Brain, Behavior, & Immunity - Health

BackgroundSchizophrenia often features low-grade neuroinflammation. Because latent toxoplasmosis (LT) is common in this population, we tested whether LT yields a biomarker pattern resembling that reported in schizophrenia. MethodsWe quantified 15 cytokines and 15 blood markers of brain injury in 65 LT-positive individuals and 103 matched LT-negative controls using multiplex immunoassays. Multivariate effects of infection, age, sex, and their interaction were assessed by MANCOVA and PERMANOVA. Effects on individual biomarkers were tested by partial Kendall correlation (controlling for age and sex). Differences in the internal correlation structure were evaluated with Mantel tests on dissimilarity matrices derived from partial correlations. ResultsLT was associated with higher KLK6, S100B, and TDP-43 and lower MIF; several other markers showed nonsignificant but sizable trends. Cytokines showed reduced IFN-{gamma}, IL-1{beta}, and MCP-1 and elevated IL-13 and IL-17 in the infected group. Sex-stratified analyses suggested stronger effects on brain-injury markers in women and on cytokines in men. Correlation structure also diverged: infected individuals exhibited more negative links between brain-injury markers and cytokines, whereas controls showed predominantly positive associations (Mantel r = 0.461, p = 0.043). The LT profile overlapped with schizophrenia in elevated KLK6 and S100B and, in men, reduced GDNF, but contrasted for MIF and for the overall cytokine pattern (no consistent IL-6/TNF- elevation). ConclusionsLT entails neuroinflammatory and neuroimmune alterations that only partly recapitulate schizophrenia; the biomarker pattern and interrelationships differ, arguing against LT as the main driver of schizophrenia-related neuroinflammation.

Recent studies have highlighted the crosstalk between neuroendocrine responses and the immune system but the mechanisms underlying this cooperation are still not well understood. The stress response is associated with peripheral inflammation suggesting that stress hormones including glucocorticoids and catecholamines could modulate the function of innate immune cells like neutrophils. Likewise, inflammatory mediators produced by immune cells are known to contribute to psychiatric diseases like major depressive disorder. Here we investigated the dynamic relationship between stress hormones and neutrophils and their contribution to mood disorders. We found that chronic restraint stress leads to plasma elevation of neutrophil extracellular traps (NETs) and increased NET formation in mice. Interestingly, the stress hormones, cortisol and epinephrine induce NET formation in human neutrophils ex vivo. Activation of neutrophils to form NETs leads to their increased expression of adrenergic and glucocorticoid receptors and neutrophil production of both cortisol and epinephrine indicating an autocrine/paracrine mechanism for the regulation of neutrophil inflammatory response by stress hormones. Strikingly, administration of NET components to mice induces depressive-like behavior. Moreover, activation of the glucocorticoid receptor in human volunteers leads to increase in gene expression of NET proteins. Furthermore, patients with major depressive disorder show gene upregulation of NET proteins. Our data highlights the bi-directional relationship between neuroendocrine processes and neutrophils that contribute to stress-induced increase in inflammation and the role of neutrophil inflammatory responses in propagation of behavioral changes following stress.

