Brain, Behavior, and Immunity最新文献

{"title":"CAP1 mediates chronic inflammatory pain-induced anxiety through cAMP/PKA/NF-κB signaling pathway in the anterior cingulate cortex of male mice.","authors":"Yu-Chen Jin, Qing-Juan Guo, Yu-Xuan Yan, Yong-Li Jiang, Da-Ke Song, Bei-Ning Lu, Cheng Zeng, Jiao Yue, Liu-Kun Yang, Rui-Xia Liu, Kun Zhang, Xu-Bo Li, Ran He, Yu-Jie Lu, Xin-Shang Wang, Shui-Bing Liu","doi":"10.1016/j.bbi.2026.107073","DOIUrl":"https://doi.org/10.1016/j.bbi.2026.107073","url":null,"abstract":"<p><p>A substantial subset of chronic pain patients suffers from comorbid anxiety, and this bidirectional exacerbation poses a major clinical challenge. Current pharmacotherapies have limited efficacy with notable side effects, underscoring the need for new targets. We successfully established a Complete Freund's Adjuvant (CFA) ‑induced chronic inflammatory pain model in male mice, which developed mechanical/thermal hyperalgesia, anxiety‑like behaviors, and Anterior Cingulate Cortex (ACC) synaptic plasticity abnormalities. RNA‑seq identified marked upregulation of ACC Adenylyl Cyclase‑Associated Protein 1 (CAP1). ACC CAP1 overexpression in naive mice selectively reduced mechanical pain and induced anxiety without affecting thermal nociception, whereas ACC CAP1 knockdown in CFA mice reversed anxiety and restored Excitatory/Inhibitory (E/I) balance while leaving pain thresholds unchanged. Mechanistically, CAP1 knockdown suppressed neuroinflammation via the Cyclic Adenosine Monophosphate (cAMP)/ Protein Kinase A (PKA)/Nuclear Factor kappa‑light‑chain‑enhancer of activated B cells (NF‑κB) pathway, as shown by reduced p‑PKA/p‑P65, cAMP, and pro‑inflammatory cytokines (Interleukin‑6, IL‑6; Interleukin‑1 beta, IL‑1β; Tumor Necrosis Factor alpha, TNF‑α). Consistent with this, an NF‑κB agonist completely blocked the anxiolytic effects of CAP1 knockdown, confirming that CAP1 acts through this signaling cascade to promote cytokine release and subsequent synaptic remodeling. Collectively, these findings establish ACC CAP1 as a critical mediator of chronic pain‑induced anxiety in male mice and suggest that targeting CAP1 may represent a promising strategy for precision intervention in pain-related affective disorders.</p>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":" ","pages":"107073"},"PeriodicalIF":7.5,"publicationDate":"2026-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149179316","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Individual susceptibility to disgust modulates neural and systemic immune responses to virtual infections.","authors":"Maren Born, Michel Akselrod, Sara Trabanelli, Matteo Girondini, Georgia Papadopoulou, Giulia Vanoni, Anthony Cornu, Tommaso Bertoni, Camilla Jandus, Andrea Serino","doi":"10.1016/j.bbi.2026.107059","DOIUrl":"https://doi.org/10.1016/j.bbi.2026.107059","url":null,"abstract":"<p><p>Disgust is a key psychological mechanism for avoiding pathogen exposure and constitutes a central component of the behavioral immune system. While disgust is thought to reduce infection risk through avoidance, it remains unclear how individual differences in disgust sensitivity shape downstream neuroimmune responses to perceived pathogen threats. Here, we show that lower disgust sensitivity is associated with stronger activation of type 1 innate lymphoid cells during exposure to infectious, compared with neutral, avatars in virtual reality. Disgust sensitivity further correlated with circulating signaling factors involved in immune regulation, including hormones related to the hypothalamic-pituitary-adrenal (HPA) axis, and eicosanoids. Linear models incorporating disgust sensitivity and threat exposure predicted these signaling factors, which in turn enabled accurate prediction of type 1 innate lymphoid cells responses using a pretrained neural network. Recreating this putative pathway, we were able to predict immune responses solely by disgust scores. Additionally, resting-state functional magnetic resonance imaging revealed that exposure to infectious avatars altered hypothalamic connectivity with brain regions involved in visual processing, peripersonal space representation, and social cognition, and these effects were modulated by individual disgust sensitivity. Together, these findings suggest that disgust sensitivity modulates multiple levels of the neuroimmune response to perceived pathogen threats. Across two complementary experiments, our results are consistent with a model linking sensory threat detection, hypothalamic signaling, and systemic immune activation. Rather than uniformly amplifying immune responses, higher disgust sensitivity appears to bias pathogen defense toward neural processing, whereas lower disgust sensitivity is associated with stronger physiological immune activation.