Brain, Behavior, and Immunity最新文献

{"title":"Evidence of microglial involvement in the childhood abuse-associated increase in perineuronal nets in the ventromedial prefrontal cortex","authors":"Claudia Belliveau ,&nbsp;Reza Rahimian ,&nbsp;Gohar Fakhfouri ,&nbsp;Clémentine Hosdey ,&nbsp;Sophie Simard ,&nbsp;Maria Antonietta Davoli ,&nbsp;Dominique Mirault ,&nbsp;Bruno Giros ,&nbsp;Gustavo Turecki ,&nbsp;Naguib Mechawar","doi":"10.1016/j.bbi.2024.12.013","DOIUrl":"10.1016/j.bbi.2024.12.013","url":null,"abstract":"<div><div>Microglia, known for their diverse roles in the central nervous system, have recently been recognized for their involvement in degrading the extracellular matrix. Perineuronal nets (PNNs), a specialized form of this matrix, are crucial for stabilizing neuronal connections and constraining plasticity. Our group recently reported increased PNN densities in the ventromedial prefrontal cortex (vmPFC) of depressed individuals that died by suicide in adulthood after experiencing childhood abuse (DS-CA) compared to matched controls. To explore potential underlying mechanisms, we employed a comprehensive approach in similar postmortem vmPFC samples, combining a human matrix metalloproteinase and chemokine array, isolation of CD11b-positive microglia and enzyme-linked immunosorbent assays (ELISA). Our findings indicate a significant downregulation of matrix metalloproteinase (MMP)-9 and tissue inhibitors of metalloproteinases (TIMP)-2 in both whole vmPFC grey matter and isolated microglial cells from DS-CA samples. Furthermore, our experiments reveal that a history of child abuse is associated with diminished levels of microglial CX3CR1 and IL33R in both vmPFC whole lysate and CD11b⁺ isolated cells. However, levels of the CX3CR1 ligand, CX3CL1 (Fractalkine), did not differ between groups. While these data suggest potential long-lasting alterations in microglial markers in the vmPFC of individuals exposed to severe childhood adversity, direct functional assessments were not conducted. Nonetheless, these findings offer insight into how childhood abuse may contribute to PNN alterations via microglial-related mechanisms.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"124 ","pages":"Pages 321-334"},"PeriodicalIF":8.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142821783","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Transcriptional signature of a hypersensitive glucocorticoid receptor variant in the neuroendocrine system suggests enhanced vulnerability to brain disorders","authors":"Eduard Murani,&nbsp;Nares Trakooljul,&nbsp;Frieder Hadlich,&nbsp;Klaus Wimmers","doi":"10.1016/j.bbi.2024.12.004","DOIUrl":"10.1016/j.bbi.2024.12.004","url":null,"abstract":"<div><div>The natural substitution Ala610Val in the porcine glucocorticoid receptor (GR_Ala610Val) leads to a profound compensatory downregulation of the hypothalamic–pituitary–adrenal (HPA) axis in early ontogeny. In this study, we leveraged this unique animal model to explore mechanisms of HPA axis regulation and consequences of its genetically-based persistent hypoactivity. To this end, we examined transcriptional signature of GR_Ala610Val in the hypothalamus, hippocampus, amygdala and adrenal gland in resting conditions (i.e. baseline glucocorticoid level) using mRNA sequencing. In addition, we studied transcriptome responses to two different doses of dexamethasone in the hypothalamus and hippocampus, depending on GR_Ala610Val. Across tissues, GR_Ala610Val consistently influenced the expression of several clustered protocadherins, particularly <em>PCDHB7</em>. Clustered protocadherins play an important role in neuronal connectivity and are implicated in different neurobiological disorders. Moreover, in line with our previous findings in blood immune cells, we found higher expression of pro-inflammatory genes, including canonical members of the TLR4 signaling pathway, in the brain of Val carriers. While the pro-inflammatory priming occurs already at resting conditions in the amygdala, in hypothalamus and