BackgroundAn overwhelming body of evidence suggests neuroimmune dysfunction as a key underlying mechanism of FASD-associated adverse CNS outcomes. While few studies have highlighted the lingering effects of prenatal alcohol exposure (PAE) on producing specific immune factors, others suggest a primed neuroimmune state in adulthood, in which a proinflammatory bias is unmasked following subsequent immune activation in later-life. However, the PAE-induced neuroimmune landscape in adulthood remains poorly defined. We hypothesized that PAE induces long-term changes in gene expression linked to neuroimmune function that may be brain region-specific. MethodsUsing long-read next-generation RNA sequencing of brain tissues from a previously established model of a moderate PAE in mice, we compared across six regions: medial prefrontal cortex (mPFC), anterior cingulate cortex (ACC), hypothalamus, hippocampus, midbrain, and medulla. A comprehensive bioinformatics analysis investigated PAE-induced changes, dysregulated gene pathways, and transcriptional regulators with a focus on neuroimmune function. ResultsOur data identified at least 60 differentially expressed genes per brain region, many of which were associated with neuroimmune function. Upregulation of multiple proinflammatory factors and pathways was observed, suggesting ongoing baseline neuroimmune activation, potentially involving PXR, TNF, TLR4, the complement pathway, and various cytokine and chemokine signaling. A comparative analysis identified multiple upstream transcriptional regulators across multiple brain regions, including MECP2, TCF7L2, and IL-4. Importantly, this unbiased analysis revealed heterogeneity across brain regions in the activation of canonical immune pathways and highlighted previously unprecedented roles of pathways such as PXR, matrix metalloproteases, and cytokine signaling (e.g., IL-15, IL-27, IL-17) in PAE. ConclusionsPAE creates a unique inflammatory signature in the adult brain, even in the absence of secondary injury, with novel patterns of region-specific changes in genes implicated in glial-immune function. These data identified potential immune targets to elucidate the mechanisms underlying behavioral dysfunction and provide a framework for future therapeutic interventions.

In animal models, exposure to heightened maternal inflammation in utero is associated with altered offspring hippocampal development, including reduced dendritic arborization and density. However, the effects of prenatal maternal inflammation (PNMI) on offspring hippocampal microstructure in humans remains unclear. Here, we examined the relationship between exposure to PNMI and neurite density in the hippocampus and its subfields among offspring during late middle age. Participants included 72 mother-offspring dyads from the Child Health and Development Studies (CHDS) cohort. Data for four inflammatory biomarkers (IL-6, IL-8, IL-1 receptor antagonist [IL-1RA], and soluble TNF receptor-II [sTNF-RII]) were available from first and second trimester maternal sera. Neurite density in the offspring hippocampus and its subfields was estimated using microstructural modeling of offsprings diffusion-weighted Magnetic Resonance Imaging data (mean age of offspring at imaging = 59 years; 51% male). We estimated the relationship between each biomarker and region-of-interests neurite density. Higher first trimester maternal IL-1RA and IL-6 levels were associated with lower offspring hippocampal neurite density. These relationships were specific to the CA3, CA4, dentate gyrus, and subiculum subfields. In addition, higher second trimester IL-6 was associated with lower subiculum neurite density. Our findings reveal that exposure to heightened prenatal levels of maternal inflammation is linked to altered offspring hippocampal microstructure in late middle age, which could have implications for memory decreases during this period and may be relevant for understanding risk of aging-related cognitive changes. Significance StatementThe contribution of prenatal maternal inflammation (PNMI) to offspring brain microstructure in later life is well established in animal models but poorly understood in humans. Our study discovered long-lasting impacts of elevated PNMI during early mid-gestation on the structural integrity of the hippocampus in offspring during late middle age. Our findings underscore the potential role of prenatal insults in aging-related neurological and cognitive decline, as the observed degradation in hippocampal microstructure is present over half a century following exposure.

Chronic adolescent stress has been shown to cause increased adverse effects in response to an immune stressor later in life including the development of anxiety and PTSD. Following stress, the production of inflammatory cytokines including IL-1{beta} and TNF is expected to increase in response to an immune challenge such as LPS. Male and female mice underwent fifteen consecutive days of predatory stress. Chronic adolescent stress was shown to increase both anxiety-like behavior (F(1, 28) = 19.82, p = 0.0001) and TNF levels within the periphery (F(1, 19) = 4.748, p = 0.0421).