</p>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":" ","pages":"107059"},"PeriodicalIF":7.5,"publicationDate":"2026-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149165727","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Blood-brain barrier disruption and microglia-associated synaptic pruning contribute to cognitive decline after electroconvulsive therapy.","authors":"Yanzhang Li, Si Xu, Mengyao Dai, Tianfeng Wang, Yang Ji, Yue Wu, Wentao Dai, Yanghua Tian","doi":"10.1016/j.bbi.2026.107063","DOIUrl":"https://doi.org/10.1016/j.bbi.2026.107063","url":null,"abstract":"<p><strong>Background: </strong>Modified electroconvulsive therapy (MECT) is a highly effective intervention for major depressive disorder (MDD), yet its broader clinical application is constrained by poorly understood cognitive side effects. We hypothesized that MECT disrupts hippocampal blood-brain barrier (BBB) integrity, permitting extravasation of peripheral factors that activate microglia, drive synaptic phagocytosis, and precipitate cognitive decline.</p><p><strong>Methods: </strong>We employed a multi-modal translational approach integrating: (1) clinical neuroimaging (rs-fMRI and DCE-MRI) and cognitive assessments in 41 MDD patients undergoing MECT (including 9 with DCE-MRI); (2) a chronic restraint stress (CRS) mouse model subjected to electroconvulsive shock (ECS), with behavioral, molecular, and transcriptomic analyses; and (3) causal validation via microglial depletion (PLX5622) and targeted BBB repair (Axitinib). In vitro, HT22 hippocampal neurons were stimulated with soluble inflammatory mediators released by primed microglia to assess direct synaptic injury.</p><p><strong>Results: </strong>MECT significantly impaired immediate and delayed associative memory and reduced left hippocampal ALFF in MDD patients; memory decline correlated with ALFF reduction. In a paired subgroup of patients, DCE-MRI revealed increased hippocampal K^trans after MECT, providing preliminary clinical imaging support for treatment-associated BBB hyperpermeability. In CRS mice, ECS downregulated tight junction proteins (Claudin-5, ZO-1, Occludin), induced Evans blue extravasation, and promoted hippocampal deposition of fibrinogen and complement C3. ECS also triggered microglial activation, enhanced PSD95 synaptic phagocytosis, elevated IL-6/IL-1β, and reduced synaptic proteins. Critically, both PLX5622-mediated microglial depletion and Axitinib-mediated BBB repair reversed these pathological changes and rescued cognitive function, establishing a dual causal validation system. Axitinib failed to suppress LPS-induced microglial activation, suggesting its protective effects were mediated via BBB restoration rather than direct immunomodulation.</p><p><strong>Conclusions: </strong>In conclusion, this study identifies a hippocampus-centered neurovascular-immune mechanism underlying MECT/ECS-related cognitive impairment. Our findings demonstrate that BBB disruption is an early upstream event that permits peripheral factors to enter the brain, activate microglia, and drive synaptic injury and cognitive decline. These results establish a novel mechanistic framework for the cognitive side effects of MECT and highlight BBB protection and microglial modulation as potential strategies for cognitive protection.