Brain, Behavior, and Immunity

Microglial activation is a common feature of neurological and inflammatory diseases and may contribute to some associated symptoms. However, methodological limitations have made it challenging to identify the specific symptoms and behavioral consequences of selective microglial activation. In this study, we examined the spectrum of symptoms elicited by acute chemogenetic activation of microglia in mice and compared them to those induced by endotoxin-driven systemic inflammation. Both interventions upregulated inflammatory gene expression in the brain, reduced voluntary wheel running, and decreased self-care. Systemic inflammation additionally caused anorexia, weight loss, reduced motivation to work for palatable food, and impaired motor performance in the rotarod test--effects not observed with chemogenetic microglial activation. By showing that acute microglial activation reproduces certain motivational aspects of the sickness response while sparing other functions, the findings might shed new light on the contribution of microglia to symptoms and behavioral alterations during disease.

Background Observational studies have reported an association between inflammation and postoperative complications but it is unclear whether these associations are causal. It is also unknown whether postoperative outcomes share a causal architecture with chronic, all-cause disease. Methods We performed bi-directional two-sample Mendelian randomization to investigate potential causal effects of 19 genetically-proxied inflammatory markers on postoperative acute kidney injury, atrial fibrillation (AF), delirium, myocardial infarction, stroke and surgical site infection, and their all-cause equivalents. Genetic instruments for inflammatory markers were sourced from nine GWAS of up to 204,402 European participants with outcome data derived from UK Biobank. Results The primary postoperative analysis showed a protective effect of down-regulated IL-6 signalling on stroke risk (OR (95% CI) 0.27 (0.11--0.69), p=0.006). However, in the all-cause analysis a causal effect on stroke was not present (OR (95% CI) 1.14 (0.75--1.24), p=0.78), whilst a robust protective effect was seen for down-regulated IL-6 with AF across all three instruments studied (all p<0.009). In postoperative and all-cause analyses, genome-wide variants for CRP showed a protective effect on delirium that was not present in cis-restricted analyses. Conclusions We found evidence supporting a potential causal role for IL-6 signalling in perioperative stroke. However, the divergence in IL-6 effects between postoperative and all-cause outcomes suggests that the inflammatory architecture of acute postoperative complications may differ from chronic disease states. Furthermore, our findings suggest previously reported associations between CRP and delirium likely represent horizontal pleiotropy rather than direct causation. Future work should interrogate local tissue responses and the immediate perioperative period.

BackgroundSickness behavior comprises a coordinated constellation of motivational, cognitive, and social alterations that emerge during systemic inflammation. Although reductions in locomotion, feeding, and social engagement have been extensively characterized, how inflammation affects ultrasonic vocal communication--an ethologically relevant index of social motivation in rodents--remains insufficiently understood. Here, we investigated how systemic immune activation alters male-female social communication in mice by jointly assessing ultrasonic vocalizations (USVs) and approach behavior. MethodsSexually experienced male mice received an intraperitoneal injection of lipopolysaccharide (LPS), and their interactions with a novel estrous female were evaluated 24 h later by quantifying USVs and approach behavior. ResultsLPS administration robustly suppressed both the total number of USVs and the duration of male approach behavior, indicating a pronounced reduction in social motivation. Beyond this quantitative suppression, LPS also induced qualitative changes in vocal output, including shifts in the proportional use of specific USV subtypes and alterations in acoustic features such as sound pressure. ConclusionsThese findings demonstrate that USVs capture multiple dimensions of inflammation-induced disruption of social communication, reflecting not only diminished motivation to engage socially but also changes in the structure of communicative signals themselves. By revealing that systemic immune activation reshapes both social approach behavior and vocal communication patterns, this study establishes USV analysis as a sensitive and translationally relevant behavioral readout for probing neuroimmune mechanisms underlying the social and communicative disturbances characteristic of sickness behavior. More broadly, our results highlight the utility of vocal communication analyses for elucidating how inflammatory processes perturb social circuits and communicative function in health and disease.