Much research investigates how inflammation might play a role in stress-mediated diseases such as heart disease and depression. However, standard longitudinal designs often have measurement lags of months or years between assessments. This status quo is at odds with evidence that inflammatory biology and stress are both highly dynamic and would require much shorter time lags to quantify change as it naturally occurs, with minimal risk of confounding or effects diluting over time. Inspired by the use of intensive longitudinal data collection in psychological research, this study collected high frequency (every 3 days) blood microsamples over 22 days as 86 incoming college students transitioned onto campus (total observations = 622 blood samples). Samples were analyzed for CRP, TNF-, IFN-{gamma}, IL-1{beta}, IL-2, IL-4, IL-6, IL-10, IL-12p70, and IL-17A. Results using both bivariate correlation and intra-class correlation coefficients (which can be used for future power analyses for longitudinal research with these proteins) demonstrate low reliability. Notably, hierarchical linear models demonstrated that, even at this frequency of assessment, most proteins were characterized by less than 6% stable between-person differences. These results provide compelling evidence that investment in intensive longitudinal data collection of immune proteins is critical for understanding how inflammatory biology might function in psychosocial models of risk and resilience.

IntroductionCOVID-19 infection caused by SARS-CoV-2 has led to significant long-term health challenges, including Long COVID or Post-COVID condition, that can include symptoms such as cognitive decline, memory loss, and concentration issues. This study investigates the prevalence and risk factors of post-COVID cognitive symptoms among individuals tested for COVID-19. MethodsA cross-sectional study was conducted in Lisbon and Tagus Valley, targeting individuals tested for COVID-19 in August 2022. Participants were selected from a random sample of 10,000 individuals. Data were collected via computer-assisted telephone interviews at 9 and 12 months post-test, covering sociodemographic details, health behaviors, pre-existing conditions, and COVID-19 symptoms. The primary outcome was the presence of at least one cognitive symptom (memory loss and/or concentration issues) at 9 and 12 months. Additionally, each symptom was assessed individually, along with a composite outcome of both symptoms concurrently. ResultsAt 9 months, memory loss was reported by 24.87% of COVID-19 positive cases versus 10.20% of negatives, and concentration issues by 15.45% of positives versus 7.45% of negatives. At 12 months, memory loss prevalence was 16.67% for positives and 9.45% for negatives, while concentration issues were 9.82% for positives and 2.99% for negatives. Additionally, the prevalence of at least one cognitive symptom was 28.24% in positive cases at 9 months compared to 12.16% in negatives, and 17.81% versus 9.95% at 12 months. Female sex was significantly associated with a higher prevalence of cognitive symptoms at both time points. DiscussionThese findings underscore the enduring cognitive impact of COVID-19, with significant disparities in cognitive symptoms between COVID-19 positive and negative individuals observed at both 9 and 12 months post-infection. The higher prevalence of memory loss and concentration issues among COVID-19 positives suggests potential neurological sequelae linked to SARS-CoV-2 infection. Notably, the association of female sex with increased cognitive symptom prevalence warrants further investigation into gender-specific vulnerabilities or biological mechanisms underlying these disparities. Addressing these persistent cognitive symptoms is crucial for long-term patient management and underscores the need for targeted interventions and comprehensive post-COVID care strategies to mitigate long-lasting health implications.

