Pub Date : 2026-01-27DOI: 10.1016/j.bbi.2026.106467
Dewei He , Yao Chen , Shengqi Liu , Xiyu Gao , Aohan Yan , Miao Xue , Juxiong Liu , Dianfeng Liu , Shoupeng Fu
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.
{"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 , Yao Chen , Shengqi Liu , Xiyu Gao , Aohan Yan , Miao Xue , Juxiong Liu , Dianfeng Liu , 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":"2026-01-27","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}
Clinical evidence suggests that patent foramen ovale (PFO) is a common comorbidity in patients with epilepsy, but shared etiology remains unclear. Maternal immune activation (MIA) is a known risk factor for neurodevelopmental disorders in offspring, including epilepsy. However, its impact on cardiac development remains largely unexplored. Here, we employed a poly(I:C)-induced severe MIA rat model and found a single MIA insult concurrently increases seizure susceptibility and PFO prevalence in offspring. Integrated transcriptomic analyses revealed convergent upregulation and functional enrichment of the Hippo signaling pathway in both the brain tissues of MIA offspring and in atrial septa from PFO rats. Critically, as the terminal effector of the Hippo pathway, Yap1 was downregulated in nucleus of endothelial cells from human epileptic brain samples by snRNA-seq analysis. We demonstrated the role of Yap1 in the pathogenesis of PFO formation using both in vivo and in vitro models. The inhibition of Yap1 on neonatal pups and HUVECs causes impaired endothelial-to-mesenchymal transition (EndMT), recapitulating the cellular defect hypothesized to underlie PFO. Collectively, these findings suggest MIA as a common etiological factor for epilepsy and PFO, implicating Hippo pathway activation and the functional repression of Yap1 as a pivotal shared mechanism that concurrently disrupts neurodevelopment and cardiac development, ultimately leading to this comorbidity.
{"title":"Maternal immune activation induces epilepsy- patent foramen ovale comorbidity in offspring.","authors":"Jiaxian Zhang, Yuxuan Peng, Xiangyang Zhou, Baichuan Li, Leihao Sha, Qipu Feng, Lei Chen","doi":"10.1016/j.bbi.2026.106465","DOIUrl":"10.1016/j.bbi.2026.106465","url":null,"abstract":"<p><p>Clinical evidence suggests that patent foramen ovale (PFO) is a common comorbidity in patients with epilepsy, but shared etiology remains unclear. Maternal immune activation (MIA) is a known risk factor for neurodevelopmental disorders in offspring, including epilepsy. However, its impact on cardiac development remains largely unexplored. Here, we employed a poly(I:C)-induced severe MIA rat model and found a single MIA insult concurrently increases seizure susceptibility and PFO prevalence in offspring. Integrated transcriptomic analyses revealed convergent upregulation and functional enrichment of the Hippo signaling pathway in both the brain tissues of MIA offspring and in atrial septa from PFO rats. Critically, as the terminal effector of the Hippo pathway, Yap1 was downregulated in nucleus of endothelial cells from human epileptic brain samples by snRNA-seq analysis. We demonstrated the role of Yap1 in the pathogenesis of PFO formation using both in vivo and in vitro models. The inhibition of Yap1 on neonatal pups and HUVECs causes impaired endothelial-to-mesenchymal transition (EndMT), recapitulating the cellular defect hypothesized to underlie PFO. Collectively, these findings suggest MIA as a common etiological factor for epilepsy and PFO, implicating Hippo pathway activation and the functional repression of Yap1 as a pivotal shared mechanism that concurrently disrupts neurodevelopment and cardiac development, ultimately leading to this comorbidity.</p>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":" ","pages":"106465"},"PeriodicalIF":7.6,"publicationDate":"2026-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146084212","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}
Traumatic brain injury (TBI) is now recognized as a systemic disease, yet the molecular and cellular mechanisms involved in the systemic immune response to TBI remain unclear. To address these limitations, we collected the brains and peripheral blood mononuclear cells (PBMCs) from the acute phase of TBI mice and performed single-cell RNA sequencing (scRNA-seq). Here, we identify a population of S100A4+ macrophages originating from circulating Ly6Chigh monocytes that infiltrate brain tissue following TBI via the CCL4-CCR1 axis, thereby exacerbating brain injury. Further mechanistic studies suggest that enhanced SPP1 output from S100A4+ macrophages following TBI triggers a microglial response via the CD44 receptor and exacerbates neuroinflammation. IRF7, as a key transcription factor (TF), drives the activation of S100A4+ macrophages following TBI, leading to the corresponding neuroinflammation and neurological deficits. An FDA-approved clinical drug, ursodeoxycholic acid, acts as an IRF7 antagonist to block the activation of S100A4+ macrophages, thereby suppressing neuroinflammation and accelerating the recovery of neurological function in TBI mice.
