Capuron L, Miller AH. Immune system to brain signaling: neuropsychopharmacological implications. Pharmacol Ther 130: 226-238

Laboratory of Nutrition and Integrative Neurobiology, NutriNeuro, INRA UMR 1286, University Victor Segalen Bordeaux 2, Bordeaux, France.
Pharmacology [?] Therapeutics (Impact Factor: 9.72). 02/2011; 130(2):226-38. DOI: 10.1016/j.pharmthera.2011.01.014
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There has been an explosion in our knowledge of the pathways and mechanisms by which the immune system can influence the brain and behavior. In the context of inflammation, pro-inflammatory cytokines can access the central nervous system and interact with a cytokine network in the brain to influence virtually every aspect of brain function relevant to behavior including neurotransmitter metabolism, neuroendocrine function, synaptic plasticity, and neurocircuits that regulate mood, motor activity, motivation, anxiety and alarm. Behavioral consequences of these effects of the immune system on the brain include depression, anxiety, fatigue, psychomotor slowing, anorexia, cognitive dysfunction and sleep impairment; symptoms that overlap with those which characterize neuropsychiatric disorders, especially depression. Pathways that appear to be especially important in immune system effects on the brain include the cytokine signaling molecules, p38 mitogen-activated protein kinase and nuclear factor kappa B; indoleamine 2,3 dioxygenase and its downstream metabolites, kynurenine, quinolinic acid and kynurenic acid; the neurotransmitters, serotonin, dopamine and glutamate; and neurocircuits involving the basal ganglia and anterior cingulate cortex. A series of vulnerability factors including aging and obesity as well as chronic stress also appears to interact with immune to brain signaling to exacerbate immunologic contributions to neuropsychiatric disease. The elucidation of the mechanisms by which the immune system influences behavior yields a host of targets for potential therapeutic development as well as informing strategies for the prevention of neuropsychiatric disease in at risk populations.

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Available from: Andrew H Miller, Dec 22, 2013
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    • "This potential link is supported by findings from preclinical studies in rodent models that directly link proinflammatory cytokines with brain 5-HTT availability through activation of MAPK pathways (Baganz and Blakely, 2013; Couch et al., 2013; Katafuchi et al., 2006; Malynn et al., 2013; Morikawa et al., 1998; Ramamoorthy et al., 1995; Samuvel, 2005; Tsao et al., 2008). There are number of pathways through which circulating inflammatory markers can signal the brain including active transport across the blood-brain barrier (BBB); second messenger signals from the endothelial lining of BBB; through afferent vagal pathways ; passage of cytokines through 'leaky' regions in the BBB (Capuron and Miller, 2011). Of particular theoretical relevance is that, in humans, the raphe nuclei (dorsal) are located close to the cerebral aqueduct making it particularly vulnerable to inflammatory signalling molecules present in the cerebral spinal fluid (CSF) (Howerton et al., 2014). "
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    ABSTRACT: Preclinical studies demonstrate that pro-inflammatory cytokines increase serotonin transporter availability and function, leading to depressive symptoms in rodent models. Herein we investigate associations between circulating inflammatory markers and brainstem serotonin transporter (5-HTT) availability in humans. We hypothesised that higher circulating inflammatory cytokine concentrations, particularly of tumour necrosis factor (TNF-α), would be associated with greater 5-HTT availability, and that TNF-α inhibition with etanercept (sTNFR:Fc) would in turn reduce 5-HTT availability. In 13 neurologically healthy adult women, plasma TNF-α correlated significantly with 5-HTT availability (rho=0.6; p=0.03) determined by [(123)I]-beta-CIT SPECT scanning. This association was replicated in an independent sample of 12 patients with psoriasis/psoriatic arthritis (rho=0.76; p=0.003). Indirect effects analysis, showed that there was a significant overlap in the variance explained by 5-HTT availability and TNF-α concentrations on BDI scores. Treatment with etanercept for 6-8weeks was associated with a significant reduction in 5-HTT availability (Z=2.09; p=0.03; r=0.6) consistent with a functional link. Our findings confirm an association between TNF-α and 5-HTT in both the basal physiological and pathological condition. Modulation of both TNF-α and 5-HTT by etanercept indicate the presence of a mechanistic pathway whereby circulating inflammatory cytokines are related to central nervous system substrates underlying major depression. Copyright © 2015. Published by Elsevier Inc.