Germinal matrix-intraventricular hemorrhage (GM-IVH) is one of the most frequent and severe neurological complications in preterm infants (PT). It triggers an inflammatory response accompanied by neuronal and glial injury and may progress to post-hemorrhagic ventricular dilatation (PHVD), thereby increasing long term disability and cognitive deficits. Nevertheless, the characteristics and evolution of the associated pathology is poorly understood. To assess neuroimmune response and neuropathology induced by GM-IVH, we quantified cytokines, glial activation and neurodegeneration makers in cerebrospinal fluid collected from 12 patients with grades III/IV GM-IVH and PHVD and 5 controls neonates from the onset of pathology up to 2 months of age. Additionally, to evaluate long-term deficits and behavioral outcomes, we used standard behavioral test including Bayley Scales of Infant and Toddler Development, Third Edition (Bayley-III) at 2 years of age. Interestingly, we found that while pathology markers such as ubiquitin carboxy-terminal hydrolase L1 (UCHL1), alpha II spectrin breakdown product 145 (SBDP145) and myelin basic protein (MBP) are elevated in PT, their level decline over time. Furthermore, cytokine profiling identified two divergent temporal trajectories (i.e., diminishing or sustained) that correspond with either neuronal or astrocytic markers. Specifically, diminishing cytokines including IL-6, IL-8, and IP-10 decreased with age and were correlated with neuronal markers such as SBDP145, UCH-L1, and MBP. In contrast, sustained cytokines such as IFN-{gamma}, IL-7, IL-13, and MCP-1 remained elevated or unchanged throughout the study period and were positively correlated with astrocyte reactivity marker GFAP. Notably, sustained cytokines were consistent with worse motor function and behavioral outcome. Together, longitudinal CSF analysis in PT with severe GM-IVH and PHVD identifies a cytokine profile that declines and correlates with neuronal and glial injury markers, and another that remains sustained and correlates with gliosis and adverse neurodevelopmental outcomes. These findings highlight potential CSF biomarkers associated with disease progression and long-term neurological impairment, providing a foundation for future evaluation of candidate therapeutic interventions.

There are multiple reports of elevated inflammation in patients with major depression. It is, however, unclear whether these reported perturbations in immune functions in depression affect the general functionality of the peripheral immune system. Here, using single-cell RNAsequencing (scRNA-seq) of peripheral blood mononuclear cells (PBMCs) extracted from blood samples collected prior to a flu vaccination administration/immunization (at baseline), we found downregulated T cell and B-cell-associated gene expression repertoire coupled with a selectively upregulated plasmablast, CD14 classical monocytes, and natural killer (NK) proliferating cell-associated gene expression in 9 depressed patients (6 females) compared to 5 healthy controls (5 females), as well as in association with depression ratings. Our cell type proportion analysis revealed shifts in immune cell populations, specifically reduced numbers of CD4+ T and CD8+ T proliferating cells, plasmablasts, and NK cells in individuals with depression compared with controls. In contrast, we found increased numbers of CD14 classical and CD16 monocytes as well as doublet cells in depressed individuals compared with controls. Although our baseline and flu vaccine challenge did not show marked differences in peripheral immune markers measured by a multiplex cytokine assay, our results suggest impaired innate and adaptive immune responses at the transcriptomic and cellular population levels in depressed patients.

Clinical studies have revealed a high comorbidity between autoimmune and psychiatric disorders, including major depressive disorder (MDD). However, the mechanisms connecting autoimmunity and depression remain unclear. Here, we aim to identify the processes linking adaptive immune abnormalities and depression. To examine this relationship, we analyzed antibody responses and autoimmunity in the chronic social defeat stress (CSDS) model in mice, and in clinical samples from patients with MDD. We show that socially stressed mice have elevated serum antibody concentrations. Activation of social stress-induced antibody responses were confirmed by detecting expansion of specific T and B cell populations particularly in the cervical lymph nodes, where brain-derived antigens are preferentially delivered. IgG antibody concentrations in the brain were significantly higher in stress-susceptible mice than in unstressed mice, and positively correlated with social avoidance. IgG antibodies accumulated around the blood vessels in brain sections from stress-susceptible mice. Moreover, sera from stress-susceptible mice exhibited high reactivity against brain tissue, and brain-reactive IgG antibody levels positively correlated with depression-like behavior. Similarly, in humans, increased peripheral levels of brain-reactive IgG antibodies were associated with increased anhedonia. Furthermore, high stress-resilience was observed in B cell-depleted mice, confirming a causal link between antibody-producing cells and depression-like behavior. This study provides novel mechanistic insights connecting stress-induced autoimmune reactions against the brain and stress susceptibility. Therapeutic strategies targeting autoimmune responses can therefore be devised to treat patients with MDD featuring immune abnormalities.

