Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the selective loss of motor neurons in the brain and spinal cord with evidence of local neuroinflammation. Regulatory T cells (Treg) exert neuroprotective effects and correlate with disease progression, but central mechanisms governing Treg development during ALS remain unclear. We investigated the thymic architecture and T cell differentiation in SOD1-G93A (mSOD1) ALS mice at multiple disease stages. Thymocyte and thymic epithelial cells (TEC) subpopulations, as well as stages of Treg differentiation and suppressive capacity, were analyzed by flow cytometry, in situ immunofluorescence, and functional assays. At late disease stage (120 days-old), mSOD1 mice displayed thymic atrophy, reduced thymocyte numbers, and decreased double-positive (DP), CD4 single-positive (SP), and Treg populations. Foxp3 expression per cell was preserved, but Treg progenitors and mature Treg numbers declined, paralleled by reduced suppressive function in vitro. TEC analysis revealed reduced total and mature medullary TEC (CD80highMHCIIhigh), despite preserved Aire expression. Foxp3+ cells were abnormally localized at cortical sites, away from mTEC, associated with migratory abnormalities and increased apoptosis. TREC evaluation revealed reduced intrathymic sjTREC, consistent with impaired proliferation and differentiation between DN and DP stages, although peripheral sj/βTREC ratios remained stable. Reduced Treg numbers were also observed in lymph nodes draining affected hindlimbs. Our findings identify the thymus as a target organ in ALS, where thymic involution, TEC loss, and Treg dysfunction may compromise immune tolerance. These alterations likely reinforce the role of the thymus in peripheral immune dysregulation and neuroinflammation observed in ALS.
Fever induced by systemic inflammation is mediated by prostaglandin E2 (PGE2), but the identity of the prostaglandin E (EP) receptor subtype responsible for the febrile response remains debated. Although EP3 receptors have been strongly implicated in fever generation, studies using pharmacological approaches and receptor-deficient mice have also suggested involvement of EP1 and EP4 receptors. Because previous studies have differed substantially with regard to experimental conditions, including ambient temperature, route of immune challenge, and injection-associated stress responses, we systematically compared the febrile response to lipopolysaccharide (LPS) in mice lacking EP1, EP2, EP3, or EP4 receptors under standardized physiological conditions. Body temperature was recorded by telemetry in mice housed at thermoneutrality and injected intravenously with LPS (30 μg/kg) through indwelling jugular catheters, permitting remote injections with minimal disturbance to the animals. Mice with global deletion of EP1, EP2, or EP3, as well as mice with nervous system-directed deletion of EP4, all maintained on a C57BL/6 background, were examined together with wild-type littermates. Wild-type mice displayed a characteristic multiphasic fever following LPS administration. Mice lacking EP1 or EP2, or with nervous system-directed deletion of EP4, exhibited febrile responses indistinguishable from those of their wild-type controls. In contrast, mice lacking EP3 failed completely to develop fever and instead displayed a pronounced hypothermic response immediately following LPS injection. These findings identify EP3 as the only prostaglandin E receptor with a non-redundant role in LPS-induced fever and support the concept that EP3-dependent signaling constitutes the final common pathway for inflammatory fever.
Clozapine may have both pro- and anti-inflammatory effects, which could contribute to its unique efficacy in treatment resistant schizophrenia (TRS). Increases in pro-inflammatory cytokines occur during the first weeks after clozapine initiation, but the changes occurring over longer periods of clozapine administration are largely unknown.This study examined C-reactive protein (CRP), tumour necrosis factor alpha (TNF-α), interferon-gamma (IFN-γ), and interleukins (IL) IL-2, IL-4, IL-6, IL-8, IL-12p70 and IL-13 prior to clozapine titration (baseline) and after 3 and 6 months of clozapine treatment in TRS. Symptom severity was assessed at the same time-points.Data were available in 53 individuals at baseline, 34 individuals at 3 months and 28 individuals at 6 months. Following correction for false discovery rate (FDR): significant effects of time were observed for IL-10 (F(2, 67.7) = 9.15, P < 0.001, q = 0.010) and TNF-α (F(2, 58.9) = 5.67, P = 0.006; q = 0.030), related to significant increases in both IL-10 and TNF-α at 3 and 6 months after commencing clozapine compared to at baseline (α = 0.05). There were no significant associations between temporal changes in peripheral inflammatory marker concentrations and changes in total symptom severity, or relationships between inflammatory marker concentrations at baseline and total symptom severity at 3 months.Concurrent increases in TNF-α and IL-10 may reflect increased activation of both pro-inflammatory and compensatory anti-inflammatory mechanisms over 6 months of clozapine treatment. Composite indices of inflammatory profile may be advantageous in future studies examining relationships with symptom improvement during clozapine treatment.