BackgroundAdverse life events and psychosocial stressors contribute to a range of neuropsychiatric disorders. However, the role of inflammatory dynamics around stress exposure remains unclear. Using TriNetX, a large international electronic health records database, we examined how systemic inflammatory activity and its temporal dynamics relate to subsequent risk of mental illness and somatic symptoms. MethodsWe compared 36,772 individuals with records of adverse life events and leukocytosis in the surrounding period with matched individuals with normal leukocyte counts, and performed an analogous comparison for socioeconomic and psychosocial stressors in cohorts of 87,936 individuals with leukocytosis and matched controls. To contrast dynamic with static inflammatory responses, we compared cohorts exhibiting leukocyte count changes with those maintaining persistently normal or persistently elevated leukocyte counts around stressor exposure. Outcomes, including new mental health and somatic symptom presentations, were evaluated within two years of the stressor. ResultsFollowing acute stressors, leukocytosis (compared with normal leukocyte counts) was associated with lower rates of subsequent anxiety disorders, cognitive symptoms and several somatic symptom diagnoses, with similar reductions in anxiety observed after chronic stressors. A dynamic inflammatory response was associated with the most favourable outcomes, with lower rates of anxiety, depression, functional neurological disorder, cognitive and sleep difficulties, fatigue, and multiple pain-related and other somatic symptoms than persistently low or high inflammation. ConclusionOur findings suggest that a well-regulated inflammatory response to stressors is associated with a reduced risk of diverse mental health and somatic outcomes, and that a transient immune activation may support recovery rather than confer risk.

Infection with SARS-CoV-2 can lead to long COVID, a chronic multisystemic condition estimated to affect approximately 400 million people worldwide. Although underlying mechanisms remain elusive, aberrant ongoing inflammation driven by Epstein-Barr virus (EBV) reactivation and persistent SARS-CoV-2 viral reservoirs have been hypothesized. We compared cellular and humoral immune responses to SARS-CoV-2 and EBV between participants with neuropsychiatric long COVID and recovered individuals. Peripheral blood mononuclear cells (PBMCs) and sera were collected from 27 long COVID individuals with [&ge;]2 neuropsychiatric symptoms and 27 matched recovered participants at 3-6 months post-COVID-19 symptom onset (PSO). PBMCs were assessed for IFN-{gamma}, IL-2, TNF, and granzyme B T-cell responses against SARS-CoV-2, EBV, and human cytomegalovirus (HCMV). Sera were evaluated for neutralizing activity against live ancestral SARS-CoV-2 and EBV, and EBV reactivation was assessed by early antigen-diffuse IgG. We observed no significant differences in SARS-CoV-2-, EBV-, or HCMV-specific T-cell responses or live virus neutralization between long COVID and recovered groups at 3-6 months PSO. EBV reactivation was additionally only detected in one neuropsychiatric long COVID participant. However, reduced EBV neutralizing capacity at 3-6 months significantly associated with fatigue at 12 months PSO. Anti-EBV viral capsid antigen IgG levels were also significantly diminished in long COVID participants and similarly trended lower in those reporting fatigue at 12 months PSO. We therefore detected no differences in SARS-CoV-2- or EBV-specific T-cell responses or serological neutralizing capacity between neuropsychiatric long COVID and recovered participants; however, diminished EBV-specific humoral immunity may serve as a prognostic marker for neuropsychiatric long COVID development. IMPORTANCEWe performed a comprehensive analysis of cellular and humoral immune responses to SARS-CoV-2, Epstein-Barr virus, and human cytomegalovirus in individuals with neuropsychiatric long COVID, a subgroup that remains poorly characterized. Although no differences in virus-specific T-cell immunity were observed between long COVID and recovered individuals, diminished Epstein-Barr virus neutralization at 3-6 months was associated with persistent or relapsing fatigue at 12 months post-COVID-19 symptom onset. Anti-viral capsid antigen IgG antibody levels were also significantly lower in neuropsychiatric long COVID participants at 3-6 months and similarly trended lower in those reporting fatigue at 12 months post-symptom onset. Together, these findings suggest that impaired humoral immunity to Epstein-Barr virus may contribute to the development or persistence of neuropsychiatric long COVID and highlight a promising future direction for mechanistic studies.