Natural anti-NMDAR1 autoantibodies are present at varying levels in the general human population, but their effects on cognitive function remain unclear. Recent human studies reported significant associations between higher blood levels of natural anti-NMDAR1 autoantibodies and potential neuroprotective outcomes in Alzheimers disease, traumatic brain injury-associated depression and PTSD symptoms, and schizophrenia. However, whether these natural autoantibodies play a causal role in emotional and cognitive function has not been investigated. Since natural autoantibodies in human blood are predominantly of the IgM isotype, we immunized Aicda mutant mice to produce only IgM isotype anti-NMDAR1 autoantibodies without IgG and IgA isotypes. Mice were tested for sensorimotor gating and conditioned fear and extinction, cross species measures of information processing and emotional memory, respectively. Mice with higher levels of IgM anti-NMDAR1 autoantibodies exhibited significantly increased sensorimotor gating and improved fear extinction recall compared with mice with baseline levels of these autoantibodies. These findings indicate that IgM anti-NMDAR1 autoantibodies are pro-cognitive, unlike previous reports of poor cognition associated with IgG anti-NMDAR1 autoantibodies. Together, these studies suggest that IgM may hold therapeutic potential for a range of neurodegenerative, neurological, and psychiatric disorders.

Acute stress activates the immune system, leading to the release of pro-inflammatory cytokines, such as interleukin-6 (IL-6). Chronic alcohol consumption alters the physiological stress systems and is associated with increased chronic inflammation. However, it remains unclear how IL-6 responds to acute stress in individuals with alcohol use disorder (AUD). Forty patients with AUD during early abstinence and 37 healthy controls (HC) completed two study visits. On one day, an acute stress induction task was performed, and on the other, a non-stressful control task, with the order of tasks being balanced. Plasma IL-6 and C-reactive protein (CRP) were measured as inflammatory markers at baseline and changes in IL-6 were assessed 90 minutes after the experimental manipulation. Patients with AUD showed significantly elevated baseline IL-6 and CRP compared to HC. In HC, inflammatory parameters were positively correlated with age and BMI, whereas in patients with AUD, they were correlated with the amount of consumed alcohol. IL-6 responses to the stress intervention did not differ between groups. Increases in IL-6 were observed on stress and control days and were larger when samples were collected via an indwelling catheter than with a butterfly needle. These findings suggest that heavy chronic alcohol use may mask the typical associations between inflammatory markers and physiological factors. However, IL-6 responses to acute stress do not differ between AUD and HC, despite increased baseline inflammation. Furthermore, the results indicate that blood collection methods can influence IL-6 measurements and highlight the importance of methodological considerations.

Post-traumatic stress disorder (PTSD) has been linked to various alterations within the immune system, yet the metabolic programming of immune cells remains unexplored. In the current cross-sectional study, we interrogated immunometabolic function by applying cell-specific metabolic flow cytometry, serum biomarker profiling, and targeted gene expression analysis in peripheral blood mononuclear cells from patients with PTSD (N=34) compared with healthy controls (N=32). PTSD was associated with higher glycolysis- and oxidative pentose phosphate pathway-related markers across adaptive and innate immune cell subsets, as well as elevated circulating interleukin-6. Expression of inflammatory- and stress-related genes was largely comparable between groups. Together, these data provide preliminary evidence for immunometabolic alterations in PTSD at both cellular and systemic levels. These results could contribute to understanding potential pathophysiological mechanisms and support further investigation of immunometabolism in PTSD.