</p>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":" ","pages":"107063"},"PeriodicalIF":7.5,"publicationDate":"2026-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149164638","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cytokine dysregulation and hippocampal neurogenesis: A shared mechanism underlying cognitive impairments across neuropsychiatric and neurodegenerative disorders.","authors":"Nuriza Tukiran, Theresa Kolb, Lucia Maggioni, Sparsha Rai, Zain Rafath, Alessandra Borsini","doi":"10.1016/j.bbi.2026.107069","DOIUrl":"https://doi.org/10.1016/j.bbi.2026.107069","url":null,"abstract":"<p><p>Neuropsychiatric and neurodegenerative disorders, such as major depressive disorder, bipolar disorder, schizophrenia, Alzheimer's disease, and Parkinson's disease, all show a neuroimmune signature with dysregulated inflammatory cytokine profile and cognitive impairment. Although these deficits are clinically relevant, the immunological mechanisms that cause cognitive dysfunction across these conditions remain poorly defined. Recent studies demonstrate that inflammatory cytokines actively modulate adult hippocampal neurogenesis, a process critical for learning, memory, and affective regulation. Here, we synthesise clinical evidence to characterise the disorder-specific inflammatory profile of each of these five disorders, representing each profile with three frequently dysregulated cytokines rather than a single cytokine signature shared across conditions. We also integrate preclinical data where cytokines induce behavioural, cognitive, and hippocampal-related deficits in animal and cellular models. Hence, this review develops a mechanistic framework that links brain-immune communication directly to cognitive impairment through hippocampal neurogenesis, thereby suggesting neuroimmune targets for therapeutic intervention.</p>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":" ","pages":"107069"},"PeriodicalIF":7.5,"publicationDate":"2026-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149164720","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Plasma proteomic signatures in bipolar disorder and their implications for data-driven patient stratification.","authors":"Bruno Pedraz-Petrozzi, Wahid Boukouaci, Ophélia Godin, Jérémy Bernard, Lauren Hasty, Jean-Romain Richard, Caroline Barau, Philippe Le Corvoisier, Pierre Solomon, Jeremie Poschmann, Moritz Spangemacher, Robert Dantzer, Andreas Meyer-Lindenberg, Husseini Manji, Golam M Khandaker, Marion Leboyer","doi":"10.1016/j.bbi.2026.107071","DOIUrl":"10.1016/j.bbi.2026.107071","url":null,"abstract":"<p><p>Bipolar disorder (BD) is a heterogeneous mood disorder that lacks robust biomarkers for biological stratification. We used high-throughput plasma proteomics to characterize case-control differences, identify proteomic subgroups within BD, and examine their associations with blood-based markers and clinical features. Plasma samples from the French I-GIVE (Immuno-Genetics, Inflammation, retroVirus, Environment) cohort, including 248 participants with BD and 76 healthy controls, were assessed using the Olink Reveal panel (1,034 proteins). Age-, sex-, and BMI-adjusted case-control analyses identified 527 differentially expressed proteins in the imputed analysis and 136 in the complete-case analysis, with high agreement in effect estimates and involvement of immune, metabolic, oxidative stress, and endothelial-related processes. Despite the large number of differentially expressed proteins, pathway enrichment was limited to B-cell receptor and chronic myeloid leukemia-related signaling in BD. Unsupervised clustering within BD identified two proteomic subgroups, with enrichment between clusters in longevity-regulating pathways, cellular senescence, FLT3 signaling, and transcription-related pathways. Among four measured inflammatory/endothelial markers, serum amyloid A was the only marker showing a significant difference between groups (FDR < 0.05). Clinical characteristics were similar across clusters, although childhood physical abuse and a greater somatic comorbidity burden were associated with the subgroup showing higher protein abundance. Our findings support biological heterogeneity within BD and suggest that proteomic subgrouping may capture variation not evident in pooled case-control analyses.