{"title":"Circulating Ly6C<sup>high</sup> monocyte-derived S100A4<sup>+</sup> macrophages exacerbate neuroinflammation and impede recovery of traumatic brain injury.","authors":"Zhichao Lu, Chenxing Wang, Yongqi Zhu, Jingwei Zhao, Yaxuan Gu, Xingjia Zhu, Weiquan Liao, Jue Zhu, Rui Jiang, Suyin Feng, Tianxi Chen, Xudong Zhao, Ziheng Wang, Qianqian Liu, Peipei Gong, Yang Yang","doi":"10.1016/j.bbi.2026.106472","DOIUrl":"https://doi.org/10.1016/j.bbi.2026.106472","url":null,"abstract":"<p><p>Traumatic brain injury (TBI) is now recognized as a systemic disease, yet the molecular and cellular mechanisms involved in the systemic immune response to TBI remain unclear. To address these limitations, we collected the brains and peripheral blood mononuclear cells (PBMCs) from the acute phase of TBI mice and performed single-cell RNA sequencing (scRNA-seq). Here, we identify a population of S100A4<sup>+</sup> macrophages originating from circulating Ly6C<sup>high</sup> monocytes that infiltrate brain tissue following TBI via the CCL4-CCR1 axis, thereby exacerbating brain injury. Further mechanistic studies suggest that enhanced SPP1 output from S100A4<sup>+</sup> macrophages following TBI triggers a microglial response via the CD44 receptor and exacerbates neuroinflammation. IRF7, as a key transcription factor (TF), drives the activation of S100A4<sup>+</sup> macrophages following TBI, leading to the corresponding neuroinflammation and neurological deficits. An FDA-approved clinical drug, ursodeoxycholic acid, acts as an IRF7 antagonist to block the activation of S100A4<sup>+</sup> macrophages, thereby suppressing neuroinflammation and accelerating the recovery of neurological function in TBI mice.</p>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"134 ","pages":"106472"},"PeriodicalIF":7.6,"publicationDate":"2026-01-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146141329","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}
Pub Date : 2026-01-26DOI: 10.1016/j.bbi.2026.106463
Dina Medina-Vera , Alba García-Baos , Mireia Medrano , Laura Martín-Chaves , Jorge Rodríguez-Capitán , Fernando Rodríguez de Fonseca , Antonia Serrano , Manuel Jiménez-Navarro , Olga Valverde , Francisco Javier Pavón-Morón
Fetal alcohol spectrum disorder is associated with lasting neurodevelopmental and cardiovascular dysfunctions. The fractalkine axis CX3CL1/CX3CR1, a chemokine and its sole known receptor expressed in microglia and myeloid/endothelial cells, coordinates neuroimmune and vascular responses. We tested whether prenatal-lactational alcohol exposure (PLAE) is associated with sex-specific dysregulation of this axis along with integrated behavioral, neuroendocrine, inflammatory, and cardiovascular signatures.
Pregnant C57BL/6 dams consumed 20% ethanol using a drinking-in-the-dark (DID) paradigm throughout gestation and lactation. Adult offspring (PND60–70) underwent behavioral testing (elevated plus maze and tail suspension test); plasma profiling of corticosterone, cytokines/chemokines, endothelial/coagulation markers, and matrix-remodeling enzymes; and cardiac transcriptional assays for stress- and inflammation-related genes (including Cx3cr1). Analyses were stratified by sex.
PLAE females exhibited increased anxiety-like behavior, two-fold higher plasma CX3CL1, and upregulated cardiac Cx3cr1 compared with control females. PLAE males showed no behavioral or endocrine changes but evidence of matrix remodeling (elevated proMMP-9, reduced sP-Selectin). Across sexes, PLAE was associated with a proinflammatory/endothelial-activation profile (elevated IL13, IL18, and PAI-1, reduced CXCL16, higher proMMP-9) and altered cardiac expression of Nr3c2, Tnfrsf1a, Tlr4, and Nfkbia, compatible with early vascular risk. Independent of exposure, females exhibited reduced immobility and higher corticosterone, IL5, IL13, sE-Selectin, and thrombomodulin. Plasma CX3CL1 correlated inversely with exploratory and stress-coping behaviors, and positively with corticosterone, inflammatory/vascular markers, and cardiac Cx3cr1 and Tnfrsf1a.
PLAE is associated with sex-specific dysregulation of the CX3CL1/CX3CR1 axis and convergent neuroimmune-vascular signatures indicative of subclinical endothelial dysfunction. These associative findings support the hypothesis that fractalkine-pathway modulation may mitigate long-term neurobehavioral and cardiovascular vulnerability after PLAE, warranting causal testing.