Fibromyalgia (FM) is a disease primarily associated with chronic widespread pain, but other common symptoms are anxiety and depression. We previously proposed that autoimmunity contributes to FM based on findings of increased immunoglobulin G binding to satellite glial cells (anti-SGC IgG) in FM subjects compared to healthy controls (HC). Emerging research suggests that an altered gut microbiota composition is connected to psychological symptoms in FM rather than pain. Gut microbiota can produce or alter bile acids (BAs) and short-chain fatty acids (SCFAs), which have immune and inflammatory functions. Here, we investigate alterations in BA and SCFA concentrations in FM subjects compared to healthy controls (HC) and potential associations with FM symptoms and anti-SGC IgG levels. Bile acids and SCFAs were quantified using liquid chromatography coupled with high-resolution mass spectrometry and anti-SGC IgG levels were assessed with immunocytochemistry. The correlations between FM symptoms, anti-SGC IgG levels, and serum concentrations of 24 BAs and 11 SCFAs in 35 FM subjects and 32 matched HC were examined. Fibromyalgia subjects had significantly higher levels of microbially produced BAs than HC. Strikingly, 11 out of 24 BAs were significantly elevated in FM subjects with high, compared to those with low, anti-SGC IgG levels. Concentrations of specific BAs were associated with increased disease severity and worse mental well-being. These results revealed increased levels of secondary BAs in FM subjects compared to HC. The strong association between BAs, anti-SGC IgG levels, and mental well-being may help elucidate the importance of BAs in the psychological symptoms of FM. Significance statementFibromyalgia (FM) is a chronic pain syndrome that significantly impacts an individuals quality of life. In addition to persistent pain, people with FM often experience depression, anxiety, and irritable bowel syndrome. Previously, we identified autoantibodies that bind to satellite glial cells in the dorsal root ganglia associated with more severe FM symptoms. Our current results demonstrate a novel association between these autoantibodies in FM and bile acids (BAs). Bile acids are essential for lipid metabolism but also act as signaling molecules. We show that patients with elevated levels of autoantibodies also exhibit increased levels of BAs. Furthermore, the BAs strongly correlate with worse FM symptom severity, particularly affecting mental well-being. Our study suggests that lowering BA levels could alleviate the psychological symptoms associated with FM.

Gulf War Illness is a chronic multi-symptom disorder experienced by over 30% of veterans from the 1990-1991 Gulf War and is increasingly recognized to be driven by underlying persistent neuroinflammation resulting from chemical and physiological exposures experienced during deployment. Despite significant advances in identifying Gulf War-relevant exposures and underlying pathobiology, effective treatment strategies for Gulf War Illness are still largely lacking. Many studies that have evaluated potential therapies for Gulf War Illness have primarily focused on a single treatment. However, through a mechanistically informed computational evaluation of blood biomarkers and gene expression in veterans with Gulf War Illness, we identified that a combination of anti-inflammatory and anti-glucocorticoid treatment may prove effective in treating Gulf War Illness. Here, we have evaluated combined treatment with the anti-TNF drug, etanercept, and anti-glucocorticoid, mifepristone, in an established long-term mouse model of Gulf War Illness of combined physiological stress and nerve agent exposure. Supporting results from the computational modeling of this treatment, we found that this drug combination significantly alleviates the underlying neuroinflammation associated with Gulf War Illness. The fusion of computational and in vivo preclinical treatment evaluation may provide a highly useful and translationally relevant means by which to identify successful treatment paradigms for Gulf War Illness.