BackgroundTraumatic brain injury (TBI) initiates a rapidly evolving neuroinflammatory response; however, the temporal relationship between early innate immune activation, T cell polarization, and neurobehavioural recovery remains poorly understood. Here, we hypothesize that interleukin-1{beta} (IL-1{beta}) is a critical upstream mediator that polarizes T cells towards pro-inflammatory and cytotoxic effector functions following TBI. MethodsUsing a controlled cortical impact model in adult male C57BL/6J mice, we mapped post-injury immune dynamics and investigated whether targeting key innate inflammatory compartments influenced subsequent T cell programming and neurological outcomes. We conducted longitudinal immune profiling by multiparameter spectral flow cytometry and quantitative polymerase chain reaction up to 10 days post-injury. Antibody-based immune depletion strategies were used to investigate neutrophil and monocyte contributions to the post-traumatic T cell response, while pharmacological inhibition of NLRP3 inflammasome by MCC950 treatment was used to investigate the contribution of IL-1{beta}. ResultsTBI elicited a structured early innate immune response, marked by rapid chemokine induction, followed by temporally distinct infiltration of neutrophils, monocytes, and dendritic cells. Neutrophils and monocytes were the predominant early IL-1{beta}-producing infiltrating populations. This was followed by a delayed adaptive phase characterized by sustained recruitment of T cell subsets (CD4+, CD8+, {gamma}{delta}+), alongside dynamic effector cytokine production (IL-17, IFN-{gamma}). Neutrophil depletion altered the early myeloid composition but did not result in durable improvements in T cell effector responses or neurobehavioral outcomes. Depletion of CCR2-dependent inflammatory monocytes reduced acute monocyte accumulation and attenuated early downstream T cell responses; however, these effects were not sustained and only resulted in modest neurobehavioural benefits. In contrast, inhibition of the NLRP3 inflammasome suppressed microglial IL-1{beta} production, without significantly altering leukocyte recruitment or subacute T cell effector phenotypes. These phenotypic changes were associated with improvements in motor and cognitive function recovery. ConclusionWe show that early monocyte IL-1{beta} signalling actively regulates downstream T cell infiltration and effector function after TBI. In addition, inhibition of NLRP3 inflammasome after TBI attenuates microglial IL-1{beta}-associated immune activation and results in behavioural improvement despite ongoing leukocyte recruitment, indicating that targeting the nature and cellular source of IL-1{beta} signalling can dissociate immune cell burden from neurological outcomes. Collectively, our findings identify myeloid IL-1{beta}-linked pathways as a viable bridge between innate and adaptive immunity post-TBI, and underscore cellular compensation as a critical design consideration for next-generation immunotherapies.

Mild traumatic brain injuries (mTBI) can substantially impact quality of life, and repetitive mTBIs (rmTBI) can amplify injury effects compared to a single injury. However, effective clinical treatments remain elusive, largely due to an incomplete understanding of the underlying injury mechanisms. Neuroinflammation has emerged as a key contributor to worse functional outcomes after mTBI/rmTBI. While microglia are traditionally viewed as primary mediators of post-injury inflammation, accumulating evidence suggests neurons play an immunomodulatory role in initiating the rmTBI inflammatory cascade through activation of intracellular proinflammatory pathways like p38 MAPK and secretion of cytokines that, in turn, stimulate microglial activation. Here, we tested whether inducible neuronal p38 knockout protects against functional, immune, and cerebrovascular consequences of a weight-drop closed head injury model of rmTBI. A battery of functional assays was conducted 4 weeks post-injury, and tissues were collected at both 4 hours and 4 weeks following final CHI. In males, neuronal p38 knockout protected against injury-induced depressive-like behavior, hyperactivity, synaptic loss, microglial reactivity, cytokine upregulation, and reduction in cerebral blood flow. In females, neuronal p38 knockout protected against risk-taking behavior and partially protected against cytokine upregulation but had limited effect on microglial reactivity and cerebral blood flow. Together, these findings identify neuronal p38 as a sex-dependent driver of rmTBI-associated neurological consequences, and they support neuronal p38-immune signaling as a mechanistically relevant therapeutic target for future studies.