{"title":"Prenatal-lactational alcohol exposure induces sex-specific CX3CL1/CX3CR1 dysregulation linked to neuroendocrine imbalance and cardiovascular risk","authors":"Dina Medina-Vera , Alba García-Baos , Mireia Medrano , Laura Martín-Chaves , Jorge Rodríguez-Capitán , Fernando Rodríguez de Fonseca , Antonia Serrano , Manuel Jiménez-Navarro , Olga Valverde , Francisco Javier Pavón-Morón","doi":"10.1016/j.bbi.2026.106463","DOIUrl":"10.1016/j.bbi.2026.106463","url":null,"abstract":"<div><div>Fetal alcohol spectrum disorder is associated with lasting neurodevelopmental and cardiovascular dysfunctions. The fractalkine axis CX<sub>3</sub>CL1/CX<sub>3</sub>CR1, a chemokine and its sole known receptor expressed in microglia and myeloid/endothelial cells, coordinates neuroimmune and vascular responses. We tested whether prenatal-lactational alcohol exposure (PLAE) is associated with sex-specific dysregulation of this axis along with integrated behavioral, neuroendocrine, inflammatory, and cardiovascular signatures.</div><div>Pregnant C57BL/6 dams consumed 20% ethanol using a drinking-in-the-dark (DID) paradigm throughout gestation and lactation. Adult offspring (PND60–70) underwent behavioral testing (elevated plus maze and tail suspension test); plasma profiling of corticosterone, cytokines/chemokines, endothelial/coagulation markers, and matrix-remodeling enzymes; and cardiac transcriptional assays for stress- and inflammation-related genes (including <em>Cx3cr1</em>). Analyses were stratified by sex.</div><div>PLAE females exhibited increased anxiety-like behavior, two-fold higher plasma CX<sub>3</sub>CL1, and upregulated cardiac <em>Cx3cr1</em> compared with control females. PLAE males showed no behavioral or endocrine changes but evidence of matrix remodeling (elevated proMMP-9, reduced sP-Selectin). Across sexes, PLAE was associated with a proinflammatory/endothelial-activation profile (elevated IL13, IL18, and PAI-1, reduced CXCL16, higher proMMP-9) and altered cardiac expression of <em>Nr3c2</em>, <em>Tnfrsf1a</em>, <em>Tlr4</em>, and <em>Nfkbia</em>, compatible with early vascular risk. Independent of exposure, females exhibited reduced immobility and higher corticosterone, IL5, IL13, sE-Selectin, and thrombomodulin. Plasma CX<sub>3</sub>CL1 correlated inversely with exploratory and stress-coping behaviors, and positively with corticosterone, inflammatory/vascular markers, and cardiac <em>Cx3cr1</em> and <em>Tnfrsf1a</em>.</div><div>PLAE is associated with sex-specific dysregulation of the CX<sub>3</sub>CL1/CX<sub>3</sub>CR1 axis and convergent neuroimmune-vascular signatures indicative of subclinical endothelial dysfunction. These associative findings support the hypothesis that fractalkine-pathway modulation may mitigate long-term neurobehavioral and cardiovascular vulnerability after PLAE, warranting causal testing.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"134 ","pages":"Article 106463"},"PeriodicalIF":7.6,"publicationDate":"2026-01-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146075710","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}
Pub Date : 2026-01-26DOI: 10.1016/j.bbi.2026.106474
Olivia C. Campbell, John R. Lukens
{"title":"Wolf in sheep’s clothing: leveraging sheep to study how maternal immune activation contributes to neurodevelopmental disorders","authors":"Olivia C. Campbell, John R. Lukens","doi":"10.1016/j.bbi.2026.106474","DOIUrl":"10.1016/j.bbi.2026.106474","url":null,"abstract":"","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"134 ","pages":"Article 106474"},"PeriodicalIF":7.6,"publicationDate":"2026-01-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146075711","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}
Pub Date : 2026-01-26DOI: 10.1016/j.bbi.2026.106471
Yeqing Zheng , Cheng Qian , Shan Wu , Bin Li , Lin Zhang , Wenjun Cheng
Depression is highly prevalent among patients with ovarian cancer, but its impact on tumor progression and the underlying mechanisms remain unclear. This study aimed to investigate the relationship between depression and ovarian cancer progression, and evaluate the potential therapeutic value of antidepressant drugs. Clinical data analysis of patients with ovarian cancer revealed a significantly elevated risk of depression in this population. Animal experiments using chronic restraint stress (CRS) and chronic unpredictable mild stress (CUMS) models have confirmed that depression-related chronic stress induces depressive-like behaviors in mice and is associated with significant enhancement of ovarian cancer growth and metastasis. Mechanistically, single-cell RNA sequencing and metabolomics demonstrated that chronic stress downregulated interferon regulatory factor 1 (IRF1) expression in tumor cells. IRF1 suppression inhibited the immune effector cells infiltration, such as macrophages, while inducing abnormal lipid metabolism and glutathione pathway dysfunction. Notably, combining antidepressant drugs with platinum-based chemotherapy reversed these pathological changes. This combination therapy upregulated IRF1 expression, restored CCR2+ macrophage infiltration, and delayed ovarian cancer progression in mice. Clinical validation further confirmed that high IRF1 expression was correlated with prolonged overall survival (OS) in patients with ovarian cancer. These findings suggest that depression may be associated with ovarian cancer progression by remodeling the immune-metabolic microenvironment. This study highlights antidepressant therapy combined with anti-tumor treatment as a potential strategy for ovarian cancer patients with comorbid depression.