Clonal hematopoiesis of indeterminate potential (CHIP) represents the presence of clonal somatic mutations in blood cells in otherwise healthy individuals. While CHIP is known to increase risk for hematologic malignancies and cardiovascular disease, its association with airborne carcinogens remains largely unknown. We investigated CHIP mutations in 9/11 World Trade Center (WTC) disaster responders (n=350), who experienced substantial exposure to a complex mix of airborne carcinogens. Ultra-deep whole-exome sequencing at 250X was performed on banked blood samples. We characterized CHIP mutations and their associations with clinical factors (age, ancestry, gender, body mass index, cardiovascular disease, stroke), laboratory parameters (peripheral blood counts), mental and cognitive assessments, exposure data, and HLA zygosity. Statistical methods included Fishers exact test, Wilcoxon rank sum test, and multivariate logistic regression. Findings were compared to unexposed controls (n=293) analyzed using identical methods. Among WTC participants, CHIP prevalence was 34.2%, with myeloid-CHIP (M-CHIP) at 16.2% and lymphoid-CHIP (L-CHIP) at 21.4%. M-CHIP prevalence correlated positively with age (p=0.02), smoking history (p=0.01), and lower platelet counts (p=0.03). The most frequent M-CHIP mutations were in DNMT3A, TET2, PPM1D, while L-CHIP mutations were in EEF1A1, DDX11 and KMT2D. Notably, DDX11 mutations were associated with lower Montreal Cognitive Assessment scores (p=6.57e-03). Comparison with unexposed controls demonstrated higher CHIP prevalence in WTC responders, particularly in those 55 or younger. Study highlights the potential utility of deep sequencing for CHIP detection with clinical, laboratory and exposure data to develop personalized risk-adapted screening programs for cancer and other CHIP-related conditions in individuals exposed to airborne carcinogens.

The prevalence of inflammatory bowel disease (IBD) has increased dramatically in recent years, particularly in pediatric populations. Successful remission with current therapies is limited and often transient, leading patients to seek alternative therapies for symptom relief, including the use of medical marijuana (Cannabis sativa). However, chronic cannabis use among IBD patients is associated with increased risk for surgical interventions. Therefore, determining the direct impact of cannabis use on immune modulation in IBD patients is of critical importance. Peripheral blood mononuclear cells of cannabis using and non-using pediatric IBD patients were phenotyped by flow cytometry and functionally assessed for their cytokine production profile. A phospho-kinase array was also performed to better understand changes in immune responses. Results were then compared with serum phytocannabinoid profiles of each patient to identify cannabinoid-correlated changes in immune responses.Results demonstrated elevated levels of a myriad of pro-inflammatory cytokines in users versus non-users. Differences in signaling cascades of activated T cells between users and non-users were also observed. A number of anti-inflammatory cytokines were inversely correlated with serum phytocannabinoids. These results suggest that cannabis exposure, which can desensitize cannabinoid receptors, may prime pro-inflammatory pathways in pediatric IBD patients. Article SummaryThis observational study examines the impact of chronic cannabis use on peripheral immune cell function in adolescent IBD patients from Childrens Hospital Colorado. Cannabis users displayed altered T cell phenotype, increased pro-inflammatory cytokine release and dephosphorylation of protective protein kinases.

Autism Spectrum Disorder (ASD) includes a range of neurodevelopmental disabilities characterized by social interaction deficits, communication impairments, and repetitive behaviors. Previous studies have shown that pro-inflammatory conditions play a key role in ASD. Here we reported that increased levels of molecules related to inflammation are present in the cerebellum and peripheral blood (PB) of mice lacking Shank3b, established model of syndromic ASD. In parallel, immune dysfunction was documented in the bone marrow (BM) and spleen of mutant mice. N-acetylcysteine (NAC) treatment rescued inflammation in the cerebellum and PB, as well as impaired production of pro-inflammatory molecules in the BM and spleen. In addition, social impairment was counteracted in NAC-treated Shank3b-/- animals. Taken together, our study further confirms the key role of cerebellar inflammation in the establishment of ASD-related behaviors. Furthermore, our findings underscore the importance of considering ASD as a systemic disorder. Our findings therefore suggest that the interplay between oxidative stress and inflammation may support ASD-related behaviors in mice.