Chronic neuroinflammation is associated with comorbidities in people with HIV (PWH) on antiretroviral therapy (ART). While cannabis use is associated with reduced neuroinflammation and neurocognitive impairment (NCI) in PWH, the underlying mechanisms are unknown. To address this gap in knowledge, we analyzed monocyte-derived macrophages (MDMs) from a cohort of 50 PWH and 33 people without HIV (mean age: 61.9 years), categorized by frequency of cannabis use (naive/low, moderate, daily). We performed immunocytochemistry, RNA sequencing, and qPCR on MDMs and quantified related biomarkers in donor plasma. In this cohort study, daily cannabis use in PWH was associated with less global neurocognitive deficits, and with an anti-inflammatory immunometabolic-phenotype in MDMs characterized by (1) a metabolic shift from glycolysis to oxidative phosphorylation, (2) higher mitochondrial numbers, (3) altered cytokine profiles (pro-inflammatory downregulation, anti-inflammatory upregulation), and (4) higher brain-derived neurotrophic factor (BDNF) expression. These cellular changes were corroborated by a plasma biomarker profile in PWH including (1) lower levels of growth differentiation factor 15 and soluble triggering receptor expressed on myeloid cells 2, and (2) higher mature BDNF/precursor BDNF ratios that correlated with better cognition. Thus, cannabis use may mitigate NCI in PWH by immunometabolically reprogramming MDM function towards an anti-inflammatory and neuroprotective state. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=140 SRC="FIGDIR/small/709579v1_ufig1.gif" ALT="Figure 1"> View larger version (42K): org.highwire.dtl.DTLVardef@15fb1adorg.highwire.dtl.DTLVardef@189d79corg.highwire.dtl.DTLVardef@aa6a89org.highwire.dtl.DTLVardef@3852f8_HPS_FORMAT_FIGEXP M_FIG C_FIG

BackgroundExposure to prenatal maternal inflammation (PNMI) has been linked to neurodevelopmental alterations in human offspring. Preclinical studies suggest that PNMI disrupts reward circuitry, particularly within mesolimbic circuits. However, the effects of PNMI on mesolimbic circuits (i.e, ventral tegmental area (VTA) projections to the hippocampus (VTA-H) and limbic striatum (VTA-LS)) in humans are not yet known. MethodsData for PNMI biomarkers [interleukin (IL)-6, IL-8, IL-1 receptor antagonist (IL-1ra), soluble TNF receptor-II (sTNF-RII)] from first trimester (T1) and second trimester (T2) maternal sera, and offspring MRI brain scans in late midlife (aged 57-63 years), were available for 89 mother-offspring dyads. Probabilistic tractography delineated bilateral VTA-H and VTA-LS tracts. Macrostructural tract measures were examined using hierarchical linear regressions. Microstructural integrity was assessed using neurite orientation dispersion and density imaging, and permutation-based cluster analyses. ResultsHigher T2 IL-1ra was associated with increased macrostructure (left VTA-H tract), whereas higher T2 sTNF-RII was associated with reduced macrostructure (right VTA-H and VTA-LS tracts) and higher T2 IL-8 (bilateral VTA-LS tracts). Microstructurally, higher T2 IL-6 was associated with increased neurite density (distal cluster, right VTA-H tract), while higher T1 IL-8 was associated with reduced neurite density (near the hippocampus in the left VTA-H tract, near the VTA in bilateral VTA-LS tracts). ConclusionsPNMI was associated with altered mesolimbic reward circuitry in offspring. This suggests that prenatal inflammation may contribute to affective and motivational disorders in offspring via alterations in mesolimbic circuitry.