hippocampus this seems to be associated with a stronger downregulation of several marker genes of homeostatic microglia, such as <em>SALL1</em>, by dexamethasone in Val carriers. Regarding the regulation of the HPA axis, GR_Ala610Val showed a dose-dependent effect on the central regulator of the axis, <em>CRH</em>, suggesting a dynamic adaptation to the glucocorticoid hypersensitivity of the Val variant. In the adrenal gland, GR_Ala610Val appears to downregulate cortisol production by impairing mitochondrial function. Overall, the transcriptional signature of GR_Ala610Val provides strong evidence that GR hypersensitivity leads to increased susceptibility to brain disorders.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"124 ","pages":"Pages 335-346"},"PeriodicalIF":8.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142823673","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Implications of the choroid plexus in Niemann-Pick disease Type C neuropathogenesis","authors":"Raquel van Gool ,&nbsp;Mariesa Cay ,&nbsp;Boyu Ren ,&nbsp;Kailey Brodeur ,&nbsp;Emma Golden ,&nbsp;Benjamin Goodlett ,&nbsp;Edward Yang ,&nbsp;Tom Reilly ,&nbsp;Caroline Hastings ,&nbsp;Elizabeth M. Berry-Kravis ,&nbsp;Pui Y. Lee ,&nbsp;Maria Di Biase ,&nbsp;Vanessa Cropley ,&nbsp;Christos Pantelis ,&nbsp;Dennis Velakoulis ,&nbsp;Ann K. Shinn ,&nbsp;Walla Al-Hertani ,&nbsp;Mark Walterfang ,&nbsp;Jaymin Upadhyay","doi":"10.1016/j.bbi.2024.12.024","DOIUrl":"10.1016/j.bbi.2024.12.024","url":null,"abstract":"<div><h3>Background</h3><div>Niemann-Pick Disease Type C (NPC) is an ultra-rare disorder characterized by progressive psychiatric and neurologic manifestations, with late infantile, juvenile, and adolescent/adult presentations. We examined morphological properties of the choroid plexus, a protective blood-cerebrospinal fluid barrier, in NPC, and their relationship with neurodegeneration, clinical status, and circulatory markers. This study also determined whether choroid plexus morphology differentiates between NPC and more prevalent illnesses, schizophrenia (SZ) and bipolar disorder (BD), which have overlapping psychiatric symptoms with adolescent and adult-onset NPC and are associated with misdiagnosis.</div></div><div><h3>Methods</h3><div>Patients with NPC were assessed using neuroimaging, clinical instruments, and plasma protein quantification focusing on inflammatory markers. Morphological properties (i.e., choroid plexus volumes) were compared between patients with NPC (n = 17), SZ (n = 20), BD (n = 24), and healthy controls (HCs, n = 106).</div></div><div><h3>Results</h3><div>Choroid plexus enlargement (p &lt; 0.05) and reduced thalamic volumes (p &lt; 0.05) were observed in NPC patients versus HCs and SZ or BD patients. A logistic regression model with choroid plexus and thalamic volumes as predictors yielded high prediction accuracy for NPC vs. HCs, NPC vs. SZ, and NPC vs. BD (area under the receiver operating characteristics curve [AUROC] of 1). Choroid plexus volumes were negatively correlated with left (p = 0.009–0.012) and right (p = 0.007–0.025) thalamic volumes, left (r = -0.69, p = 0.003) and right (r = -0.71, p = 0.002) crus I of the cerebellum, and greater severity on the NPC-Suspicion Index psychiatric subscale (ρ = 0.72, p = 0.042). Targeted protein expression quantification revealed differential expression of TGFA, HLA-DRA, TNFSF12, EGF, INFG, and IL-18 in NPC patients vs. HCs (p &lt; 0.05), with higher choroid plexus volumes correlating with IL-18 levels (ρ = 0.71, p = 0.047).</div></div><div><h3>Conclusion</h3><div>The choroid plexus may play a critical role in NPC neuropathogenesis and serve as a novel biomarker for monitoring neurodegenerative and inflammatory processes in NPC.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"124 ","pages":"Pages 376-384"},"PeriodicalIF":8.