Purpose Child maltreatment has lasting adverse effects on both physical and mental health and is associated with reduced quality of life. In Colombia, this problem remains highly prevalent. Childhood maltreatment has been identified as a risk factor for multiple chronic conditions, including cardiovascular disease, autoimmune disorders, cancer, and stress-related psychiatric disorders such as major depressive disorder. Early-life exposure to chronic stress is associated with immunological alterations, including increased production of pro-inflammatory cytokines, and the development of a chronic low-grade inflammatory state. Against this background, we investigated the association between a history of childhood maltreatment, systemic low-grade inflammation, and the distribution of leukocyte populations exhibiting features of senescence in patients with breast cancer. Methods We included 20 women diagnosed with breast cancer, who completed the Childhood Trauma Questionnaire-Short Form (CTQ-SF). Peripheral blood was collected to isolate plasma and PBMCs. Plasma cytokines were measured using a Cytometric Bead Array. Markers of immune senescence and exhaustion in monocytes, NK cells, and T cells were analyzed by flow cytometry. Results The CTQ-SF assessment revealed a high prevalence of severe-to-extreme childhood maltreatment, with 40% of participants reporting severe physical abuse, 35% severe emotional abuse, and 40% severe physical neglect. Immunologically, CM+ patients exhibited significantly higher TNF-α levels and significantly reduced HLA-DR expression on intermediate monocytes compared with CM− patients. Conclusions This exploratory pilot study suggests that childhood maltreatment may be associated with an altered inflammatory profile in breast cancer patients. Larger prospective studies are warranted to confirm these findings and determine their clinical significance.
Perinatal psychiatry has gained increasing attention as a public health priority, given the high prevalence and burden of mental health conditions during pregnancy and the postpartum period. While research has predominantly focused on depressive disorders, growing evidence suggests that a broader range of psychiatric conditions may significantly influence obstetric and neonatal outcomes.Unlike previous works primarily centered on perinatal depression, this narrative review provides an integrated and transdiagnostic overview of perinatal psychiatric disorders – including mood, anxiety, psychotic, obsessive-compulsive, trauma-related disorders, and borderline personality disorder – and their association with adverse maternal, obstetric, and neonatal outcomes.Across diagnostic categories, psychiatric disorders during pregnancy are consistently associated with increased risks of hypertensive disorders, preterm birth, altered fetal growth, operative delivery, and neonatal complications. However, findings remain heterogeneous, largely derived from observational studies, and often limited by variability in diagnostic assessment and outcome definitions. Shared pathophysiological pathways– including hypothalamic-pituitary-adrenal axis dysregulation, inflammatory activation, hormonal fluctuations, and psychosocial stressors – may partially explain the convergence of different psychiatric disorders on similar perinatal outcomes.Taken together, these findings highlight the need to move beyond a depression-centered framework in perinatal psychiatry. Early identification, individualized risk–benefit assessment, and integrated multidisciplinary care may contribute to improved maternal and offspring outcomes. Future research should prioritize longitudinal designs and standardized outcome measures to disentangle disorder-specific and shared mechanisms.