</p>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":" ","pages":"107071"},"PeriodicalIF":7.5,"publicationDate":"2026-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149163412","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Anti-inflammatory IL-4 shapes the architecture of presynaptic glutamatergic puncta of human and murine sensory neurons for pain sensitivity.","authors":"David Zimmermann, Clemens L Schöpf, Buket Ucar, Daniel Vasconcelos, Georg Kern, Giada Musso, Sofia Dotta, Letizia Marvaldi, Niels Eijkelkamp, Kai Kummer, Stephanie Zur Nedden, Theodora Kalpachidou, Maximilian Zeidler, Jiri Palecek, Michaela Kress","doi":"10.1016/j.bbi.2026.107060","DOIUrl":"10.1016/j.bbi.2026.107060","url":null,"abstract":"<p><p>The pleiotropic anti-inflammatory cytokine interleukin 4 (IL-4) not only modulates immune responses but also plays important roles in the nervous system by mediating itch, antinociception and neuroregeneration. Here, we assessed the expression and function of IL-4, its receptors, and downstream signaling pathways in human induced pluripotent stem cell derived nociceptors (iNocs), organotypic mouse spinal cord cultures, and in in vivo models. In silico analyses of human and mouse dorsal root ganglion (DRG) single cell transcriptomes revealed that a specific subpopulation of murine and human sensory neurons expressed IL4R and IL13RA1 (but very little IL2RG) receptor subunits highlighting conserved neuron responsiveness to IL-4. In iNocs, exogenous IL-4 induced de novo formation of presynaptic vGLUT1-positive puncta. Pharmacological inhibition of Janus kinases 1/2, STAT6, protein kinase C isoforms, or the translation initiation factor eIF4E significantly attenuated the IL-4-associated increase in vGLUT1-positive puncta. Transcriptomic profiling of iNocs revealed IL-4-regulated biological processes associated with neuronal development and synaptic organization. Consistently, IL-4 increased mean-firing-rate in iNocs and increased vGLUT1 expression in mouse organotypic spinal cord cultures treated with IL-4, in vitro. Intrathecal or intranasal IL-4 treatment enhanced both, inhibitory and excitatory synaptic activity in acute spinal cord slices, and this was associated with a decrease in mechanical and thermal sensitivity but normal sensorimotor coordination in vivo. These findings position IL-4 as key regulator of presynaptic glutamatergic organization for primary afferent neuron connectivity in the spinal dorsal horn and support a critical role for IL-4 in the excitation - inhibition balance of pain processing spinal neuronal networks.</p>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":" ","pages":"107060"},"PeriodicalIF":7.5,"publicationDate":"2026-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149164346","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Beta-adrenergic receptor mediated inhibitory control of CD16⁺ monocyte inflammation is associated with neurobehavioral response to social exclusion and peripheral arterial stiffness a function of HIV.","authors":"R McIntosh, R Sharma, J D Lobo, K Howard, S Pallikkuth, P J Gianaros, B E Hurwitz","doi":"10.1016/j.bbi.2026.107039","DOIUrl":"https://doi.org/10.1016/j.bbi.2026.107039","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;Growing evidence suggests the experience of social exclusion is associated with increased risk for cardiovascular disease (CVD), however the psycho-neuro-immune mechanisms involved remain unclear. Peripheral blood mononuclear cells (PBMCs) play an important role in the etiology of peripheral artery disease. Previous research has uncovered beta-adrenergic receptor inhibitory control (BARIC) of inflammation is blunted in PBMCs from individuals at greater risk for CVD. Chronic HIV disease fits within this paradigm given these individuals living with the virus are more likely to report discrimination and cardiometabolic disease. The current study uses an fMRI task to evaluate whether magnitude of a neural response to the experience of social exclusion is associated with the in-vitro time course of BARIC in CD16&lt;sup&gt;+&lt;/sup&gt; monocytes in relation to peripheral arterial stiffness.