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142845687","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Maternal immune activation and adverse infant outcomes: Who is most at risk and how do we identify them?","authors":"Rachel A. Hill","doi":"10.1016/j.bbi.2024.12.016","DOIUrl":"10.1016/j.bbi.2024.12.016","url":null,"abstract":"","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"124 ","pages":"Pages 363-364"},"PeriodicalIF":8.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142827331","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sphingosine-1-phosphate receptor 3 activation promotes sociability and regulates transcripts important for anxiolytic-like behavior","authors":"Jose Castro-Vildosola ,&nbsp;Chris-Ann Bryan ,&nbsp;Nasira Tajamal ,&nbsp;Sai Anusha Jonnalagadda ,&nbsp;Akhila Kasturi ,&nbsp;Jacqueline Tilly ,&nbsp;Isabel Garcia ,&nbsp;Renuka Kumar ,&nbsp;Nathan T. Fried ,&nbsp;Tamara Hala ,&nbsp;Brian F. Corbett","doi":"10.1016/j.bbi.2024.12.001","DOIUrl":"10.1016/j.bbi.2024.12.001","url":null,"abstract":"<div><div>We previously demonstrated that sphingosine-1-phosphate receptor 3 (S1PR3) in the medial prefrontal cortex (mPFC) prevents reductions in sociability normally caused by stress. S1PR3 is a ubiquitously expressed G-protein coupled receptor that regulates immune system function, although its regulation of other biological processes is not well understood. Pharmacological activators of S1PR3 might provide important insights for understanding the neural substrates underlying sociability. Here we show that in mice, systemic injections of an S1PR3-specific agonist, CYM5541, promotes sociability in males and females whereas an S1PR3-specific antagonist, CAY10444, increases amygdala activation and increases social avoidance, particularly in females. S1PR3 expression is increased in the mPFC and dentate gyrus of females compared to males. RNA sequencing in the mPFC reveals that S1PR3 activation alters the expression of transcripts related to immune function, neurotransmission, transmembrane ion transport, and intracellular signaling. This work provides evidence that S1PR3 agonists, which have classically been used as immune modulators, might also be used to promote social behavior and, potentially, relieve symptoms of social anxiety. S1PR3 might be an important hub gene for mitigating maladaptive effects of stress as it reduces inflammatory processes, increases transcripts linked to anxiolytic neurotransmission, and promotes social behavior.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"124 ","pages":"Pages 205-217"},"PeriodicalIF":8.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142784188","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Biological pathways underlying the relationship between childhood maltreatment and Multimorbidity: A Two-Step, multivariable Mendelian randomisation study.","authors":"Vilte Baltramonaityte, Ville Karhunen, Janine F Felix, Brenda W J H Penninx, Charlotte A M Cecil, Graeme Fairchild, Yuri Milaneschi","doi":"10.1016/j.bbi.2025.01.024","DOIUrl":"https://doi.org/10.1016/j.bbi.2025.01.024","url":null,"abstract":"<p><p>Childhood maltreatment has been associated with multimorbidity of depression, coronary artery disease and type 2 diabetes. However, the biological mechanisms underlying this association remain unclear. We employed two-step and multivariable Mendelian randomisation (MR) to understand the role of three potential biological mediating mechanisms - inflammation (92 proteins), metabolic processes (54 markers), and cortisol - in the link between childhood maltreatment liability and multimorbidity. Using summary statistics from large-scale genome-wide association studies of European ancestry for childhood maltreatment (N = 185,414) and multimorbidity (N_effective = 156,717), we tested for the presence of an indirect effect via each mediator individually. We found a potential role of metabolic pathways. Up to 11 % of the effect of childhood maltreatment on multimorbidity was mediated by triglycerides (indirect effect [95 %CI]: 0.018 [0.009-0.027]), 8 % by glycated haemoglobin (indirect effect: 0.013 [0.003-0.023]), and up to 7 % by high-density lipoprotein cholesterol (indirect effect: 0.011 [0.005-0.017]). We did not find evidence for mediation via any inflammatory protein or cortisol. Our findings shed light on the biological mechanisms linking childhood maltreatment liability to multimorbidity, highlighting the role of metabolic pathways. Future studies may explore underlying pathways via non-biological mediators (e.g., lifestyle factors) or via multiple mediators simultaneously.