Background Studies indicate an association between pain perception and inflammatory response. However, the expression of inflammatory cytokines in the regulation of the interaction between pain and other coexisting symptoms related to pain, such as fatigue, remains largely unknown. Aim This study utilizes a comprehensive screening method for inflammatory biomarkers to objectively study their relation to fatigue and other patient reported outcomes, such as depression and sleep disturbances, in a cohort entailing patients with chronic pain and controls reporting no pain. Material and methods 36 patients with chronic pain and 36 healthy pain free controls were included. To investigate possible differences between patients and controls, the QUICKPLEX SQ 120 with a panel of 71 pro- and anti-inflammatory proteins was used. Patient reported data covering aspects of fatigue, fatigability, mood and sleep was also administered. Results No apparent difference in abundance of inflammatory substances was found between patients and controls. Likewise, no association was between levels of inflammatory biomarkers and performance on objectively measured cognitive fatigability. However, an explorative multivariate PCA analysis with immunological response as the determinant revealed five specific clusters, two clusters of controls and three patient clusters. One patient cluster had an overall lower concentration level of inflammatory substances compared to the other clusters. This cluster reported higher levels of general fatigue (trait fatigue) and state fatigue as well as higher proportions of pain localizations, perceived helplessness, insomnia, depressive symptoms, and anxiety. Conclusion This study underscores the complexity of pain perception and its interplay with inflammatory responses, as well as the individual experience of fatigue and other co-occurring symptoms. We argue that patients with chronic pain do not constitute a homogeneous group, and that simple patient–control comparisons may be insufficient to elucidate the underlying inflammatory processes involved. Our findings suggest that chronic pain patients who report higher levels of fatigue, sleep disturbances, and depressive symptoms might exhibit inflammatory response proteins associated with tissue-repair mechanisms. We speculate that this pattern could indicate a response driven more by central pain mechanisms.
Puberty is a critical developmental period marked by heightened vulnerability to stress. Exposure to pubertal stress can have lasting effects on behaviour, immune function, and the gut–brain axis. The NLRP3 inflammasome and gut microbiome are key regulators of neuroinflammation, yet their roles across distinct pubertal stress paradigms remain unclear. This study compared behavioural, immune, and microbial outcomes in 120 CD1 mice following chronic unpredictable stress (CUS; 14 or 28 days) or 7-day sleep disruption (SD) in pubertal males and females. Behavioural testing revealed stressor- and sex-specific effects: females spent more time in the open arms of the elevated plus maze, SD reduced open-arm exploration, 14-day CUS reduced centre activity in the open field, and SD increased immobility in the forced swim test. Plasma cytokines showed divergent patterns, with IL-22 elevated across stress conditions and IL-17A highest following 28-day CUS and in females overall. In the prefrontal cortex, SD males exhibited increased NLRP3 and CASP1 mRNA expression, whereas 28-day CUS females showed reduced NFκB1, and NFκB2 expression was elevated in stress-exposed males. In the hippocampus, 28-day CUS females demonstrated coordinated reductions in NFκB1, NLRP3, and CASP1 expression. Microbiome analyses indicated that SD and 14-day CUS produced the most substantial alterations, characterized by reductions in short-chain fatty acid–producing taxa (Ligilactobacillus, Acetatifactor, Christensenella) and enrichment of stress-associated genera (Flintibacter, Oscillospiraceae). Together, these findings indicate that stressor type and sex differentially shape behavioural, neuroimmune, and microbial profiles during puberty, with sleep disruption exerting particularly strong effects on behavioural and gut–immune regulation.
Young women are disproportionately affected by trauma, developing post-traumatic stress disorder (PTSD) at roughly twice the rate of men. Elevated levels of C-reactive protein, Interleukin-6 (IL-6), and Tumor Necrosis Factor-alpha (TNF-α) are frequently found in individuals with trauma history. Given that sex hormones have been shown to have a broad range of both pro- and anti-inflammatory effects, the purpose of our study was to investigate associations of subclinical inflammation and sex hormones in trauma-exposed premenopausal women. We hypothesized that circulatory levels of sex hormones, particularly estradiol, would be negatively associated with concentrations of inflammatory cytokines in our cohort of premenopausal women, underscoring the potent cardioprotective nature of estradiol via inhibition of inflammation. We recruited 113 trauma-exposed (56.5% with PTSD) premenopausal women [Age (28 ± 7 years), BMI (27 ± 6 kg/m2)]. We collected blood samples to quantify serum levels of sex hormones, inflammatory cytokines, using the quantitative sandwich enzyme immunoassay technique (ELISA) and a Luminex assay, respectively. A composite inflammatory score was derived from eleven inflammatory biomarkers (IL-1α, IL-1β, IL-1ra, IL-6, IL-8, IL-17E, MCP-1, IFN-γ, TNF- α, IL-6R, TNF-R2) using principal component analysis. Linear regression models on the entire sample revealed that higher circulatory levels of estradiol and progesterone were associated with higher subclinical inflammation. These findings are contrary to our hypothesis and suggest that trauma and psychopathology in premenopausal women might affect how the immune system responds to circulating levels of sex hormones.