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;BOLD response to the exclusion versus inclusion trials of a modified Cyberball task were measured in 25 people living with HIV (PWH) (50.8 ± 10.3 yrs) and 19 people living without HIV (PWoH) (52.8 ± 11.9 yrs.). CD16&lt;sup&gt;+&lt;/sup&gt; monocytes, collected 45 min before, 45 min and 90 min after Cyberball, were isolated using magnetic bead separation (StemCell™) before 18-hr co-stimulation with lipopolysaccharide (LPS) and the non-selective beta-receptor agonist isoproterenol. BARIC was operationalized as the difference in TNF-α expressed by LPS-stimulated CD16&lt;sup&gt;+&lt;/sup&gt; monocytes without vs. with isoproterenol. A repeated measures ANCOVA assessed whether BOLD response to social exclusion in the subgenual anterior cingulate (sgACC), relates to change in BARIC of TNF-α over the experiment. The interactive effect of HIV+ status and BARIC on peripheral arterial stiffness was evaluated using multiple regression while controlling for age and gender.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;Whole-brain analysis revealed sgACC BOLD activation was significantly greater in the sgACC during exclusion compared to inclusion trials surviving FWE small-volume correction (p &lt; 0.05, FWE-SVC). Compared to the middle and highest tercile, individuals within the lowest tercile of sgACC BOLD activation showed BARIC pre-task followed by a post-task decline and recovery of BARIC at 90 min post-task (F(1,32) = 5.741, p = 0.023, η2 = 0.152). Although these neuro-immune associations were not moderated by HIV status, greater BARIC was associated with lower arterial stiffness in PWoH and higher arterial stiffness in PWH (β = -0.89, t = -2.176, p = 0.040).&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusion: &lt;/strong&gt;This study supports the role of sgACC in processing social exclusion and relevance of this biobehavioral response to the time course of beta-adrenergic receptor-mediated inhibitory control of TNF-α expression in intermediate and non-classical monocytes and further provides preliminary evidence of paradoxical association between greater BARIC of monocyte inflammation and a","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":" ","pages":"107039"},"PeriodicalIF":7.5,"publicationDate":"2026-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149104261","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sex-biased toll-like receptor 4 signaling in nociplastic pelvic pain.","authors":"Melissa E Lenert, Michel Pontari, Esmeralda Hildago-Lopez, J Quentin Clemens, Chelsea M Kaplan, Steven E Harte, Andrew Schrepf","doi":"10.1016/j.bbi.2026.107032","DOIUrl":"https://doi.org/10.1016/j.bbi.2026.107032","url":null,"abstract":"<p><p>Sex differences in neuroimmune crosstalk have been identified in preclinical research, yet sex divergent immune pathways in people with chronic pain remain poorly understood. We previously identified ex vivo whole-blood stimulation of toll-like receptor-4 (TLR4), a highly conserved innate immune receptor, as a marker of nociplastic pain in female patients with urologic pain, but whether this occurs in males is unknown. Male (n=73) and female (n=135) patients with chronic urologic pain recruited from university-based tertiary urology clinics were compared on pain, urinary symptoms, and immune response to ex vivo TLR4 stimulation. Cross-sectional analyses demonstrated that female patients with widespread or comorbid pain exhibited heightened global TLR4 responses compared to female patients with pelvic-localized pain and male patients. Conversely, male patients with comorbid pain demonstrated downregulated regulatory TLR4 responses compared to male patients with pelvic-localized pain. These findings reveal distinct immunological phenotypes between male and female chronic pain patients based on pain distribution (pelvic-localized versus widespread/comorbid). This work provides foundational evidence for sex-specific immune mechanisms, with implications for the identification and treatment of nociplastic pain.