</p>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":" ","pages":""},"PeriodicalIF":8.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143122207","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Do specific myelin autoantibodies and increased cerebral dopamine neurotrophic factor in the context of inflammation predict the diagnosis of attention deficit hyperactivity disorder in medication-free children?","authors":"Mustafa Esad Tezcan ,&nbsp;Fatih Ekici ,&nbsp;Cüneyt Ugur ,&nbsp;Ümmügülsüm Can ,&nbsp;Serdar Karatoprak ,&nbsp;Gökçeçiçek Arıcı Sağlıyan ,&nbsp;Ekrem Furkan Uçak ,&nbsp;Ahmet Güleç ,&nbsp;Vefa Erbasan ,&nbsp;Barıs Sen ,&nbsp;Fulya Simsek ,&nbsp;Abdullah Enes Atas","doi":"10.1016/j.bbi.2024.11.026","DOIUrl":"10.1016/j.bbi.2024.11.026","url":null,"abstract":"<div><h3>Background</h3><div>The aim of this study was to investigate the serum levels of anti-myelin basic protein (anti-MBP), anti-myelin oligodentrocyte glycoprotein (anti-MOG), myelin-associated glycoprotein (MAG), high-sensitivity C-reactive protein (hs-CRP), cerebral dopamine neurotrophic factor (CDNF), cerebellin-1, and reelin and their relationships with clinical severity and irritability behaviours in children with attention deficit (AD) hyperactivity disorder (ADHD) and typically developing (TD) healthy controls.</div></div><div><h3>Methods</h3><div>In this study, 141 children with ADHD between the ages of 8 and 14 years who were medication-free and 135 TD healthy controls were included. The serum levels of anti-MBP, anti-MOG, MAG, CDNF, hs-CRP, cerebellin, and reelin were measured using enzyme-linked immunosorbent assay kits. The Turgay <em>Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition</em> (<em>DSM-IV</em>)-based Screening and Evaluation Scale for Attention Deficit and Disruptive Behavior Disorders–Parent Form (TDSM-IV-O) and the affective reactivity index (ARI) scale were used to assess clinical severity and irritability behaviours in the children.</div></div><div><h3>Results</h3><div>The MAG, CDNF, hs-CRP, reelin, and cerebellin levels were significantly higher in the ADHD group than in the control group, but no significant differences in anti-MBP and anti-MOG levels were found between the groups. Compared with the controls, the patients with ADHD showed significantly higher scores on the ARI self- and parent-report scales. The reelin, hs-CRP, and MAG levels were significantly associated with the TDSM-IV-O AD scores, AD and oppositional defiant (OD) disorder scores and hyperactivity, and OD and conduct disorder scores, respectively. Hs-CRP was significantly associated with anti-MBP and cerebellin levels. In an analysis of covariance, the results were unchanged even after controlling for potential confounders such as age, body mass index, and sex.</div></div><div><h3>Conclusion</h3><div>This study demonstrates that MAG, CDNF, hs-CRP, reelin, and cerebellin levels may play a potential role in the pathogenesis of ADHD.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"124 ","pages":"Pages 125-136"},"PeriodicalIF":8.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142766332","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Unraveling morphine tolerance: CCL2 induces spinal cord apoptosis via inhibition of Nrf2 signaling pathway and PGC-1α-mediated mitochondrial biogenesis","authors":"Ju Jie,&nbsp;Ren Jihao,&nbsp;Li Zheng,&nbsp;Liu Jie,&nbsp;Peng Xiaoling,&nbsp;Zhao Wei,&nbsp;Gao Feng","doi":"10.1016/j.bbi.2024.12.011","DOIUrl":"10.1016/j.bbi.2024.12.011","url":null,"abstract":"<div><h3>Background</h3><div>Morphine effectively relieves severe pain but leads to analgesic tolerance with long-term use.