Sepsis is a life-threatening syndrome caused by a dysregulated host response to infection and involves failure of immune, metabolic, respiratory, cardiovascular, thermal, endocrine, and autonomic regulation. In this review, we propose that the carotid body may act as a peripheral interoceptive checkpoint in the transition from adaptive host defense to immunometabolic decompensation. The discussion is organized around four interconnected dimensions. First, we examine inflammatory and metabolic signals that may be detected by the carotid body during sepsis, including cytokines, lactate, glucose, hypoxemia, acid-base disturbances, and other energetic stress signals. Second, we discuss the respiratory consequences of carotid body activation or dysfunction, with emphasis on ventilation, hypoxic chemosensitivity, and ventilatory responses during systemic inflammation. Third, we address cardiovascular and autonomic consequences, including sympathetic activation, vascular tone, arterial pressure, organ perfusion, and recruitment of the splanchnic anti-inflammatory pathway. Fourth, we consider inflammation-induced carotid body remodeling and the resulting loss of sensory fidelity. Experimental evidence indicates that circulating TNF-α activates carotid body afferents and recruits sympathetic anti-inflammatory pathways, whereas severe or persistent inflammation can alter carotid body structure, chemosensory gain, and afferent output. Although direct clinical evidence remains limited, this framework identifies the carotid body as a testable neuroimmune interface. Early stimulus-coupled activation may support respiratory, cardiovascular, autonomic, metabolic, and immune adaptation, whereas persistent inflammation may produce elevated tonic afferent activity, reduced stimulus-evoked responsiveness, and impaired sensory discrimination.
Post-acute sequelae of SARS-CoV-2 infection (PASC) is a major public health consequence of COVID-19. Persistent PASC symptoms affect multiple physiological systems, including the nervous system. The etiology of PASC is unknown; however, brain-mediated symptoms may arise from dysregulated neuroinflammatory processes. We have reported that intra-cisterna magna (ICM) administration of the SARS-CoV-2 spike (S)1 antigen in rats induces behavioral alterations, prolonged neuroinflammation, and reduced brain corticosterone. Inappropriate neuroinflammation triggered by immune challenge suppresses motivated behaviors, including voluntary wheel running (VWR), and disrupts diurnal rhythms. Accordingly, this study tested the hypothesis that S1 reduces VWR distance and changes diurnal activity patterns. Given evidence that regular physical activity reduces inflammation, we also determined whether VWR attenuates the neuroinflammatory effects of S1. Male Sprague-Dawley rats were housed with either locked (sedentary) or unlocked (VWR) running wheels. After 12 days, rats received ICM S1 or vehicle and remained undisturbed while VWR was recorded for 17 days. S1-treated rats ran less and showed disrupted diurnal VWR patterns compared with vehicle controls. Eighteen days post-ICM injections, sedentary S1-treated rats, but not VWR rats, exhibited persistent elevation of hypothalamic gene expression of IL1β, MhcII, Tlr2, and Tlr4. In contrast, VWR S1-treated rats, but not sedentary S1-treated rats, had elevated hypothalamic corticosterone 18 days post-injection. Taken together, S1 in the brain produces behavioral symptoms of PASC and prolonged neuroinflammation. Despite reductions in total running distance after S1, VWR was sufficient to block the persistent upregulation of neuroinflammatory genes. Brain corticosterone may contribute to the impacts of S1 and VWR.
Arginine vasopressin (AVP) is a pleiotropic neuroendocrine hormone with diverse physiological functions that have important implications for immune regulation. Although AVP has been reported to exert both immunostimulating and immunosuppressive effects, its actions on immune function are highly context-dependent and arise largely from its established roles in stress physiology, vascular regulation, osmoregulation, and thermoregulation. AVP influences immune activity indirectly through modulation of the hypothalamic-pituitary-adrenal (HPA) axis, blood flow, vascular and lymphatic permeability, fluid balance, and fever responses - all of which shape immune cell trafficking, activation, and inflammatory signaling. In addition, the expression of AVP and its receptors on immunocompetent cells - including T cells, dendritic cells, macrophages, neutrophils, and microglia - supports a role for direct, cell-specific AVP signaling, although the functional consequences of these interactions remain incompletely defined. AVP signaling affects both innate and adaptive immune responses by altering immune cell proliferation, migration, differentiation, and cytokine production in a manner that depends on receptor subtype, cellular content, and physiological state. These immunomodulatory properties are particularly relevant in conditions characterized by neuroendocrine dysregulation, including chronic stress, acquired brain injury, and autoimmune disease, where AVP contributes to cerebral edema, blood-brain barrier disruption, dysregulated HPA axis feedback, and secondary immune activation. This review synthesizes current evidence describing how AVP shapes immune function through integrated neuroendocrine, vascular, and cellular mechanisms, highlights key gaps in mechanistic understanding, and discusses the therapeutic potential - and limitations - of targeting AVP signaling in inflammatory and neuroimmune disease.
