Brain, Behavior, and Immunity最新文献

{"title":"Circulating Ly6Chigh monocyte-derived S100A4+ macrophages exacerbate neuroinflammation and impede recovery of traumatic brain injury","authors":"Zhichao Lu ,&nbsp;Chenxing Wang ,&nbsp;Yongqi Zhu ,&nbsp;Jingwei Zhao ,&nbsp;Yaxuan Gu ,&nbsp;Xingjia Zhu ,&nbsp;Weiquan Liao ,&nbsp;Jue Zhu ,&nbsp;Rui Jiang ,&nbsp;Suyin Feng ,&nbsp;Tianxi Chen ,&nbsp;Xudong Zhao ,&nbsp;Ziheng Wang ,&nbsp;Qianqian Liu ,&nbsp;Peipei Gong ,&nbsp;Yang Yang","doi":"10.1016/j.bbi.2026.106472","DOIUrl":"10.1016/j.bbi.2026.106472","url":null,"abstract":"<div><div>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 Ly6C^high 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.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"134 ","pages":"Article 106472"},"PeriodicalIF":7.6,"publicationDate":"2026-05-01","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}

{"title":"Atovaquone/proguanil use and zoster vaccination are associated with reduced Alzheimer’s disease risk in two cohorts: implications for a latent Toxoplasma gondii mechanism","authors":"Ariel Israel ,&nbsp;Abraham Weizman ,&nbsp;Sarah Israel ,&nbsp;Shai Ashkenazi ,&nbsp;Shlomo Vinker ,&nbsp;Eli Magen ,&nbsp;Eugene Merzon","doi":"10.1016/j.bbi.2026.106473","DOIUrl":"10.1016/j.bbi.2026.106473","url":null,"abstract":"<div><div>Alzheimer’s disease (AD) is a progressive neurodegenerative disorder with a multifactorial and incompletely understood etiology. Identifying exposures associated with reduced AD risk may help generate mechanistic hypotheses and inform future prevention strategies. To investigate such associations, we analyzed electronic health records from a national Israeli health provider, retrospectively comparing 9124 individuals with AD to 18,248 matched controls. We systematically screened prior medication purchases recorded up to 10 years before diagnosis. Significant associations, adjusted for residual confounding, were further evaluated in the TriNetX network, where large propensity score-matched cohorts were compared for incident dementia following medication exposure or vaccination.</div><div>Among all exposures assessed, strong protective associations were observed for atovaquone-proguanil, an antiprotozoal agent with established activity against <em>Toxoplasma gondii</em>, and for two different varicella-zoster virus (VZV) vaccines. These associations persisted after adjustment for demographic factors, comorbidities, and baseline healthcare utilization, and were independently reproduced in TriNetX across three strata of exposure age (50–59, 60–69, 70–79 years). In addition, <em>T. gondii</em> seropositivity was associated with increased dementia risk among individuals tested.</div><div>In exploratory analyses, the magnitude of the association between atovaquone-proguanil and subsequent dementia appeared to differ according to prior VZV vaccination status, suggesting a possible interaction between protozoal suppression and antiviral immunity. Together, these findings provide population-level evidence consistent with a latent <em>T. gondii</em>-related mechanism in AD pathogenesis, and highlight testable targets for future mechanistic and interventional research.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"134 ","pages":"Article 106473"},"PeriodicalIF":7.6,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146096682","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":"Spatiotemporal PET imaging of P2X7R-driven neuroinflammation using [18F]GSK1482160 after experimental acute spinal cord injury in mice","authors":"Jiaxing Shi ,&nbsp;Kun Wang ,&nbsp;Yuyi Hou ,&nbsp;Sirui Wu ,&nbsp;Yifan Qiu ,&nbsp;Xiang Liu ,&nbsp;Lihua Huang ,&nbsp;Shiyanjin Zhang ,&nbsp;Hongjun Jin ,&nbsp;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 [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.</div></div><div><h3>Methods</h3><div>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.</div></div><div><h3>Results</h3><div>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.</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":"2026-05-01","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}

{"title":"Maternal immune activation induces epilepsy- patent foramen ovale comorbidity in offspring","authors":"Jiaxian Zhang ,&nbsp;Yuxuan Peng ,&nbsp;Xiangyang Zhou ,&nbsp;Baichuan Li ,&nbsp;Leihao Sha ,&nbsp;Qipu Feng ,&nbsp;Lei Chen","doi":"10.1016/j.bbi.2026.106465","DOIUrl":"10.1016/j.bbi.2026.106465","url":null,"abstract":"<div><div>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 <em>in vitro</em> 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.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"134 ","pages":"Article 106465"},"PeriodicalIF":7.6,"publicationDate":"2026-05-01","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}

