circadian regulation (Koike et al, 2012), with evidence in patients with BD suggesting a high dependence of behavior and psychopathology on the characteristics of the biological clock (Harvey, 2008;Benedetti and Terman, 2013;McClung, 2013): both neurons and glia express cellular circadian rhythms, coordinated in the brain by the suprachiasmatic nuclei by a diffusible signal (Slat et al, 2013), and with a thermolabile circulating factor influencing the endogenous rhythm of the clock molecular machinery to produce circadian behaviors (Pagani et al, 2011). An activated monocyte pro-inflammatory state, with a high inflammatory set point of circulating monocytes at the transcriptome level (Padmos et al, 2008) and in vivo activation of brain microglia (Haarman et al, 2014), has been associated with BD and parallels development in the offspring of patients with BD (Padmos et al, 2009;Mesman et al, 2015); again, pro-inflammatory cytokines diffuse into the brain via VT in the ECM. Lithium, the mainstay for the long-term treatment of BD and the only drug able to specifically counteract the signs of both WM and GM disruption associated with the illness (Benedetti et al, , 2015, has major effects on water homeostasis and increases the water content of the brain (Phatak et al, 2006;Regenold, 2008;Benedetti et al, 2015), thus probably also modifying the structure of the ECM and influencing the metabolite clearance which is coupled with changes of the interstitial fluid volume (Xie et al, 2013).…”

Section: The Possible Relevance Of the Brain Gmn In Psychiatry And Nementioning

confidence: 99%

On the role of the extracellular space on the holistic behavior of the brain

Marcoli¹,

Agnati²,

Benedetti

et al. 2015

Reviews in the Neurosciences

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AbstractMultiple players are involved in the brain integrative action besides the classical neuronal and astrocyte networks. In the past, the concept of complex cellular networks has been introduced to indicate that all the cell types in the brain can play roles in its integrative action. Intercellular communication in the complex cellular networks depends not only on well-delimited communication channels (wiring transmission) but also on diffusion of signals in physically poorly delimited extracellular space pathways (volume transmission). Thus, the extracellular space and the extracellular matrix are the main players in the intercellular communication modes in the brain. Hence, the extracellular matrix is an ‘intelligent glue’ that fills the brain and, together with the extracellular space, contributes to the building-up of the complex cellular networks. In addition, the extracellular matrix is part of what has been defined as the global molecular network enmeshing the entire central nervous system, and plays important roles in synaptic contact homeostasis and plasticity. From these premises, a concept is introduced that the global molecular network, by enmeshing the central nervous system, contributes to the brain holistic behavior. Furthermore, it is suggested that plastic ‘brain compartments’ can be detected in the central nervous system based on the astrocyte three-dimensional tiling of the brain volume and on the existence of local differences in cell types and extracellular space fluid and extracellular matrix composition. The relevance of the present view for neuropsychiatry is discussed. A glossary box with terms and definitions is provided.

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Genetic and Environmental Influences on Pro-Inflammatory Monocytes in Bipolar Disorder

Abstract: The association of the monocyte pro-inflammatory state with BD is primarily the result of a common shared environmental factor.

Cited by 51 publications

References 44 publications

T Cell Deficits and Overexpression of Hepatocyte Growth Factor in Anti-inflammatory Circulating Monocytes of Middle-Aged Patients with Bipolar Disorder Characterized by a High Prevalence of the Metabolic Syndrome

T Cell Deficits and Overexpression of Hepatocyte Growth Factor in Anti-inflammatory Circulating Monocytes of Middle-Aged Patients with Bipolar Disorder Characterized by a High Prevalence of the Metabolic Syndrome

Discordant patterns of bacterial translocation markers and implications for innate immune imbalances in schizophrenia

On the role of the extracellular space on the holistic behavior of the brain

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