Purpose:We aimed to identify protein patterns in peripheral blood mononuclear cells (PBMCs) associated with autism spectrum disorder (ASD) diagnosis and clinical heterogeneity and to explore their relevance to biological processes implicated in ASD. Methods:PBMC proteomic profiles were examined in a Thai cross-sectional cohort of 191 children with ASD and 106 typically developing (TD) controls. Mass spectrometry (LC-MS/MS) was performed to identify differentially expressed proteins (DEPs). Exploratory classification performance was assessed by ROC analysis across clinical subgroups. Associations between DEPs and behavioral and cognitive symptoms were evaluated using mixOmics multivariate integration. DEPs were further assessed for overlap with ASD-associated genes and previously reported ASD blood and brain proteomic datasets, and functionally annotated using protein-protein interaction and enrichment analyses. Results:Thirty-nine annotated proteins were differentially expressed between children with ASD and TD controls, while a subset was associated with heterogeneity within ASD. Several DEPs were encoded by known ASD-associated genes and overlapped with proteins previously reported in ASD blood and brain studies. Functional analyses identified enrichment of cytoskeletal and chromatin-associated pathways, including an actin-centered protein interaction network. Multivariate integration analyses revealed associations between these proteins and behavioral, social, emotional, sensory, and cognitive phenotypes, while subgroup analyses indicated subtle molecular heterogeneity within ASD. Conclusion:PBMC proteomic profiles identified molecular signatures associated with ASD diagnosis and clinical heterogeneity in this discovery cohort. Exploratory network analyses highlighted cytoskeletal- and chromatin-associated proteins, supporting further evaluation of peripheral proteomics as a tool for investigating ASD biology and biologically informed stratification.
Microglial P2Y12 receptor is a key regulator of neuroimmune homeostasis, but its role in integrating sleep, glymphatic influx, and microglial dynamics across sexes remains to be further investigated. In this study, we employed the P2Y12 antagonist MRS2395 for pharmacological inhibition in adult male and female C57BL/6 J mice. We assessed glymphatic influx, microglial density and morphology across multiple brain regions, sleep architecture via EEG, and behavioral outcomes. P2Y12 blockade disrupted sleep-stage glymphatic influx, microglial parameters, and sleep architecture, with the greater effects observed in females, particularly a greater suppression of glymphatic influx during sleep and more severe sleep fragmentation, characterized by increased state transitions and altered spectral power. In both sexes, P2Y12 inhibition reduced microglial branching complexity. Locomotor activity, cognitive performance, and anxiety-like behaviors did not differ significantly between the two sexes. These results preliminarily suggest that the microglial P2Y12 receptor pathway exerts sex-differential effects on glymphatic influx and sleep architecture during the rest phase, behavioral effects occurred but did not significantly differ between sexes in the short term.
Background:Increasing evidence indicates that gut dysbiosis and gut-brain axis dysfunction contribute to postoperative cognitive dysfunction (POCD) following general anaesthesia. Although ulinastatin, a urinary trypsin inhibitor, has been reported to exert anti-inflammatory and neuroprotective effects, its role in the gut microbiome and microbiome-related metabolites in POCD remains unclear. Methods:A total of 30 18-month-old male Sprague-Dawley rats were randomly allocated to the Ulinastatin group or the Control group. Ulinastatin (50,000 U/mL) or normal saline (1 mL) was intraperitoneally administered before general anaesthesia, which was maintained with isoflurane 1.5 vol% for 2 h. Cognitive function was assessed using the Y-maze test. Lactobacillus viable counts, short-chain fatty acid (SCFA) levels and nuclear factor erythroid 2-related factor 2 (Nrf2) expression were evaluated by microbiological analysis, enzyme-linked immunosorbent assay (ELISA) and immunohistochemical staining, respectively. Results:Y-maze performance did not differ between groups before general anaesthesia. However, a significant decline after anaesthesia was observed only in the Control group (p < 0.001). Lactobacillus viable counts showed a similar pattern, with a significant reduction in the Control group but preservation in the Ulinastatin group (p < 0.001). The Ulinastatin group had significantly higher SCFA levels in the gut, blood, and brain than did the Control group (all p < 0.001). Nrf2 expression in both the gut and brain was also significantly higher in the Ulinastatin group (both p = 0.0001). Conclusion:Preoperative administration of ulinastatin prevented cognitive decline after general anaesthesia. The protective effect of ulinastatin was associated with control of gut dysbiosis.