</p>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":" ","pages":"107032"},"PeriodicalIF":7.5,"publicationDate":"2026-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149073546","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Permeability of the intestinal epithelial and blood-brain barriers as therapeutic targets in inflammatory depression.","authors":"Tiffany C Ho, Gabriel A Vignolle, Danny J J Wang, Arpana Church","doi":"10.1016/j.bbi.2026.107028","DOIUrl":"https://doi.org/10.1016/j.bbi.2026.107028","url":null,"abstract":"<p><p>Inflammation has emerged as a compelling causal contributor to depression, serving both as a biological pathway underlying specific depressive symptoms (notably anhedonia, fatigue, and cognitive difficulties) and as a defining feature in a subtype of this disorder characterized by elevated levels of circulating cytokines. Understanding when and how immune dysfunction results in depression within clinical trials is needed to advance biomarker-guided clinical research and to accelerate novels treatments for those suffering from depression. In this context, gut microbes and intestinal epithelial barrier (IEB) integrity directly influence systemic cytokine levels and peripheral immune activation-these immune signals, in turn, modulate neural circuits involved in mood, reward, and stress reactivity through several pathways. Many of these signals converge on the blood-brain barrier (BBB), the permeability of which regulates the entry of peripheral cytokines and immune cells into the central nervous system and consequently shapes neuroinflammatory responses that contribute to depressive symptoms. In this narrative review, we contend that immune-gut-brain system is critical for understanding mechanisms and potential treatments for inflammatory depression. We synthesize evidence linking inflammation to IEB and BBB permeability, summarize barrier biomarkers relevant for depression, and highlight future directions of research that focus on fortifying dual barrier dysfunction as a novel intervention target for inflammatory depression. By considering the inflammatory mechanisms that shape IEB and BBB integrity, the field will be positioned to identify upstream drivers of these sources of inflammation, refine mechanistic models of transdiagnostic symptoms relevant to inflammation (anhedonia, fatigue, executive dysfunction), and develop more targeted or personalized intervention strategies for those suffering from these conditions.</p>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":" ","pages":"107028"},"PeriodicalIF":7.5,"publicationDate":"2026-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149058281","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"HCA2 activation confers neuroprotection in Parkinson’s disease models by suppressing oxidative stress and ferroptosis via the Nrf2/MGST1/GPX4 pathway","authors":"Dewei He ,&nbsp;Yao Chen ,&nbsp;Shengqi Liu ,&nbsp;Xiyu Gao ,&nbsp;Aohan Yan ,&nbsp;Miao Xue ,&nbsp;Juxiong Liu ,&nbsp;Dianfeng Liu ,&nbsp;Shoupeng Fu","doi":"10.1016/j.bbi.2026.106467","DOIUrl":"10.1016/j.bbi.2026.106467","url":null,"abstract":"<div><div>Emerging evidence implicates oxidative stress and ferroptosis as key contributors to Parkinson’s disease (PD) progression. While the niacin receptor HCA2 has been linked to antioxidant effects, its role in modulating neuronal oxidative damage and ferroptosis remains unexplored. This study focuses on the impact of HCA2 on inhibiting neuronal oxidative damage and mitigating ferroptosis. Results revealed that HCA2-deficient mice demonstrated increased vulnerability to MPTP-induced PD pathogenesis. Mechanistically, HCA2 activation inhibits oxidative stress and ferroptosis via Nrf2/MGST1/GPX4-mediated reduction of ROS and mitochondrial damage. Furthermore, in vivo results showed that activation of HCA2 in dopaminergic neurons significantly alleviated MPTP-induced neurodegeneration and motor dysfunction through upregulation of MGST1, supporting its therapeutic potential. In conclusion, this study provides robust evidence that HCA2 offers neuroprotection in PD models by concurrently suppressing oxidative stress and ferroptosis. These findings position HCA2 as a promising target for therapeutic intervention in neurodegenerative disorders.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"134 ","pages":"Article 106467"},"PeriodicalIF":7.6,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146075664","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}