{"title":"Depression-related chronic stress promotes ovarian cancer progression via metabolic dysfunction and IRF1-mediated immune suppression","authors":"Yeqing Zheng , Cheng Qian , Shan Wu , Bin Li , Lin Zhang , Wenjun Cheng","doi":"10.1016/j.bbi.2026.106471","DOIUrl":"10.1016/j.bbi.2026.106471","url":null,"abstract":"<div><div>Depression is highly prevalent among patients with ovarian cancer, but its impact on tumor progression and the underlying mechanisms remain unclear. This study aimed to investigate the relationship between depression and ovarian cancer progression, and evaluate the potential therapeutic value of antidepressant drugs. Clinical data analysis of patients with ovarian cancer revealed a significantly elevated risk of depression in this population. Animal experiments using chronic restraint stress (CRS) and chronic unpredictable mild stress (CUMS) models have confirmed that depression-related chronic stress induces depressive-like behaviors in mice and is associated with significant enhancement of ovarian cancer growth and metastasis. Mechanistically, single-cell RNA sequencing and metabolomics demonstrated that chronic stress downregulated interferon regulatory factor 1 (<em>IRF1</em>) expression in tumor cells. <em>IRF1</em> suppression inhibited the immune effector cells infiltration, such as macrophages, while inducing abnormal lipid metabolism and glutathione pathway dysfunction. Notably, combining antidepressant drugs with platinum-based chemotherapy reversed these pathological changes. This combination therapy upregulated <em>IRF1</em> expression, restored <em>CCR2<sup>+</sup></em> macrophage infiltration, and delayed ovarian cancer progression in mice. Clinical validation further confirmed that high <em>IRF1</em> expression was correlated with prolonged overall survival (OS) in patients with ovarian cancer. These findings suggest that depression may be associated with ovarian cancer progression by remodeling the immune-metabolic microenvironment. This study highlights antidepressant therapy combined with anti-tumor treatment as a potential strategy for ovarian cancer patients with comorbid depression.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"134 ","pages":"Article 106471"},"PeriodicalIF":7.6,"publicationDate":"2026-01-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146075665","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}
Pub Date : 2026-01-26DOI: 10.1016/j.bbi.2026.106469
Shuqing Zhu , Ying Zhou , Ziyuan Ye , Meng Sun , Gang Shu , Songbo Wang , Qingyan Jiang , Lina Wang
Toll-like receptor 4 (TLR4) is a pattern recognition receptor involved in innate immune responses; it is widely expressed on microglia in the central nervous system and is involved in inflammatory responses. However, recent studies have shown that TLR4 is expressed on various types of neurons and participates in emotion regulation. CRH neurons and OXT neurons, two key neurons in the paraventricular nucleus (PVN) that regulate anxiety, have been widely studied. Here, we revealed that TLR4 is involved in anxiety regulation in the PVN and that knocking out PVN-TLR4 significantly increased anxiety-like behaviors in male and female mice. Furthermore, PVNCRH-TLR4 KO significantly increased anxiety-like behavior and induced obesity in mice, whereas PVNOXT-TLR4 KO had no significant effect on anxiety or obesity. We found that the absence of TLR4 significantly reduces the activity of CRH neurons and that the downstream nuclear projection of PVN-CRH neurons to the medial supramammillary nucleus (SuMM) is key to regulating anxiety. Activating the CRH projection SuMM circuit can significantly reverse anxiety-like behaviors in mice. Our research suggests that TLR4 deficiency in CRH neurons in the paraventricular nucleus, rather than in OXT neurons, is responsible for inducing anxiety and obesity, whereas inhibition of the CRH projection SuMM circuit is key to generating anxiety.