Communication between gut microbiota and immune cells within the brain is essential for neurotypical development. Specifically, microglia are known to play a key role in regulating and supporting neural progenitor stem cell production during brain development, and are sensitive to changes in the maternal gut microbial composition during perinatal development. Here, we employed a germ-free (GF) porcine paradigm to examine how the absence of the microbiome affects microglial dynamics during a key epoch of brain development. We utilized automated software to evaluate microglial density and morphology across three developmentally significant regions: the ventricular/subventricular zone (VZ/SVZ), the prefrontal subcortical white matter (PFCSWM), and layers II/III of the prefrontal cortex (PFCII-III). We found no significant differences in microglial morphology or density in the VZ/SVZ or PFCSWM. In contrast, the PFCII-III of P16 piglets exhibited an increase in microglia density paired with morphologies indicative of an activated/reactive functional state. Notably, these effects were identified with no overall changes in microglial density in any of the regions assessed. Transcriptomics on RNA isolated from the PFCII-III revealed a significant upregulation of genes related to neuroinflammation, in agreement with a region-specific microglial and immune response in the absence of microbial colonization during postnatal development. Together, these findings build on the limited knowledge available on how microbiota influence brain development in large animal model organisms with high similarities to human brain anatomy and developmental trajectories. Significance StatementThe prefrontal cortex of porcine display unique, ramified microglia which are sensitive to germ-free conditions whereby they display alterations in morphology with a more transcriptionally reactive signature. These findings indicate that microglia are regionally sensitive to stimuli in the periphery, and studies in lissencephalic mammalian models may not be directly correlative to other higher-order species. The neuroanatomical heterogeneity of microglia across species is informative and understudied, but necessary, to draw conclusions on the array of perturbations spanning neurodevelopmental trajectories in health and disease.

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.

ObjectiveSevere infections have been implicated in dementia risk, but their associations with detailed patterns of cognitive performance, and whether poorer cognition in turn increases risk for certain infections, remain unclear. We examined bidirectional associations between hospital-treated infections and domain-specific cognitive function in a cohort of older adults. MethodsWe analysed data from the English Longitudinal Study of Ageing Harmonised Cognitive Assessment Protocol (ELSA-HCAP), conducted in 2018 and linked to national inpatient records. Pre-HCAP hospital-treated infections were identified from 1997 to 2018; post-HCAP incident infections were ascertained from 2018 to 2024. Cognitive performance was assessed at HCAP using 21 standardised neuropsychological tests summarised into general and four domain-specific scores (executive function, memory, language, and visuospatial ability). Linear regression assessed associations between pre-HCAP hospital-treated infections and standardised cognitive scores; Cox models estimated associations between cognition and risk of incident hospital-treated infections after HCAP. All models were adjusted for sociodemographic, lifestyle, and health covariates. ResultsOf 1,159 participants aged [&ge;]65 at HCAP (631 [54.1%] female; mean [SD] age, 75.6 [7.2] years), 351 (30.3%) had a hospital-treated infection before HCAP. Prior hospitalisation for any infection was associated with lower general cognition ({beta} = -0.11 SD, 95% CI -0.21 to -0.02) and poorer executive function ({beta} = -0.19, -0.28 to -0.09), with similar patterns across infection types. Lower respiratory tract infections were additionally associated with poorer memory ({beta} = -0.20, -0.36 to -0.04). Cognitive scores were progressively lower among individuals with more frequent or prolonged infection-related hospitalisations, sepsis, or cardiovascular disease. Prospectively, over a mean (SD) 4.8 (1.9) years of follow-up, 271 incident hospital-treated infections occurred. Each 1-SD higher general cognition was associated with a 36% lower risk of any subsequent hospital-treated infection (HR 0.64, 0.53 to 0.78), and with consistent associations across cognitive domains for all-cause and bacterial infections. Executive function alone showed a strong association with viral infections, especially COVID-19 (HR 0.59, 0.44 to 0.80). ConclusionSevere infections were primarily associated with poorer executive function. Conversely, cognitive vulnerability across multiple domains was associated with increased susceptibility to infections requiring hospital care, while poorer executive function was specifically associated with viral infection risk. These findings support a reinforcing infection-cognition cycle in later life and cognitively tailored infection-prevention strategies.

Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a chronic multisystem disease characterized by profound fatigue, post-exertional malaise, cognitive impairment, and autonomic dysfunction. Its pathophysiology is incompletely understood and likely involves complex interactions between immune, autonomic, and metabolic dysregulation. Despite features with potential relevance for anesthesia and perioperative care, evidence to guide anesthetic management in individuals with ME/CFS remains limited. We therefore performed a retrospective matched-pair analysis to generate clinical data on perioperative responses and identify areas for future research. Methods: We conducted a retrospective matched-pair analysis at a single tertiary center. All patients with ME/CFS undergoing general anesthesia from 2015 to 2026 were identified using ICD-10 codes (G93.3 and U09.9) with additional manual verification and matched 1:1 to controls for comparison. Patients with confounding diagnoses or American Society of Anesthesiologists physical status above III were excluded. The analysis focused on intraoperative hemodynamic parameters, including baseline, post-induction, median, and lowest recorded systolic blood pressure and heart rate, as well as early postoperative outcomes in the post-anesthesia care unit (PACU), including maximum pain scores and requirement for rescue analgesia. Results: Out of 189 individuals identified through ICD-10 codes, 15 matched pairs were included after application of exclusion criteria. ME/CFS patients exhibited lower lowest recorded intraoperative systolic blood pressure (90 [82.5-95.0] mmHg in ME/CFS vs 100 [90.0-110.0] mmHg in controls, p = 0.044) as well as lower lowest heart rate (50 [40.0-57.5] bpm in ME/CFS vs 60 [50.0-65.0] bpm in controls, p = 0.012). Vasopressor use and fluid administration did not differ, and no episodes of severe hypotension or perioperative adverse events were observed. Postoperative pain was higher in ME/CFS, with higher maximum pain scores (NRS 5.0 [4.0-6.0] in ME/CFS vs 1.0 [0.0-4.0] in controls, p = 0.008) and more frequent opioid rescue analgesia (80% in ME/CFS vs 33% in controls, p = 0.039). Postoperative nausea or vomiting, oxygen supplementation, and PACU length of stay were similar between groups. Conclusions: General anesthesia appears hemodynamically well tolerated in individuals with ME/CFS. In contrast, postoperative pain burden is increased and may require tailored analgesic strategies. Post-exertional malaise, a key disease feature with potentially delayed onset and significant impact, was not captured in this study and remains an important target for future research. These hypothesis-generating findings highlight the need for prospective studies to optimize perioperative management and evaluate patient-relevant outcomes in ME/CFS.

Poor sleep is linked to consumption of sugary foods/beverages and high neural responsivity to palatable food cues. Yet, whether hedonic liking for sweet taste explains these associations remains unclear. We examined cross-sectional associations of five sleep traits (chronotype, sleep duration, insomnia frequency, snoring, daytime dozing) and a composite sleep score with sweet food liking, and total and free sugar intake in 76,734 UK Biobank participants (39-72 years, 56.3% female). Models adjusted for age, sex, ethnicity, socioeconomic deprivation, and body mass index (Bonferroni-corrected =0.0025). Evening chronotype, more frequent insomnia and daytime dozing, and lower composite sleep score were associated with higher sweet food liking. Associations with intake were stronger for free than total sugar. Evening chronotype was associated with higher free sugar intake (g/day: {beta}=1.523, 1.309-1.737; g/1000 kcal: {beta}=0.450, 0.361-0.538), and daytime dozing showed a dose-response (dozing often vs never/rarely: g/day {beta}=6.307, 4.631-7.983). Snoring was associated with higher absolute (but not energy-adjusted) free sugar intake. A healthier sleep score was associated with lower free sugar intake (g/day {beta}=-2.193 [-2.464 to -1.922]; g/1000 kcal {beta}=-0.691 [-0.804 to -0.579]) but higher energy-adjusted total sugar intake ({beta}=0.633 [0.485-0.781]). Mediation analyses indicated sweet liking accounted for 15%-91% of several sleep trait and free sugar intake associations (indirect effects p<0.001). Poorer sleep health, particularly evening chronotype and daytime sleepiness, was associated with greater sweet liking and higher free sugar intake, with sweet liking partially mediating associations between sleep traits and sugar consumption. Sweet-taste liking may represent an underexamined pathway linking sleep/circadian disruption to free sugar intake.