<!--> <!-->The molecular mechanisms underlying morphine tolerance remain incompletely understood. Existing literature suggests that chemokine CCL2, present in the spinal cord, plays a role in central nervous system inflammation, including neuropathic pain. Nevertheless, the precise mechanism through which CCL2 mediates morphine tolerance has yet to be elucidated. Consequently, this study aims to investigate the molecular pathways by which CCL2 contributes to the development of morphine analgesic tolerance.</div></div><div><h3>Methods</h3><div>Rats were administered intrathecal morphine (10 μg/5 μl) twice a day for seven consecutive days to induce a model of morphine nociceptive tolerance. Western blotting and quantitative real-time polymerase chain reaction (qRT-PCR) were used to detect the expression levels of CCL2 and its related mechanism molecules. Immunofluorescence was used to detect the localization of CCL2 in the spinal cord. Intrathecal injections of inhibitors or agonists to artificially regulate the expression of relevant molecules. The thermal tail-flick experiment was performed to evaluate morphine tolerance in rats.</div></div><div><h3>Results</h3><div>Morphine-induced CCL2 expression was significantly increased in spinal cord, while conversely, the expressions of Nrf2 and PGC-1a were downregulated. Immunofluorescence showed that the enhanced immune response of CCL2 mainly co-localized with neurons. In vivo, we confirmed that intrathecally injection of CCL2 inhibitor Bindarit could effectively alleviate the occurrence of apoptosis and alleviate morphine tolerance. Similarly, pretreatment with Nrf2 signaling pathway agonist Oltipraz and PGC-1α agonist ZLN005 also achieved similar results, respectively. ROS Fluorescence Assay Kit indicated that increasing the expression of PGC-1α could alleviate the occurrence of apoptosis by reducing the level of ROS.</div></div><div><h3>Conclusion</h3><div>Our data emphasize that chemokine CCL2 inhibited the Nrf2 signaling pathway and PGC-1α-mediated mitochondrial biogenesis, alleviating the occurrence of apoptosis in spinal cord, thereby participating in morphine tolerance. This may provide new targets for the treatment of morphine tolerance.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"124 ","pages":"Pages 347-362"},"PeriodicalIF":8.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142817140","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Childhood allergy and anxiety/depression in early adulthood: A longitudinal study in the ALSPAC birth cohort","authors":"Sophie J. Fairweather ,&nbsp;Gemma Hammerton ,&nbsp;Lavinia Paternoster ,&nbsp;Simon Gilbody ,&nbsp;Hannah J. Jones ,&nbsp;Golam M. Khandaker","doi":"10.1016/j.bbi.2024.11.029","DOIUrl":"10.1016/j.bbi.2024.11.029","url":null,"abstract":"<div><h3>Background</h3><div>Allergic disease and common mental disorders frequently co-occur. However, little is known about the longitudinal impact of childhood allergy on the subsequent risk of developing anxiety or depression, and the possible biological mechanisms for this.</div></div><div><h3>Methods</h3><div>We performed longitudinal analyses of data from the Avon Longitudinal Study of Parents and Children (ALSPAC) birth cohort. The baseline sample comprised n = 5256 children with allergy data available at age 7yrs. We used multivariable regression to test associations between childhood allergy at age 7yrs and: <strong>a)</strong> four inflammatory markers at age 9yrs; <strong>b)</strong> depression and anxiety measures between ages 10-24yrs. Allergy measures included biological markers (total serum immunoglobulin E (tIgE), number of positive skin prick tests (SPTs)), and presence of eczema, asthma and/or food allergy (mother reported). Inflammatory markers were interleukin-6 (IL-6), C-reactive protein (CRP), IL-4 and IL-13. We used structural equation modelling to test whether inflammatory markers mediated the association between tIgE and depression/anxiety.