{"title":"Loss of TLR4 on CRH neurons instead of OXT neurons in PVN induces anxiety-like behavior and obesity in mice","authors":"Shuqing Zhu , Ying Zhou , Ziyuan Ye , Meng Sun , Gang Shu , Songbo Wang , Qingyan Jiang , Lina Wang","doi":"10.1016/j.bbi.2026.106469","DOIUrl":"10.1016/j.bbi.2026.106469","url":null,"abstract":"<div><div>Toll-like receptor 4 (TLR4) is a pattern recognition receptor involved in innate immune responses; it is widely expressed on microglia in the central nervous system and is involved in inflammatory responses. However, recent studies have shown that TLR4 is expressed on various types of neurons and participates in emotion regulation. CRH neurons and OXT neurons, two key neurons in the paraventricular nucleus (PVN) that regulate anxiety, have been widely studied. Here, we revealed that TLR4 is involved in anxiety regulation in the PVN and that knocking out PVN-TLR4 significantly increased anxiety-like behaviors in male and female mice. Furthermore, PVN<sup>CRH-TLR4 KO</sup> significantly increased anxiety-like behavior and induced obesity in mice, whereas PVN<sup>OXT-TLR4 KO</sup> had no significant effect on anxiety or obesity. We found that the absence of TLR4 significantly reduces the activity of CRH neurons and that the downstream nuclear projection of PVN-CRH neurons to the medial supramammillary nucleus (SuMM) is key to regulating anxiety. Activating the CRH projection SuMM circuit can significantly reverse anxiety-like behaviors in mice. Our research suggests that TLR4 deficiency in CRH neurons in the paraventricular nucleus, rather than in OXT neurons, is responsible for inducing anxiety and obesity, whereas inhibition of the CRH projection SuMM circuit is key to generating anxiety.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"134 ","pages":"Article 106469"},"PeriodicalIF":7.6,"publicationDate":"2026-01-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146075712","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}
Pub Date : 2026-01-26DOI: 10.1016/j.bbi.2026.106466
Kaipeng Xie
Background
Postpartum depression (PPD) has multiple cascading negative effects on maternal and infant health. Inflammation is a potential factor for the development of PPD. However, lymphocyte-based inflammatory biomarkers, including platelet-to-lymphocyte ratio (PLR), neutrophil-lymphocyte ratio (NLR) and monocyte-lymphocyte ratio (MLR), and PPD remains understudied, especially in U.S. women.
Methods
We conducted a cross-sectional study based on the National Health and Nutrition Examination Survey (NHANES) from 2007 to 2020 pre-pandemic data. Based on demographics and reproductive questionnaires, two strategies were employed to include eligible postpartum women. PPD symptoms were assessed using the PHQ-9 questionnaire. Weighted logistic regression models, restricted cubic spline (RCS) models, eXtreme Gradient Boosting (XGBoost) machine learning (ML) model, subgroup analysis and sensitivity analyses were performed to analyze the relationships between these biomarkers and PPD symptoms.
Results
A total of 1,361 postpartum women within the 3-year postpartum period based on strategy 1, and 762 women ranges from one to twenty-eight months postpartum based on strategy 2 were included in analyses. After adjusted for all covariates, PLR during the postpartum period was significantly associated with the reduced risk of PPD symptoms based on both strategies (OR = 0.49, 95% CI: 0.26–0.94, P = 0.033; OR = 0.30, 95% CI: 0.15–0.60, P < 0.001). There was a non-linear relationship between PLR and the risk of PPD symptoms (P-non-linear = 0.011, P-non-linear = 0.001). ML revealed PLR as one important variable for PPD symptoms. Interestingly, postpartum time modified the association between PLR and PPD symptoms (P for interaction = 0.026). The association was significant in women within 12 months postpartum (OR = 0.23, 95% CI: 0.11–0.49, P < 0.001) but not in women with beyond 12 months postpartum. Sensitivity analyses validated the robustness of our findings.
Conclusions
PLR during the postpartum period is an independent risk factor for PPD symptoms in U.S. women, exhibiting its potential as a novel marker for PPD symptoms.
产后抑郁症（PPD）对母婴健康有多重连锁负面影响。炎症是PPD发展的潜在因素。然而，基于淋巴细胞的炎症生物标志物，包括血小板-淋巴细胞比率（PLR）、中性粒细胞-淋巴细胞比率（NLR）和单核细胞-淋巴细胞比率（MLR），以及PPD的研究仍然不足，特别是在美国女性中。方法基于2007年至2020年全国健康与营养检查调查（NHANES）大流行前数据进行横断面研究。基于人口统计和生殖问卷，采用两种策略纳入符合条件的产后妇女。使用PHQ-9问卷评估PPD症状。采用加权logistic回归模型、受限三次样条（RCS）模型、极限梯度增强（XGBoost）机器学习（ML）模型、亚组分析和敏感性分析来分析这些生物标志物与PPD症状之间的关系。结果采用策略1的产后3年内共纳入1361例产后妇女，采用策略2的产后1 ~ 28个月共纳入762例。在对所有协变量进行调整后，产后PLR与两种策略下PPD症状风险的降低显著相关（OR = 0.49, 95% CI: 0.26-0.94, P = 0.033; OR = 0.30, 95% CI: 0.15-0.60, P < 0.001）。PLR与PPD症状风险呈非线性关系（p -非线性= 0.011，p -非线性= 0.001）。ML显示PLR是PPD症状的一个重要变量。有趣的是，产后时间改变了PLR与PPD症状之间的关系（相互作用P = 0.026）。这种关联在产后12个月内的妇女中显著（OR = 0.23, 95% CI: 0.11-0.49, P < 0.001），但在产后12个月以上的妇女中不显著。敏感性分析验证了我们研究结果的稳健性。结论产后splr是美国女性PPD症状的独立危险因素，有可能成为PPD症状的新标志物。