BackgroundLoneliness is a psychosocial stressor associated with elevated risk of severe mental illness (SMI), including major depressive disorder (MDD), schizophrenia (SCZ), and bipolar disorder (BD). Loneliness is theorized to become biologically embedded via inflammation-related mechanisms, yet its causal relationship with SMI and the role of inflammatory signaling remain unclear. AimsTo investigate whether loneliness causally influences SMI risk and whether inflammatory cytokines mediate this relationship. MethodWe applied univariable Mendelian randomization (MR) to estimate the causal effect of loneliness on SMI and multivariable MR (MVMR) to assess mediation by inflammatory signaling. We integrated genome-wide association study (GWAS) summary statistics for loneliness and SMI with genetic instruments for inflammatory cytokines. MVMR models estimated the direct effect of loneliness after accounting for inflammatory signaling using eQTL and pQTLs for interleukin-1 receptor antagonist (IL-1RA), interleukin-6 (IL-6), IL-6 receptor (IL-6R), tumor necrosis factor alpha (TNF-), and TNF receptors (TNF-R1/2). Bidirectional MR examined potential reverse causal pathways between inflammation, SMI, and loneliness. ResultsMR provided evidence consistent with a causal effect of loneliness on SCZ and MDD. Results were also consistent with inflammatory cytokine pathways for IL-1RA, IL-6R, and TNF-R1, partially mediating the loneliness-SCZ and loneliness-MDD causal effect. No significant effects were identified for BD in UVMR or MVMR models. Bidirectional MR suggested evidence of reverse causation between SCZ and loneliness. ConclusionsThe findings support a causal risk-increasing effect of loneliness on SCZ and MDD, partially mediated by systemic inflammatory signaling, implicating pathways as a plausible mechanistic link between psychosocial stress and mental illness risk and highlighting potential opportunities for prevention and targeted intervention through inflammation and social pathways.

Social isolation refers to an extreme form of social deprivation that has enduring effects on the brain and behavior. Adolescents show selective vulnerability to such heightened social stress, displaying aberrant behavior and psychiatric ailments. The post-weaning social isolation rodent model has been widely used to recapitulate such behavioral anomalies and delineate their mechanistic bases. Here, we aim to identify how prolonged social isolation during adolescence affects neuroimmune responses in both sexes and the implications for behavioral outcomes, particularly aggression. While males subjected to adolescent isolation were hyper-aggressive with pathological signs, females showed reduced social exploration and inactivity. Cytokine profiling in core brain regions implicated in aggression revealed reduced interleukin 6 (IL6) levels, specifically in the hypothalamus, in both sexes. Other proinflammatory cytokines, including interferon-gamma and interleukin-1beta, were unaltered. IL6-responsive genes, SOCS3 and TIMP1, were also downregulated in the hypothalamus of both socially isolated males and females. The hypothalamus is crucial for stress responsiveness and the expression of excessive aggression. Despite behavioral dimorphism, reduced IL6 levels in both sexes may indicate differences in downstream signaling and roles beyond classical immune responses. Our findings suggest that hypothalamic IL6 may be a key mediator of adolescent social isolation, which is associated with aberrant behavior, including aggression.

Background: Acute necrotizing encephalopathy (ANE) is a rare and severe neurologic complication of viral infection in children, thought to result from a hyperacute cytokine storm causing blood-brain barrier disruption and central nervous system injury. Despite characteristic clinical and radiologic features, ANE remains poorly understood at the molecular level, with no validated biomarkers or targeted therapies. We aimed to determine whether genetic predisposition to ANE due to RANBP2 variants is associated with a distinct immunologic signature. Methods: We conducted a prospective biological study of familial ANE (ANE1, NCT06731790). We included 23 heterozygous carriers of the RANBP2 c.1754C>T (p.Thr585Met) variant from 10 families, and 28 noncarriers (median age, 40 years [range, 4-72]). Soluble immune mediators, transcriptomic analyses, multiparameter flow cytometry, and cellular imaging were analysed in peripheral blood mononuclear cells (PBMCs) and monocytes. Baseline and resiquimod stimulated immune responses were analysed within the same statistical model, with genetic status as the primary predictor. Findings: The RANBP2 Thr585Met mutation was associated with a dysregulated inflammatory phenotype characterized by reduced basal mediator production and exaggerated TNF- responses following stimulation (estimated difference, +2,098 pg/mL; 95% CI, 1,121 to 3,076; P=0.0001). Transcriptomic and flow cytometry analyses showed broad reprogramming of myeloid cells with enrichment of CXCR3-high CD14-high subsets. Expansion of these populations was associated with increased long-term disease burden. The RANBP2 variant was the only independent factor associated this inflammatory phenotype. Interpretation: RANBP2-associated ANE is characterised by a distinct immunological signature that can inform disease stratification and support the development of targeted immunotherapeutic approaches.