{"title":"miR-322-5p mediates maternal immune activation-induced schizophrenia-like behaviors via regulation of the BDNF/TrkB/AKT signaling pathway","authors":"Qiang Fu ,&nbsp;Yaobo Li ,&nbsp;Xiaodong Li ,&nbsp;Yong Cheng ,&nbsp;Yang Du ,&nbsp;Jiaquan Liang","doi":"10.1016/j.bbi.2026.106298","DOIUrl":"10.1016/j.bbi.2026.106298","url":null,"abstract":"<div><div>Maternal immune activation (MIA) is a key environmental risk factor for neurodevelopmental disorders such as schizophrenia. MicroRNAs are critical regulators of brain development, yet their role in MIA-induced pathology remains unclear. We found that miR-322-5p was significantly upregulated in the prefrontal cortex of MIA-exposed offspring and directly targeted the 3′ untranslated region of <em>brain-derived neurotrophic factor (BDNF)</em>, inhibiting its expression. This upregulation impaired <em>BDNF/TrkB/AKT</em> signaling and reduced the synaptic protein <em>PSD95</em>, leading to hypoactivity, cognitive deficits, social impairments, and disrupted sensorimotor gating. Inhibition of miR-322-5p or overexpression of <em>BDNF</em> in the prefrontal cortex restored signaling and reversed both behavioral and molecular abnormalities. These results identify miR-322-5p as a key mediator of MIA-induced neuropathology via repression of <em>BDNF</em> signaling and suggest its potential as a therapeutic target in neurodevelopmental disorders.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"134 ","pages":"Article 106298"},"PeriodicalIF":7.6,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146092168","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":"Insights into mesenchymal stem/stromal cell conditioned media as a long-lasting treatment for pain and psychiatric comorbidities in a murine model of osteoarthritis","authors":"Giada Amodeo ,&nbsp;Stefania Niada ,&nbsp;Giulia Galimberti ,&nbsp;Silvia Franchi ,&nbsp;Elena Della Morte ,&nbsp;Michela Taiana ,&nbsp;Simona Piccolo ,&nbsp;Stefania Ceruti ,&nbsp;Laura de Girolamo ,&nbsp;Anna Teresa Brini ,&nbsp;Paola Sacerdote","doi":"10.1016/j.bbi.2026.106297","DOIUrl":"10.1016/j.bbi.2026.106297","url":null,"abstract":"<div><div>Osteoarthritis (OA) is a prevalent musculoskeletal condition characterized by chronic pain and often accompanied by psychiatric comorbidities, such as anxiety and depression. The mesenchymal/stromal cell (MSC) secretome has emerged as promising therapy due to its immunomodulatory and regenerative properties. This study aimed to compare the therapeutic efficacy of standard (CM) and cytokine-primed conditioned media (CM⁺) derived from human adipose-derived MSCs in mitigating pain, mood alterations and neuroinflammation in a murine OA model. OA was induced by intra-articular injection of monoiodoacetate in male C57BL/6J mice. On day 7, mice received a single intravenous dose of CM or CM⁺ at two concentrations. Pain-related behavior was assessed by mechanical and thermal nociceptive tests. Anxiety- and depression-like behaviors were evaluated through open field, light/dark box, and forced swim tests. Pro- and anti-inflammatory cytokines and (neuro)inflammatory markers were analyzed in OA joint, and in the peripheral and central nervous system. Peripheral innervation and substance P were assessed in OA paw skin. Both CM and CM⁺ reduced painful and affective symptoms in a dose-dependent manner. However, CM (from non-primed MSCs) exhibited faster onset and longer-lasting effects, up to 17 days post-injection, compared to CM⁺.</div><div>CM also led to greater improvements in neuroinflammatory profiles, rebalancing cytokine pattern and macrophage polarization across peripheral and central tissues. MSC secretome, especially when generated without inflammatory priming, represents a safe and long-lasting therapeutic option for OA pain and associated mood disorders. These findings highlight its clinical potential as an innovative multi-targeted biological therapy.