{"title":"Lymphocyte-based inflammatory biomarkers during the postpartum period and postpartum depression symptoms in U.S. women","authors":"Kaipeng Xie","doi":"10.1016/j.bbi.2026.106466","DOIUrl":"10.1016/j.bbi.2026.106466","url":null,"abstract":"<div><h3>Background</h3><div>Postpartum depression (PPD) has multiple cascading negative effects on maternal and infant health. Inflammation is a potential factor for the development of PPD. However, lymphocyte-based inflammatory biomarkers, including platelet-to-lymphocyte ratio (PLR), neutrophil-lymphocyte ratio (NLR) and monocyte-lymphocyte ratio (MLR), and PPD remains understudied, especially in U.S. women.</div></div><div><h3>Methods</h3><div>We conducted a cross-sectional study based on the National Health and Nutrition Examination Survey (NHANES) from 2007 to 2020 pre-pandemic data. Based on demographics and reproductive questionnaires, two strategies were employed to include eligible postpartum women. PPD symptoms were assessed using the PHQ-9 questionnaire. Weighted logistic regression models, restricted cubic spline (RCS) models, eXtreme Gradient Boosting (XGBoost) machine learning (ML) model, subgroup analysis and sensitivity analyses were performed to analyze the relationships between these biomarkers and PPD symptoms.</div></div><div><h3>Results</h3><div>A total of 1,361 postpartum women within the 3-year postpartum period based on strategy 1, and 762 women ranges from one to twenty-eight months postpartum based on strategy 2 were included in analyses. After adjusted for all covariates, PLR during the postpartum period was significantly associated with the reduced risk of PPD symptoms based on both strategies (OR = 0.49, 95% CI: 0.26–0.94, <em>P</em> = 0.033; OR = 0.30, 95% CI: 0.15–0.60, <em>P</em> < 0.001). There was a non-linear relationship between PLR and the risk of PPD symptoms (<em>P</em>-non-linear = 0.011, <em>P</em>-non-linear = 0.001). ML revealed PLR as one important variable for PPD symptoms. Interestingly, postpartum time modified the association between PLR and PPD symptoms (<em>P</em> for interaction = 0.026). The association was significant in women within 12 months postpartum (OR = 0.23, 95% CI: 0.11–0.49, <em>P</em> < 0.001) but not in women with beyond 12 months postpartum. Sensitivity analyses validated the robustness of our findings.</div></div><div><h3>Conclusions</h3><div>PLR during the postpartum period is an independent risk factor for PPD symptoms in U.S. women, exhibiting its potential as a novel marker for PPD symptoms.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"134 ","pages":"Article 106466"},"PeriodicalIF":7.6,"publicationDate":"2026-01-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146075713","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}
Pub Date : 2026-01-22DOI: 10.1016/j.bbi.2026.106279
Jiaxing Shi , Kun Wang , Yuyi Hou , Sirui Wu , Yifan Qiu , Xiang Liu , Lihua Huang , Shiyanjin Zhang , Hongjun Jin , Hai Lu
Background
The severe inflammatory cascade after spinal cord injury (SCI) is a major driver of secondary injury. Precise monitoring and effective intervention in neuroinflammation are critical for functional recovery. After SCI, microglia accumulate at the lesion site and the P2X7 receptor (P2X7R) on their surface becomes markedly hyperactivated. However, the spatiotemporal activation profile and role of P2X7R in SCI remain unclear. In this study, with [18F]FDG as a reference tracer, we evaluated the feasibility of the P2X7R-specific PET tracer [18F]GSK1482160 for dynamic tracking the spatiotemporal progression of neuroinflammation after SCI.
Methods
An acute mouse model of SCI was established. PET/CT imaging with [18F]GSK1482160 and, for comparison, [18F]FDG was performed in SCI (n = 60) and control (n = 48) mice. Basso Mouse Scale (BMS) scoring, histological staining, and Western blotting (WB) were conducted at 1, 3, 7, 14, and 28 days post injury (dpi). To evaluate therapeutic potential, a selective P2X7R antagonist was administered to SCI mice and efficacy was assessed.
Results
At 1 dpi, [18F]GSK1482160 uptake in SCI mice was lower than in time-matched controls (0.54 ± 0.10 vs. 1.00 ± 0.10). Uptake then increased significantly from 3 dpi (1.14 ± 0.13 vs. 0.96 ± 0.14) to 28 dpi (3.16 ± 0.20 vs. 1.00 ± 0.13) and was significantly associated with BMS scores. In contrast, [18F]FDG uptake remained consistently high throughout the observation period and showed no correlation with BMS scores. Treatment with a P2X7R antagonist significantly reduced [18F]GSK1482160 uptake at 7 dpi compared with the time-matched vehicle-treated SCI group (1.51 ± 0.17 vs. 1.94 ± 0.21) and improved BMS scores. Histological findings and WB results were consistent with the imaging results. Unless otherwise stated, n = 6 per group at each time point and data are presented as mean ± standard deviation.