Background: Mental disorders have been associated with systemic chronic inflammation, and conditions such as depression and schizophrenia are increasingly linked to inflammatory processes. Soluble urokinase plasminogen activator receptor (suPAR) is a biomarker of chronic inflammation and has proven useful as a prognostic marker in various somatic diseases. This review examines the evidence for suPAR use in psychiatric populations and evaluates its potential role in clinical psychiatry. Method: A systematic search of Embase and PubMed was conducted using three concepts: biomarker, mental health–related terms, and psychotropics. Clinical and epidemiological studies investigating mental disorders with quantitatively measured suPAR were included. Screening was performed independently by two investigators. Results: Of 2781 identified studies, 32 met inclusion criteria. Elevated plasma suPAR levels were consistently observed in patients with psychosis and major depression, whereas findings for other psychiatric disorders were less conclusive. Evidence for predictive or prognostic applications remains sparse and inconclusive. Higher suPAR levels were associated with increased risk of subsequent antidepressant use and hospital admission for depression. Additionally, higher baseline suPAR levels were linked to a greater likelihood of antidepressant response and faster treatment effects. Discussion: It remains unclear whether elevated suPAR reflects immune activation intrinsic to psychiatric disorders or confounding factors such as lifestyle or psychotropic medication. Longitudinal data on suPAR and symptom development are lacking. Although suPAR is a potential biomarker within psychiatry, methodological inconsistencies persist, and its routine clinical use in psychiatry is premature.
Background The human immune system is highly susceptible to seasonal changes, however it is unknown whether this holds true during pregnancy. This study assessed whether C-Reactive Protein (CRP) levels are moderated by season of sample collection and/or a person's tendency to have low mood during the fall-winter months (Seasonal Affective Disorder or SAD) in a Canadian pregnancy and birth cohort. As overweight/obesity has been associated with both elevated CRP and fall-winter SAD, the moderating effect of overweight/obesity on these seasonal effects was also examined. Methods Maternal plasma CRP was measured at weeks 11-19 and 24-30 of pregnancy. Separate Generalized Linear Models were used to predict these two CRP levels using a 2 season of collection (fall-winter vs. spring-summer) by 2 seasonal group (yes/no for lifetime SAD) by 2 pre-pregnancy BMI group (healthy weight vs. overweight/obese) design. Results A significant 3-way interaction predicted CRP levels at pregnancy weeks 24-30 (F = 8.49, df = 1, 353, p = .004), with the highest levels in mothers with the combination of fall/winter plasma sampling, meeting screening criteria for lifetime SAD, and being overweight/obese. The respective 2-way season of sampling by BMI group interaction was also highly significant (F = 8.18, df = 1, 353; p = .004). Unexpectedly, these various results were independent of state depression and maternal anti-depressant use. No seasonal differences were found for early pregnancy CRP levels. Conclusions Overweight/obese mothers had greater fall/winter increases in later pregnancy CRP levels than did healthy weight mothers, further boosted by a maternal history of fall-winter SAD. Both environmental and individual-level seasonality may be critical considerations for future research on gestational inflammation.