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"134 ","pages":"Article 106297"},"PeriodicalIF":7.6,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146028393","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":"Higher CSF sTREM2 is related to slower hippocampal atrophy and cognitive decline independently of pTau181 levels","authors":"Henry Gilreath Stephenson ,&nbsp;Tobey J. Betthauser ,&nbsp;Erin Jonaitis ,&nbsp;Carol Van Hulle ,&nbsp;Gwendlyn Kollmorgen ,&nbsp;Clara Quijano-Rubio ,&nbsp;Michael Ewers ,&nbsp;Jannis Denecke ,&nbsp;Tyler K. Ulland ,&nbsp;Nathaniel A. Chin ,&nbsp;Ozioma C. Okonkwo ,&nbsp;Cynthia M. Carlsson ,&nbsp;Sanjay Asthana ,&nbsp;Sterling C. Johnson ,&nbsp;Kaj Blennow ,&nbsp;Henrik Zetterberg ,&nbsp;Barbara B. Bendlin","doi":"10.1016/j.bbi.2026.106468","DOIUrl":"10.1016/j.bbi.2026.106468","url":null,"abstract":"<div><div>Heightened <em>TREM2</em>-dependent microglial activation is thought to protect against the negative effects of Alzheimer’s disease (AD) neuropathology, but data in preclinical disease and in the context of aging are lacking. This study examined the association of longitudinal hippocampal atrophy and memory composite scores with baseline soluble TREM2 (sTREM2) in the cerebrospinal fluid in two large, well-characterized samples of elderly individuals. It was hypothesized that higher sTREM2 would be associated with slower atrophy and cognitive decline and that this effect would be stronger in those with higher AD neuropathology. Linear mixed effects models predicting hippocampal volume and cognitive decline tested interactions between sTREM2 and time (years since baseline) to see whether higher sTREM2 was associated with slower atrophy and cognitive decline, controlling for pTau181 and its interaction with time. A three-way interaction between pTau181, sTREM2, and time was then added to determine whether AD pathology moderated effects of sTREM2. Results showed that higher sTREM2 was associated with slower hippocampal atrophy and cognitive decline independently of pTau181 levels. Further analysis showed that cognitive effects were moderated by pTau181 levels such that beneficial effects of sTREM2 were stronger at higher levels of pTau181, though this effect was very small, and the interaction between sTREM2 and time remained significant. These findings suggest that higher <em>TREM2</em>-dependent microglial activation, as indexed by sTREM2, may indicate subtle resilience not just to the effects of AD but to age-related neurodegeneration more broadly.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"134 ","pages":"Article 106468"},"PeriodicalIF":7.6,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146155621","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":"Dickkopf-1 release by the bone marrow upon ischemic stroke bridges neurovascular and immune deregulations","authors":"Romain Menet ,&nbsp;Maxime Bernard ,&nbsp;Sarah Lecordier ,&nbsp;Esther Trudel ,&nbsp;Anne-Sophie Allain ,&nbsp;Félix Distéfano-Gagné ,&nbsp;Josée Seigneur ,&nbsp;Natija Aldib ,&nbsp;Yacine Haili ,&nbsp;Frédéric Bretzner ,&nbsp;David Gosselin ,&nbsp;Ayman ElAli","doi":"10.1016/j.bbi.2026.106294","DOIUrl":"10.1016/j.bbi.2026.106294","url":null,"abstract":"<div><div>Neurovascular and immune alterations decisively govern definitive damage maturation after stroke. Dickkopf (DKK)1 elevated levels in the blood circulation of stroke patients correlate with poor outcomes. Herein, we report that <em>Dkk1</em> mRNA expression is not endogenously present in the healthy brain, and is barely and sparsely detectable at the lesion site in experimental ischemic stroke. Notably, we reveal a progressive increased protein expression of peripheral DKK1 in the subacute phase. Using genetic tools and bone marrow replacement approaches to mediate conditional DKK1 tissue-specific induction in conjunction with imaging, molecular, transcriptomic and functional studies, we demonstrate that DKK1 high levels at stroke onset accelerate subacute injury progression via deregulation of neurovascular functions. DKK1 prolonged post-stroke elevated levels mediate a chronic neuroinflammation associated with anxiety-like behaviors. DKK1 restricted induction in the bone marrow is sufficient to accelerate the subacute damage progression. DKK1 modulates the subacute peripheral immune response, suggesting that its <em>de novo</em> bone marrow expression represents a novel mechanism to regulate hematopoiesis in response to stroke. Neutralization of DKK1’s biological activity improves stroke outcomes. Our results indicate that DKK1 bone marrow release is a major determinant of definitive damage maturation after stroke and that its neutralization constitutes a promising disease-modifying therapeutic avenue.