Exposure to early life adversity (ELA) in the form of physical and/or psychological abuse or neglect increases the risk of developing psychiatric and inflammatory disorders later in life. It has been hypothesized that exposure to ELA results in persistent, low grade inflammation that leads to increased disease susceptibility by amplifying the crosstalk between stress-processing brain networks and the immune system, but the mechanisms remain largely unexplored. The meninges, a layer of three overlapping membranes that surround the central nervous system (CNS)- duramater, arachnoid, and piamater - possess unique features that allow them to play a key role in coordinating immune trafficking between the brain and the peripheral immune system. These include a network of lymphatic vessels that carry cerebrospinal fluid from the brain to the deep cervical lymph nodes, fenestrated blood vessels that allow the passage of molecules from blood to the CNS, and a rich population of resident mast cells, master regulators of the immune system. Using a mouse model of ELA consisting of neonatal maternal separation plus early weaning (NMSEW), we sought to explore the effects of ELA on duramater mast cell histology and expression of inflammatory markers in male and female C57Bl/6 mice. We found that mast cell number, activation level, and relative expression of pseudopodia differ across duramater regions, and that NMSEW exerts region-specific effects on mast cells in males and females. Using gene expression analyses, we next found that NMSEW increases the expression of inflammatory markers in the duramater of females but not males, and that this is prevented by pharmacological inhibition of mast cells with ketotifen. Together, our results show that ELA drives sex-specific, long-lasting effects on the duramater mast cell population and immune-related gene expression, suggesting that the long-lasting effects of ELA on disease susceptibility could be partly mediated by meningeal function.

ObjectiveThis study aims to investigate how neuroinflammation alters gliogenic regulatory pathways and glial cell fate decisions, with a focus on identifying clinically relevant mechanisms that may increase susceptibility to glial-derived brain tumors. By linking inflammatory signaling to early disruptions in gliogenesis, this study seeks to inform future strategies for risk assessment, early detection, and potential therapeutic intervention in inflammation-associated neuro-oncology. BackgroundNeuroinflammation alters gliogenic signaling by disrupting key regulatory pathways such as FGFR3, JAK-STAT, STAT3, and others. This dysregulation affects glial cell differentiation and lineage decisions, contributing to impaired neurodevelopment and increased susceptibility to glial-derived brain tumors, particularly gliomas. Understanding these inflammatory mechanisms is essential for identifying early biomarkers, evaluating long-term tumor risk, and developing strategies to prevent or mitigate neuro-oncological outcomes in individuals with acute or chronic CNS inflammation. MethodsDatabases, including PubMed, MEDLINE, Google Scholar, and both open-access and subscription-based journals, were searched without date restrictions to investigate the brain inflammation induced disruption of gliogenic regulators (FGFR3, JAK-STAT, STAT3, S100, Hey1, HES1, DTX, IL-6, NF-{kappa}B, Neuregulin-1, MAPK/MEK, E2F/TCFL2, NFIX/Ephrins/Netrins) resulting in glial cell fate dysregulations and Its contribution to brain tumor risk. Studies meeting the criteria outlined in the methods section were systematically reviewed to address the research question. This study adheres to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. ResultsNeuroinflammation significantly alters gliogenic regulators, including FGFR3, JAK-STAT, STAT3, S100, IL-6, and NF-{kappa}B, disrupting normal glial maturation, migration, and lineage commitment. This leads to aberrant cell fate decisions, sustained proliferation, and genomic instability, conditions favorable for glioma initiation. Pro-inflammatory pathways, notably IL-6 and NF-{kappa}B, drive oxidative stress and cellular dysfunction, reinforcing the tumor-permissive environment. These insights point to the clinical relevance of inflammation-driven glial dysregulation in brain tumor pathogenesis. ConclusionDisruption of gliogenic regulators by neuroinflammation alters glial fate specification, promotes proliferative stress, and contributes to oncogenic transformation within the CNS. These findings emphasize the need to clinically monitor individuals with significant or recurrent brain inflammation for long-term neuro-oncological risks. Early recognition of these disturbances may guide risk stratification, surveillance, and development of anti-inflammatory or gliogenesis-targeted interventions to prevent glial-origin brain tumors.