Cancer progression is profoundly influenced by the complex interplay between the tumor microenvironment (TME), the immune system, and the patient's psychological state. This review delineates a critical pathway linking chronic stress to worsened cancer outcomes through inflammatory factors, anti-tumor immune suppression, and the induction of behavioral comorbidities. We postulate that sustained stress hormone signaling via the sympathetic nervous system and hypothalamic-pituitary-adrenal axis activation orchestrates a systemic immunosuppressive cascade. A central mechanism is the stress-induced expansion and functional polarization of myeloid cells, including myeloid-derived suppressor cells, tumor-associated macrophages, and neutrophils within the TME. These cells foster a pro-tumoral milieu by impairing T-cell function, promoting angiogenesis, and facilitating metastasis, among other processes. Beyond the local TME, stress-mediated inflammation propagates to the central nervous system, compromising the blood-brain barrier and activating microglia. This neuroinflammatory response drives structural and functional remodeling in key brain regions such as the prefrontal cortex, hippocampus, and amygdala, providing a biological basis for depression and anxiety often seen in patients with cancer. This creates a vicious cycle wherein psychological distress exacerbates tumor-promoting inflammation and immune evasion, which in turn worsens behavioral symptoms. Critically, clinical evidence now links psychological stress to chemoresistance and poor responses to immunotherapy. We argue that integrating stress-reducing interventions and strategies targeting neuroinflammation into cancer care is not merely supportive but essential to disrupt this detrimental cycle. A multidisciplinary approach that concurrently targets the tumor, the immune system, and the patient's mental well-being holds the promise of improving both survival and quality of life.
Obesity has been associated with cognitive impairment, yet the contribution of obesity-related genetic liability to cognition across the lifespan remains unclear. Here, we investigated associations between body mass index (BMI), obesity polygenic risk score (PRS), and cognitive performance in 796 individuals from the FOR2107 Marburg-Münster Affective Disorders Cohort Study (MACS). Cognitive function was assessed using a neuropsychological test battery covering working memory, episodic memory, attention, processing speed, executive function, and crystallized intelligence. Multivariate analyses of covariance revealed significant age-dependent associations of both BMI (ηp2(BMI*age) = 0.038, F (10,771) = 3.06, p = 0.001) and obesity PRS (ηp2(PRS*age) = 0.028, F (10,763) = 2.20, p = 0.016) with cognitive performance, indicating that these associations differed across lifespan. No significant sex moderation or overall multivariate associations of BMI or PRS with cognition were observed. Both interactions remained significant after adjustment for education, perceived stress, and childhood trauma. In a sensitivity analysis, the PRS*age interaction remained significant after additional adjustment for BMI. Follow-up linear regression analyses revealed that increasing age was associated with a more negative relationship of BMI with episodic memory (B = -0.087, SE = 0.029, p = 0.003) and a more positive relationship with crystallized intelligence (B = 0.089, SE = 0.032, p = 0.005). Similarly, increasing age was associated with a more negative relationship of obesity PRS with episodic memory (B = -0.083, SE = 0.031, p = 0.008) and a more positive relationship with working memory (B = 0.073, SE = 0.034, p = 0.032). Ultimately, our findings suggest that age is a key moderator of the associations between BMI, PRS, and cognition. The persistence of the PRS*age interaction after adjustment for BMI indicates that obesity-related genetic liability may influence cognition through mechanisms beyond current body weight.
Sepsis survivors often experience long-term cognitive and mental health impairment. We lack a clear understanding of the biological mechanisms driving impairment after sepsis and the factors that make a brain vulnerable to dysfunction after sepsis. We hypothesize that amyloid pathology, which is neuroinflammatory and accumulates with age even in cognitively normal people, is a latent risk factor for post-sepsis decline driven in part by neuroinflammation and microglial dysfunction. We induced sepsis via polymicrobial abdominal infection (cecal ligation and puncture; CLP) in young adult 5xFAD mice to model early amyloid pathology. 5xFAD CLP mice demonstrated generalized conditioned fear response and impaired cognition in the puzzle box task. Brain transcriptomics revealed persistent upregulation of neuroinflammatory pathways after resolution of the infection, with a distinct increase in 5xFAD CLP survivor mice. Complement gene expression and C3aR protein were heightened in 5xFAD mice, while C3 increased after infection. Microglial synaptic phagocytosis, a potential mechanism driving brain dysfunction after sepsis, was increased in 5xFAD CLP survivor mice 3 weeks after infection. While there was a small C3aRhigh microglial population in 5xFAD brains, the change in synaptic phagocytosis occurred in microglia with basal levels of C3aR expression. Overall, our findings suggest that early amyloid pathology synergistically heightens the behavioral change, neuroinflammation, and microglial synaptic phagocytosis caused by sepsis.