Conclusions
P2X7R-targeted PET/CT molecular imaging enables monitoring of the spatiotemporal evolution of neuroinflammation after SCI. These findings support the therapeutic potential of P2X7R-targeted interventions and underscore the importance of P2X7R in advancing SCI management and individualized precision therapy.
背景：脊髓损伤后严重的炎症级联反应是继发性损伤的主要驱动因素。神经炎症的精确监测和有效干预对功能恢复至关重要。脊髓损伤后，小胶质细胞在损伤部位聚集，其表面的P2X7受体（P2X7R）明显亢进。然而，P2X7R在脊髓损伤中的时空激活特征和作用尚不清楚。在本研究中，我们以[18F]FDG作为参考示踪剂，评估了p2x7r特异性PET示踪剂[18F]GSK1482160动态跟踪脊髓损伤后神经炎症时空进展的可行性。方法：建立急性脊髓损伤小鼠模型。用[18F]GSK1482160和[18F]FDG对SCI （n = 60）和对照组（n = 48）小鼠进行PET/CT成像，以进行比较。分别于伤后1、3、7、14和28 d （dpi）进行Basso小鼠评分（BMS）、组织学染色和Western blotting （WB）。为了评估治疗潜力，我们给脊髓损伤小鼠注射了一种选择性P2X7R拮抗剂，并评估了其疗效。结果：在1 dpi时，[18F]脊髓损伤小鼠的GSK1482160摄取低于时间匹配的对照组（0.54 ± 0.10 vs. 1.00 ± 0.10）。摄取从3 dpi（1.14 ± 0.13 vs. 0.96 ± 0.14）显著增加到28 dpi(3.16 ± 0.20 vs. 1.00 ± 0.13)，并与BMS评分显著相关。相反，[18F]FDG摄取量在整个观察期内始终保持较高，与BMS评分没有相关性。与时间匹配的药物治疗组相比，P2X7R拮抗剂治疗显著降低[18F]GSK1482160在7 dpi时的摄取（1.51 ± 0.17 vs. 1.94 ± 0.21）并改善BMS评分。组织学和WB结果与影像学结果一致。除另有说明外，每个时间点每组n = 6，数据以平均值 ± 标准差表示。结论：p2x7r靶向PET/CT分子成像可以监测脊髓损伤后神经炎症的时空演变。这些发现支持了P2X7R靶向干预的治疗潜力，并强调了P2X7R在推进SCI管理和个性化精确治疗中的重要性。
{"title":"Spatiotemporal PET imaging of P2X7R-driven neuroinflammation using [18F]GSK1482160 after experimental acute spinal cord injury in mice","authors":"Jiaxing Shi , Kun Wang , Yuyi Hou , Sirui Wu , Yifan Qiu , Xiang Liu , Lihua Huang , Shiyanjin Zhang , Hongjun Jin , Hai Lu","doi":"10.1016/j.bbi.2026.106279","DOIUrl":"10.1016/j.bbi.2026.106279","url":null,"abstract":"<div><h3>Background</h3><div>The severe inflammatory cascade after spinal cord injury (SCI) is a major driver of secondary injury. Precise monitoring and effective intervention in neuroinflammation are critical for functional recovery. After SCI, microglia accumulate at the lesion site and the P2X7 receptor (P2X7R) on their surface becomes markedly hyperactivated. However, the spatiotemporal activation profile and role of P2X7R in SCI remain unclear. In this study, with [<sup>18</sup>F]FDG as a reference tracer, we evaluated the feasibility of the P2X7R-specific PET tracer [<sup>18</sup>F]GSK1482160 for dynamic tracking the spatiotemporal progression of neuroinflammation after SCI.</div></div><div><h3>Methods</h3><div>An acute mouse model of SCI was established. PET/CT imaging with [<sup>18</sup>F]GSK1482160 and, for comparison, [<sup>18</sup>F]FDG was performed in SCI (n = 60) and control (n = 48) mice. Basso Mouse Scale (BMS) scoring, histological staining, and Western blotting (WB) were conducted at 1, 3, 7, 14, and 28 days post injury (dpi). To evaluate therapeutic potential, a selective P2X7R antagonist was administered to SCI mice and efficacy was assessed.</div></div><div><h3>Results</h3><div>At 1 dpi, [<sup>18</sup>F]GSK1482160 uptake in SCI mice was lower than in time-matched controls (0.54 ± 0.10 vs. 1.00 ± 0.10). Uptake then increased significantly from 3 dpi (1.14 ± 0.13 vs. 0.96 ± 0.14) to 28 dpi (3.16 ± 0.20 vs. 1.00 ± 0.13) and was significantly associated with BMS scores. In contrast, [<sup>18</sup>F]FDG uptake remained consistently high throughout the observation period and showed no correlation with BMS scores. Treatment with a P2X7R antagonist significantly reduced [<sup>18</sup>F]GSK1482160 uptake at 7 dpi compared with the time-matched vehicle-treated SCI group (1.51 ± 0.17 vs. 1.94 ± 0.21) and improved BMS scores. Histological findings and WB results were consistent with the imaging results. Unless otherwise stated, n = 6 per group at each time point and data are presented as mean ± standard deviation.</div></div><div><h3>Conclusions</h3><div>P2X7R-targeted PET/CT molecular imaging enables monitoring of the spatiotemporal evolution of neuroinflammation after SCI. These findings support the therapeutic potential of P2X7R-targeted interventions and underscore the importance of P2X7R in advancing SCI management and individualized precision therapy.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"134 ","pages":"Article 106279"},"PeriodicalIF":7.6,"publicationDate":"2026-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146043867","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}