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"134 ","pages":"Article 106294"},"PeriodicalIF":7.6,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146017357","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":"BMP7 alleviates trigeminal neuralgia by suppressing oxidative stress and activation of satellite glial cells via the NRF2/HO-1 pathway","authors":"Meiqin Li ,&nbsp;Gaopeng Guan ,&nbsp;Xin Li ,&nbsp;Dingquan Zou ,&nbsp;Wei Zhang ,&nbsp;Kai Chen ,&nbsp;Yanying Xiao ,&nbsp;Yaping Wang ,&nbsp;Meng Wang","doi":"10.1016/j.bbi.2026.106277","DOIUrl":"10.1016/j.bbi.2026.106277","url":null,"abstract":"<div><h3>Background</h3><div>The trigeminal ganglion (TG) is a central hub for craniofacial injurious messaging, and its abnormal function is closely related to the pathogenesis of trigeminal neuralgia (TN). Bone morphogenetic protein 7 (BMP7), a pleiotropic cytokine with both neuroprotective and anti-inflammatory effects, has been shown to have therapeutic potential for neuropathic pain (NP) and neurodegenerative diseases. However, it remains to be elucidated whether BMP7 is involved in the pathological process of TN through the regulation of TG.</div></div><div><h3>Objective</h3><div>This study aimed to investigate whether BMP7 alleviates TN by modulating oxidative stress and activation in satellite glial cells (SGCs) of the TG.</div></div><div><h3>Methods</h3><div>A rat model of TN was established by chronic constriction injury of the distal infraorbital nerve (CCI-dION). Primary rat SGCs were activated with IL-1β to create an <em>in vitro</em> model. The role of BMP7 in regulating oxidative stress was assessed through <em>in vivo</em> knockdown and <em>in vitro</em> overexpression experiments. The NRF2 inhibitor ML385 was employed to validate the essential role of the NRF2/HO-1 pathway in BMP7-mediated SGC functional modulation.</div></div><div><h3>Results</h3><div>Following successful CCI-dION model establishment, TN rats showed significantly reduced mechanical pain thresholds, aggravated cold allodynia, and increased spontaneous pain behaviors, accompanied by decreased BMP7 expression, enhanced SGC activation, and elevated ROS levels in TG. These pathological phenotypes were consistently reproduced in BMP7-knockdown rats. In IL-1β-stimulated SGCs, BMP7 silencing mimicked pathological changes, while BMP7 overexpression reversed IL-1β effects − a rescue blocked by ML385. Critically, <em>in vivo</em> BMP7 overexpression attenuated CCI-dION-induced pain, oxidative stress, and SGC activation.</div></div><div><h3>Conclusion</h3><div>This study demonstrates that BMP7 alleviates TN by suppressing oxidative stress and activation of SGCs through activation of the NRF2/HO-1 pathway, highlighting its therapeutic potential for TN treatment.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"134 ","pages":"Article 106277"},"PeriodicalIF":7.6,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145984470","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":"Inhibition of the NFATc2/FKBP5 axis alleviates microglial neuroinflammation by regulating arachidonic acid metabolism in Parkinson’s disease","authors":"Yao Si ,&nbsp;Xue Zhao ,&nbsp;Lei Wu ,&nbsp;Xueying Li ,&nbsp;Pusheng Quan ,&nbsp;Shi Yan ,&nbsp;Xinyu Zhang ,&nbsp;Lige Han ,&nbsp;Lifen Yao ,&nbsp;Fan Yang","doi":"10.1016/j.bbi.2026.106296","DOIUrl":"10.1016/j.bbi.2026.106296","url":null,"abstract":"<div><div>Microglia-induced neuroinflammation is among the core pathological hallmarks of Parkinson’s disease (PD). FKBP5, which has been implicated in stress-related disorders, is recognized as a key regulator of inflammatory responses. However, the role and mechanism of FKBP5 in PD remain unclear. In the present study, we revealed that reducing FKBP5 levels via shRNA targeting microglia or pharmacological inhibition with SAFit2 could mitigate motor impairment and dopamine neuronal loss,<!--> <!-->as well as reduce<!--> <!-->arachidonic acid (AA) and proinflammatory factors (IL-6, TNF-α, and iNOS) levels in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice. Conversely, FKBP5 knockdown in 1-methyl-4-phenylpyridinium (MPP⁺)-treated BV2 microglia reduced inflammatory marker expression and targeted the inhibition of AA synthesis. Moreover, we revealed that NFATc2, a transcription factor of FKBP5, was significantly involved in AA generation and proinflammatory cytokine expression both <em>in vivo</em> and <em>in vitro</em>. In the MPP⁺-treated microglia, FKBP5 upregulation reversed the inhibition of AA signaling pathways induced by NFATc2 silencing. Furthermore, PD patients presented elevated mRNA expression of NFATc2 and FKBP5 in the peripheral blood, which were positively correlated with disease severity and serum AA levels, respectively. These findings highlight the involvement of the NFATc2/FKBP5 signaling pathway in AA-induced microglial neuroinflammation, indicating that NFATc2/FKBP5 may serve as PD biomarkers and targets for therapeutic interventions.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"134 ","pages":"Article 106296"},"PeriodicalIF":7.6,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145996196","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}