    Brain Behavior and Immunity 08/2015; DOI:10.1016/j.bbi.2015.08.005 · 5.89 Impact Factor
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    • "The inflammatory activity has been shown to be associated with cognitive performance in obese women [10]. The role of neuroinflammation and cytokines in mood disorders and cognitive impairment have also been demonstrated by both animal studies [11– 13]) and clinical data [14] [15]. "
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    ABSTRACT: Cytokines and chemokines regulate many functions in the body including the brain. The interactions between adipose tissue and the central nervous system (CNS) are important for the regulation of energy balance. CNS function is also influenced by age. The aim of the present study was to investigate the effects of body mass index (BMI) and age on cytokine and chemokine levels in cerebrospinal fluid. Cerebrospinal fluid samples (n=89) were collected from patients undergoing routine surgical procedures. The samples were analyzed using the multiplex proximity extension assay (PEA) in which 92 different cytokines are measured simultaneously using minute sample volume. We found no significant correlations between age and cytokine levels for any of the studied markers. In contrast, at a false discovery rate of 10%, 19 markers were significantly associated with BMI (in decreasing significance: FGF-5, ADA, Beta-NGF, CD40, IL-10RB, CCL19, TGF-alpha, SIRT2, TWEAK, SCF, CSF-1, 4E-BP1, DNER, LIF-R, STAMPB, CXCL10, CXCL6, VEGF-A and CX3CL1). This study reveals a clear effect of BMI on cytokine and chemokine levels in cerebrospinal fluid. Copyright © 2015. Published by Elsevier Ltd.
    Cytokine 07/2015; DOI:10.1016/j.cyto.2015.07.010 · 2.66 Impact Factor
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    • "(Neurauteretal.,2008).Cytokine-inducedGTP-CH1activation, classicallyassessedbymeasuringincreasedproduction ofneopterin,isindeedabletoimpairthedopaminergic neurotransmission(FelgerandMiller,2012)whichisknown tobeinvolvedinmooddisordersandcognitivedysfunctions, includinginconditionsofchronicimmunestimulation(Brydon etal.,2008;Capuronetal.,2012).Consistentwiththese findings,reducedBH4levelshavebeenreportedinpatients withpsychiatricdisorders(Hashimotoetal.,1994;Hoekstra etal.,2001).Similarly,increasedbloodneopterinconcentrations correlatewithagreaterincidenceofdepressiveepisodesin patientswithmajordepression(Celiketal.,2010).Interestingly, chroniclow-gradeinflammationthatisclassicallyreportedin elderlypeopleisassociatedwithactivationofbothIDOandGTP- CH1(Oxenkrug,2010;Capuronetal.,2011b).Moreimportantly, theseenzymaticactivationshavebeenshowntoparticipatein thepathophysiologyofneuropsychiatricsymptoms,whose prevalenceisoftenhighinagedpopulation(Oxenkrug, 2010;Capuronetal.,2011b).Ofnote,inadditiontoimpair monoaminergicneurotransmission,bothenzymescontributes toincreaseoxidativestress(FelgerandMiller,2012;Stoneetal., 2012;Campbelletal.,2014).Increasedneopterinlevelshave beenreportedinobeserats(Finkelsteinetal.,1982)andhumans (Ledochowskietal.,1999;Oxenkrugetal.,2011),suggesting thatactivationoftheGTP-CH1enzymebycytokines,andthe consequentalterationsofdopamineneurotransmission,may contributetothedevelopmentofneuropsychiatricsymptoms reportedinobesity.Althoughthisassumptionstillneedstobe confirmed,itisworthmentioningthatalterationsofdopamine function,togetherwithalterationsinbasalganglia/reward circuitryhavebeenreportedinobesepatients(deWeijeretal., 2011;Volkowetal.,2011).Moreover,depressive-likebehavior isassociatedinDIOmicewithalterationsinstriatalcircuitry, supportingarolefordopamine-relateddisruptionsinobesityassociateddepressivesymptoms(SharmaandFulton ,2013). "
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    ABSTRACT: Obesity is associated with a high prevalence of mood disorders and cognitive dysfunctions in addition to being a significant risk factor for important health complications such as cardiovascular diseases and type 2 diabetes. Identifying the pathophysiological mechanisms underlying these health issues is a major public health challenge. Based on recent findings, from studies conducted on animal models of obesity, it has been proposed that inflammatory processes may participate in both the peripheral and brain disorders associated with the obesity condition including the development of emotional and cognitive alterations. This is supported by the fact that obesity is characterized by peripheral low-grade inflammation, originating from increased adipose tissue mass and/or dysbiosis (changes in gut microbiota environment), both of which contribute to increased susceptibility to immune-mediated diseases. In this review, we provide converging evidence showing that obesity is associated with exacerbated neuroinflammation leading to dysfunction in vulnerable brain regions associated with mood regulation, learning, and memory such as the hippocampus. These findings give new insights to the pathophysiological mechanisms contributing to the development of brain disorders in the context of obesity and provide valuable data for introducing new therapeutic strategies for the treatment of neuropsychiatric complications often reported in obese patients.
    Frontiers in Neuroscience 07/2015; 9:229. DOI:10.3389/fnins.2015.00229 · 3.66 Impact Factor
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