Brain, Behavior, and Immunity最新文献

{"title":"Reduced dementia risk in middle-aged and older atopic dermatitis patients treated with dupilumab: A target trial emulation.","authors":"Yi-Hsuan Fan, Kuo-Sheng Fan, Teng-Li Lin","doi":"10.1016/j.bbi.2026.106796","DOIUrl":"10.1016/j.bbi.2026.106796","url":null,"abstract":"<p><strong>Background: </strong>Middle-aged and older adults with atopic dermatitis (AD) are at increased risk of dementia, possibly driven by chronic inflammation and involving IL-4 and IL-13 pathways. Whether treatment with dupilumab, an IL-4/IL-13 inhibitor, influences subsequent dementia risk in this population remains unclear.</p><p><strong>Methods: </strong>This target trial emulation study utilized the TriNetX database. Patients aged ≥ 50 years with AD were identified and divided into two groups: those newly prescribed dupilumab and those newly prescribed conventional systemic agents without dupilumab exposure. Propensity score matching (1:1) was performed based on age, sex, race, and comorbidities. Dementia risk was assessed using Cox regression.</p><p><strong>Results: </strong>After matching, each group included 10,039 patients (∼52% female; mean age, 63 years; 63% White). The 5-year cumulative incidence of dementia was lower among dupilumab users than controls (2.37% vs 3.33%; P = 0.001). Dupilumab use was associated with a reduced risk of all-cause dementia (HR 0.68; 95% CI, 0.54-0.86), with similar reductions observed across dementia subtypes, including secondary (HR 0.69; 95% CI, 0.48-0.99), unspecified (HR 0.70; 95% CI, 0.53-0.93), and Alzheimer's dementia (HR 0.61; 95% CI, 0.40-0.93). Subgroup and sensitivity analyses showed consistent results, with control outcome analyses supporting the robustness of the findings. In a validation analysis of middle-aged and older asthma patients, dupilumab users likewise had a lower dementia risk than omalizumab users (HR 0.68; 95% CI, 0.47-0.98).</p><p><strong>Conclusions: </strong>Dupilumab use was associated with a reduced risk of dementia in middle-aged and older adults with AD compared with conventional systemic agents.</p>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":" ","pages":"106796"},"PeriodicalIF":7.6,"publicationDate":"2026-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147833935","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}

{"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":"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":"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":"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":"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":"A novel circuit driven by hypothalamic corticotropin-releasing hormone neurons mediates postoperative memory deficits.","authors":"Xin Qing, Peng Wang, Jun Li, Xin Cheng, Beijia Gao, Zhengyu Li, Hu Liu, Zhilai Yang, Jiqian Zhang, Zhiheng Liu, Dijia Wang, Gaolin Qiu, Mervyn Maze, Xuesheng Liu","doi":"10.1016/j.bbi.2026.106791","DOIUrl":"10.1016/j.bbi.2026.106791","url":null,"abstract":"<p><p>Perioperative neurocognitive disorders (PND) contribute substantially to morbidity and mortality; however, no therapeutic target has yet been identified. We hypothesized that the neural circuit underlying this surgical complication involves corticotropin-releasing hormone (CRH) neurons in the paraventricular nucleus of the hypothalamus (PVN). Using optogenetics, chemogenetics, electrophysiology, and behavioral tests, we demonstrate that surgery activates PVN ^CRH neurons. These neurons, via CRH receptor 1 (CRHR1), innervate glutamatergic (Glu) neurons in the hippocampal subiculum (Sub), ultimately leading to memory impairments. The PVN ^CRH receive projections from Glu neurons in the parabrachial nucleus (PBN), a brain region involved in processing peripheral sensory stimuli. Postoperative memory deficit is associated with activation of the PBN ^Glu-PVN ^CRH-Sub ^Glu circuit; chemogenetic inhibition of this circuitry rescues the memory deficit. Additionally, surgery-induced upregulation of circulating interleukin-1β (IL-1β) mediates activation of the PBN ^Glu-PVN ^CRH-Sub ^Glu circuit. This provides direct evidence linking peripheral inflammation to central cognitive dysfunction via a defined neural pathway. These findings advance our understanding of brain-body interactions in neurocognitive disorders and identify an anatomical target for potential intervention in PND.</p>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":" ","pages":"106791"},"PeriodicalIF":7.6,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147810802","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":"Dietary allergen promotes sex-specific leukocyte trafficking and alters the brain immune cell populations in subclinically sensitized mice.","authors":"Dilini Vimarshani Ekanayake Ekanayake Mudiyanselage, Geetika Verma, Kumi Nagamoto-Combs","doi":"10.1016/j.bbi.2026.106793","DOIUrl":"10.1016/j.bbi.2026.106793","url":null,"abstract":"<p><p>Dietary allergens can affect mood and cognition in some sensitized individuals without eliciting immediate or severe physical reactions. However, if these \"subclinically sensitized,\" allergen-tolerant individuals continue to consume offending allergens, they may be at a greater risk of chronic peripheral inflammation that affects brain function and behavior via neuroinflammation. To elucidate potential mechanisms by which immune responses to consumed allergens are communicated to the central nervous system (CNS), we investigated the accumulation of leukocytes in the brain and the trafficking of peripheral leukocytes to the CNS in our mouse model of subclinical cow's milk allergy (CMA). Male and female C57BL/6J mice were sensitized to a bovine β-lactoglobulin (BLG, Bos d 5) or the vehicle alone and subsequently placed on an allergen-containing diet for 2 weeks. The activity and cognitive function of the mice were assessed by a series of behavioral tests, and the number and phenotypes of the leukocytes in the brain were determined by flow cytometry and immunofluorescence. The frequencies of CXCR5⁺ leukocytes were significantly elevated, specifically in BLG-sensitized male mice after allergen consumption. Immunostaining showed that the increases in CXCR5⁺ cells were most evident in the dorsomedial frontoparietal cortical regions, where CMA-associated microgliosis was observed. However, the majority of these cells were neurons, and CXCR5⁺ peripheral leukocytes primarily accumulated in the rostral-rhinal hub region of the dura mater. These results suggest that allergen consumption by subclinically sensitized individuals prompts CXCR5-mediated leukocyte chemotaxis to the dura and alters cortical neuron phenotype, presenting a potential mechanism for peripherally triggered neuroinflammation.</p>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":" ","pages":"106793"},"PeriodicalIF":7.6,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147810902","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}