</div></div><div><h3>Results</h3><div>tIgE and having ≥ 1 positive SPT at age 7 were associated with IL-6 levels at age 9 (adjusted β = 0.09; 95 % CI 0.06–0.13; p &lt; 0.001 and adjusted β = 0.06; 95 % CI 0.03–0.09; p &lt; 0.001 respectively), but not with CRP, IL-4 or IL13 levels. We found no strong evidence of an association between childhood allergy and subsequent depression/anxiety during adolescence and early adulthood. This finding was consistent across biological and mother-reported allergy measures.</div></div><div><h3>Conclusions</h3><div>Biological markers of childhood allergy are associated with IL-6, a key inflammatory cytokine. However, childhood allergy may not have a large long-term effect on subsequent depression/anxiety.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"124 ","pages":"Pages 226-236"},"PeriodicalIF":8.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142811907","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Central and peripheral kynurenine pathway metabolites in COVID-19: Implications for neurological and immunological responses","authors":"Xueqi Li ,&nbsp;Arvid Edén ,&nbsp;Susmita Malwade ,&nbsp;Janet L. Cunningham ,&nbsp;Jonas Bergquist ,&nbsp;Jacob Ahlberg Weidenfors ,&nbsp;Carl M. Sellgren ,&nbsp;Göran Engberg ,&nbsp;Fredrik Piehl ,&nbsp;Magnus Gisslen ,&nbsp;Eva Kumlien ,&nbsp;Johan Virhammar ,&nbsp;Funda Orhan ,&nbsp;Elham Rostami ,&nbsp;Lilly Schwieler ,&nbsp;Sophie Erhardt","doi":"10.1016/j.bbi.2024.11.031","DOIUrl":"10.1016/j.bbi.2024.11.031","url":null,"abstract":"<div><div>Long-term symptoms such as pain, fatigue, and cognitive impairments are commonly observed in individuals affected by coronavirus disease 2019 (COVID-19). Metabolites of the kynurenine pathway have been proposed to account for cognitive impairment in COVID-19 patients.</div><div>Here, cerebrospinal fluid (CSF) and plasma levels of kynurenine pathway metabolites in 53 COVID-19 patients and 12 non-inflammatory neurological disease controls in Sweden were measured with an ultra-performance liquid chromatography-tandem mass spectrometry system (UPLC-MS/MS) and correlated with immunological markers and neurological markers. Single cell transcriptomic data from a previous study of 130 COVID-19 patients was used to investigate the expression of key genes in the kynurenine pathway.</div><div>The present study reveals that the neuroactive kynurenine pathway metabolites quinolinic acid (QUIN) and kynurenic acid (KYNA) are increased in CSF in patients with acute COVID-19. In addition, CSF levels of kynurenine, ratio of kynurenine/tryptophan (rKT) and QUIN correlate with neurodegenerative markers. Furthermore, tryptophan is significantly decreased in plasma but not in the CSF. In addition, the kynurenine pathway is strongly activated in the plasma and correlates with the peripheral immunological marker neopterin. Single-cell transcriptomics revealed upregulated gene expression<del>s</del> of the rate-limiting enzyme <em>indoleamine 2,3- dioxygenase1</em> (<em>IDO1</em>) in CD14⁺ and CD16⁺ monocytes that correlated with type II-interferon response exclusively in COVID-19 patients.</div><div>In summary, our study confirms significant activation of the peripheral kynurenine pathway in patients with acute COVID-19 and, notably, this is the first study to identify elevated levels of kynurenine metabolites in the central nervous system associated with the disease. Our findings suggest that peripheral inflammation, potentially linked to overexpression of <em>IDO1</em> in monocytes, activates the kynurenine pathway. Increased plasma kynurenine, crossing the blood–brain barrier, serves as a source for elevated brain KYNA and neurotoxic QUIN. We conclude that blocking peripheral-to-central kynurenine transport could be a promising strategy to protect against neurotoxic effects of QUIN in COVID-19 patients.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"124 ","pages":"Pages 163-176"},"PeriodicalIF":8.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142766320","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}