BackgroundChildren who are HIV-exposed but uninfected (HEU) are at increased risk of neurodevelopmental delays, yet neuroimmune pathways linking perinatal HIV exposure to school readiness remain unclear. MethodsIn the Drakenstein Child Health Study, 268 children (94 HEU, 174 HIV-unexposed [HU]) underwent magnetic resonance spectroscopy in midline parietal grey and left parietal white matter regions at 6-7 years. Peripheral blood serum immune markers were measured in pregnancy and in children at 6 weeks, 2, 3, and 5 years. Linear mixed-effects models characterised child immune trajectories and linear regressions tested associations with creatine-referenced neurometabolite ratios and school readiness scores. ResultsMothers living with HIV had higher sCD14 and lower MMP-9, NGAL, and GM-CSF than mothers without HIV (p<0.05). Perinatal HIV exposure was associated with altered trajectories of child sCD14, GM-CSF, IL-1{beta}, IL-5, IL-10, and YKL-40. At 6-7 years, children who were HEU had lower parietal grey matter glutamate ratios and lower left parietal white matter choline ratios. By school entry, immune-neurometabolite associations were predominantly driven by child serum markers; IL-8 emerged as a consistent correlate across developmental stages. Children who were HEU had lower language scores than HU peers. Left parietal white matter choline ratios were positively associated with language and overall school readiness in HU children, but not HEU. ConclusionsPerinatal HIV exposure was associated with alterations in immune development, neurometabolites reflecting both white matter maturation and neuronal health, and school readiness. Our findings highlight potential neuroimmune pathways contributing to neurodevelopmental risks in children who are HEU.

Intracerebral hemorrhage (ICH) causes high morbidity and mortality, with neurotoxic inflammation driven by infiltrating monocytes. Therapeutic options remain limited. Here we performed single-cell RNA sequencing and plasma cytokine analysis on peripheral blood samples from ICH patients treated with the immunomodulatory drug BAF312 (Siponimod) or placebo at days 1, 3, and 7 post ICH. In the absence of treatment, the inflammatory response peaked at day 3 post ICH. BAF312 markedly reduced peripheral blood T and B lymphocyte numbers by day 3. BAF312 also impacted the myeloid response, suppressing TNF signaling in classical and non-classical monocytes. Multiple cytokine signaling pathways were decreased, though BAF312 did not impact plasma cytokine or chemokine concentrations. Notably, increased monocyte TNF signaling correlated with better functional outcome, possibly related to the positive role of monocytes during the subacute stage of ICH. These findings suggest that BAF312 suppresses peripheral immune responses after ICH and supports a complex role of monocytes in this disease.

Anorexia nervosa is characterized by maladaptive eating behavior and cognitive dysfunction, which could be explained by a neuroinflammation. A gut dysbiosis could link gastrointestinal alterations to central dysfunctions, particularly via the toll-like receptor 4 (TLR4), which has been shown to play a key role in the activity-based anorexia (ABA) model. We aimed to evaluate the neuroinflammation and its behavioral consequences in the ABA model, and to decipher the role of the microbiota-gut-brain axis, and more specifically of TLR4, in these alterations of the central nervous system. We show that chronic restriction is more strongly associated with gut inflammation, cecal microbiota alteration and neuroinflammatory processes in the hippocampus than acute restriction. The hippocampal glial response is characterized by a loss of astrocyte density, and an increased number of deramified microglia. We further demonstrate that these alterations are independent of TLR4 expressed by intestinal epithelial cells. In conclusion, our results highlight that the chronicity of ABA-associated undernutrition alters the response of glial cells in the hippocampus that is linked with changes in microbiota composition, highlighting the importance of faster diagnosis and treatment of AN.