Pub Date : 2026-01-22DOI: 10.1016/j.bbi.2026.106295
Guangshen Li , Yang Luo , Tianyu Zhu , Chunmao Chen , Zhanyang Qian , Haijun Li
Secondary spinal cord injury (SCI) involves neuroinflammatory mechanisms such as microglial pyroptosis, which aggravates neural impairment via NLRP3 inflammasome activation. Although liraglutide (Lr) is commonly used for managing blood glucose, it also exhibits anti-inflammatory effects. Previous studies from our group have shown that glucagon-like peptide-1 receptor (GLP-1R) activation in microglia attenuates neuroinflammation and promotes functional recovery after SCI, the precise mechanism linking GLP-1R to the inhibition of pyroptosis remained unclear. Here, we report that high-dose Lr (independent of its metabolic effects) significantly improves functional and histological outcomes in a murine SCI model, and these benefits are abolished in GLP-1R−/− mice. In vitro, RNA sequencing, combined with pharmacological and genetic approaches, revealed that Lr, via the PI3K/Akt/transcription factor EB (TFEB) axis, by upregulates Fanconi anemia complementation group C (FANCC) to suppress pyroptosis. Crucially, FANCC knockdown both elevated p38 phosphorylation and blocked the anti-pyroptotic effect of Lr, thereby establishing FANCC as an essential downstream mediator. This signaling cascade culminates in the inhibition of p38-dependent NLRP3 inflammasome activation. Collectively, our work defines a novel GLP-1R/PI3K/Akt/TFEB/FANCC/p38 pathway through which Lr alleviates secondary SCI, identifying FANCC as a pivotal neuroprotective node and supporting the translational potential of GLP-1R modulation in SCI.
{"title":"Activation of GLP-1R ameliorates microglial pyroptosis after spinal cord injury by restoring FANCC expression","authors":"Guangshen Li , Yang Luo , Tianyu Zhu , Chunmao Chen , Zhanyang Qian , Haijun Li","doi":"10.1016/j.bbi.2026.106295","DOIUrl":"10.1016/j.bbi.2026.106295","url":null,"abstract":"<div><div>Secondary spinal cord injury (SCI) involves neuroinflammatory mechanisms such as microglial pyroptosis, which aggravates neural impairment via NLRP3 inflammasome activation. Although liraglutide (Lr) is commonly used for managing blood glucose, it also exhibits anti-inflammatory effects. Previous studies from our group have shown that glucagon-like peptide-1 receptor (GLP-1R) activation in microglia attenuates neuroinflammation and promotes functional recovery after SCI, the precise mechanism linking GLP-1R to the inhibition of pyroptosis remained unclear. Here, we report that high-dose Lr (independent of its metabolic effects) significantly improves functional and histological outcomes in a murine SCI model, and these benefits are abolished in GLP-1R<sup>−/−</sup> mice. In vitro, RNA sequencing, combined with pharmacological and genetic approaches, revealed that Lr, via the PI3K/Akt/transcription factor EB (TFEB) axis, by upregulates Fanconi anemia complementation group C (FANCC) to suppress pyroptosis. Crucially, FANCC knockdown both elevated p38 phosphorylation and blocked the anti-pyroptotic effect of Lr, thereby establishing FANCC as an essential downstream mediator. This signaling cascade culminates in the inhibition of p38-dependent NLRP3 inflammasome activation. Collectively, our work defines a novel GLP-1R/PI3K/Akt/TFEB/FANCC/p38 pathway through which Lr alleviates secondary SCI, identifying FANCC as a pivotal neuroprotective node and supporting the translational potential of GLP-1R modulation in SCI.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"134 ","pages":"Article 106295"},"PeriodicalIF":7.6,"publicationDate":"2026-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146043882","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}
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