Journal of Neuroinflammation最新文献

{"title":"Ischemic injury triggers a protective microglial phenotype in models of Aβ pathology.","authors":"Michael Candlish, Jan Hofmann, Desirée Brösamle, Annika Haessler, Murphy DeMeglio, Angelos Skodras, Georgi Tushev, Eloah S De Biasi, Stefan Günther, René Wiegandt, Heidi Theis, Elena De Domenico, Nina Sofia Hermann, Peter Breunig, Christina Sauerland, K Peter R Nilsson, Marc D Beyer, Mario Looso, Maike Windbergs, Sigrun Roeber, Jochen Herms, Jonas J Neher, Andreas G Chiocchetti, Jasmin K Hefendehl","doi":"10.1186/s12974-026-03897-x","DOIUrl":"10.1186/s12974-026-03897-x","url":null,"abstract":"<p><p>Microglia are highly plastic cells that are capable of integrating subsequent insults. As the majority of Alzheimer's Disease (AD) patients also show cerebrovascular pathology, we here aimed to dissect the interactions between AD and ischemic brain injury on the microglial response to amyloid beta (Aβ) pathology. Unexpectedly, ischemic stroke in the context of cerebral β-amyloidosis drives the emergence of a neuroprotective microglial phenotype characterized by an ApoE-enriched transcriptional state and enhanced lipid handling. These microglia promote the rapid formation of highly compact Aβ plaques that are relatively inert and strikingly reminiscent of those observed in cognitively resilient AD patients. Our findings thus reveal that the microglial response to Aβ pathology is not a fixed trajectory toward dysfunction, but retains a capacity for beneficial reprogramming when engaged by the appropriate stimulus. Beyond characterizing this comorbid state, our data identify specific molecular pathways, centered on ApoE, complement activation, and lysosomal processing, that may be amenable to therapeutic targeting to promote protective microglial function in AD.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":" ","pages":""},"PeriodicalIF":11.5,"publicationDate":"2026-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13292430/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148211633","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The role of persistent inflammation in failed recovery after perinatal brain injury: is resolution the cure?","authors":"Hawley Helmbrecht, Maryam Ardalan, Lynne Kelly, Shenandoah Robinson, Bobbi Fleiss, Derek G Doherty, Pierre Gressens, Carina Mallard, Eleanor J Molloy, Lauren L Jantzie","doi":"10.1186/s12974-026-03900-5","DOIUrl":"10.1186/s12974-026-03900-5","url":null,"abstract":"<p><p>Perinatal brain injury (PBI) is a major predictor of neurological disability. Commonly associated with prematurity, infection, stroke, hypoxia-ischemia, hemorrhage, and/or toxin exposure, PBI triggers acute and persistent systemic inflammation. There are many stages of vulnerability to PBI during development including pregnancy, birth - term and preterm, and neonatal age. The vulnerable stages can compound inflammation through injury to the placental-fetal-brain axis, adaptive and innate immune system development, neural-immune communication, and central nervous system maturation. Neonates exhibit unique inflammatory signatures and lasting neural-immune responses to various etiologies. Chronic immune dysregulation and priming to a secondary, later-in-life immune challenge defines different forms of PBI while shaping the neonatal and adult immune response with long-term changes. Immunomodulated changes impact regulatory, helper and innate T cells, neutrophils, natural killer cells and immune responsiveness. The major routes of persistent and compounding inflammation in PBI are perinatal neural-immune interactions, cytokine influx, and glial crosstalk. Most treatments are not administered long enough or in the optimal time window to combat sustained inflammation in tertiary and quaternary phases of PBI pathophysiology and are ineffective in reducing neonatal mortality and morbidity and promoting functional recovery. Indeed, persistent systemic and central inflammation is a likely explanation for failed recovery of PBI after the resolution of acute insults. We propose attenuating persistent inflammation and normalizing systemic immune reactivity as key to reducing the functional impact of PBI throughout the lifespan through various avenues including therapeutic treatment, gut microbiome modulation, and novel immunomodulation from preclinical research.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":" ","pages":""},"PeriodicalIF":11.5,"publicationDate":"2026-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13483626/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148194746","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Microglial galectin-3 disrupts parvalbumin interneurons and hippocampal synchrony, driving cognitive deficits.","authors":"Min Jia, Hua Shao, Si-Qi Ma, Wen-Xue Liu, Meng Cai, Tong Zhu, Shan Xu, Gui-Zhou Li, Shuai-Fei Lu, Jin-Chun Shen, Jiang Chen, Yun Stone Shi, Kenji Hashimoto, Guang-Fen Zhang, Mu-Huo Ji, Jian-Jun Yang","doi":"10.1186/s12974-026-03889-x","DOIUrl":"10.1186/s12974-026-03889-x","url":null,"abstract":"<p><p>Sepsis-associated encephalopathy (SAE), a devastating neurological complication of systemic inflammation, affects approximately 70% of patients with sepsis. It not only increases mortality but also leaves survivors with persistent cognitive deficits. However, the mechanisms underlying SAE progression remain incompletely understood. Here, using a lipopolysaccharide (LPS)-induced mouse model of SAE, we identify microglial galectin-3 (Gal-3) as a central pathogenic mediator driving systemic inflammation-induced cognitive impairment. Mechanistically, systemic LPS challenge robustly upregulates microglial Gal-3, which in turn activates Toll-like receptor 2 (TLR2) signaling and promotes NLRP3/AIM2 inflammasome assembly. This microglia-driven inflammatory cascade substantially exacerbates local oxidative stress, leading to selective structural and functional impairment of hippocampal parvalbumin (PV) interneurons. Dysfunction of these critical interneurons disrupts theta/gamma oscillations, impairs excitatory/inhibitory (E/I) balance and synaptic plasticity, and ultimately results in severe cognitive decline. Supporting this pathogenic cascade, pharmacological inhibition of Gal-3 with TD139 effectively suppresses TLR2/inflammasome activation, attenuates oxidative stress, and prevents memory deficits. Conversely, targeted rAAV-mediated overexpression of Gal-3 in microglia is sufficient to recapitulate neuroinflammation, PV-interneuron injury, oscillatory abnormalities, and cognitive impairment. Finally, chemogenetic reactivation of hippocampal PV interneurons using DREADDs restores theta/gamma oscillations and ameliorates LPS-induced cognitive deficits. Together, our findings define a coherent pathogenic axis linking microglial Gal-3 upregulation to PV interneuron-dependent network desynchronization and highlight Gal-3 as a promising therapeutic target for inflammation-associated cognitive disorders.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":" ","pages":""},"PeriodicalIF":11.5,"publicationDate":"2026-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13483578/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148175932","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Single-cell analysis of skin and blood reveals systemic immune responses to ultraviolet B and their impairment in MS.","authors":"Simon Falk, Julia Krämer, Sonja Leson, Davide Pilo, Marie Deffner, Patrick Ostkamp, I-Na Lu, Tilman Schneider-Hohendorf, Andreas Schulte-Mecklenbeck, Christian Wünsch, Catharina C Gross, Kerstin Steinbrink, Antje Bischof, Catharina Korsukewitz, Gerd Meyer Zu Hörste, Luisa Klotz, Carsten Weishaupt, Heinz Wiendl, Nicholas Schwab","doi":"10.1186/s12974-026-03887-z","DOIUrl":"10.1186/s12974-026-03887-z","url":null,"abstract":"<p><p>Sunlight is a fundamental immune-modulating factor with implications for the pathogenesis of autoimmune diseases such as multiple sclerosis (MS). MS incidence and severity increase with latitude, historically attributed to diminished ultraviolet (UV) exposure and lower serum vitamin D (VitD) levels. While high-level VitD supplementation yields moderate clinical benefit in early MS, the broader immunomodulatory potential of UV radiation remains poorly understood. To further investigate this effect on the immune transcriptome, we conducted a clinical trial (NCT05627609) in which healthy donors (HD) and MS patients were irradiated with narrowband UVB, followed by single-cell transcriptomic analysis of immune cells from the skin, blood, and cerebrospinal fluid (CSF). We revealed profound UV effects not only in the skin but also in peripheral blood and, preliminarily, in CSF. These included immune-modulating and migratory signatures across multiple cell populations, focusing on UVB triggered re-circulating myeloid- and CD8⁺ T cells, revealing a blunted translation from skin to blood in MS. Patients showed an exaggerated cutaneous immune activation with elevated stress-responsive genes (NR4A1, JUN, HSPA1B), while HD showed stronger induction of homeostatic and regulatory genes (EEF1A1, TPT1, TMSB4X) in blood. This uncovers a dysfunctional axis of immunoregulation in MS and reveals the immuno-landscape underlying the latitude-associated MS risk.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":" ","pages":""},"PeriodicalIF":11.5,"publicationDate":"2026-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13288836/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148156907","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Neuronal toll-like receptor-4 regulation of matrix metalloproteinase-9 activity mediates dentate circuit dysfunction after traumatic brain injury.","authors":"Deepak Subramanian, Erick M Contreras, Laura Dovek, Razieh Jaberi, Emmanuel Green, Ysabelle K Lao, Iryna M Ethell, Vijayalakshmi Santhakumar","doi":"10.1186/s12974-026-03890-4","DOIUrl":"10.1186/s12974-026-03890-4","url":null,"abstract":"<p><p>Neuroinflammatory pathways activated by traumatic brain injury (TBI) are critical mediators of long-term neurological dysfunction and represent promising therapeutic targets. Toll-like receptor 4 (TLR4), an innate immune receptor, was previously shown to contribute to increased seizure susceptibility and cognitive deficits in rats after lateral fluid percussion injury (FPI). However, the cellular and molecular mechanisms underlying TLR4-mediated circuit dysfunction early after brain injury are not fully understood. In this study, we define a cell- and circuit- specific neuroimmune-enzyme effector signaling axis that mediates early post-TBI circuit dysfunction in the hippocampal Dentate Gyrus (DG). Using ex vivo electrophysiology in rat and mouse models one week after brain injury, we demonstrate that neuronal TLR4 signaling regulates both excitatory and inhibitory synaptic inputs to dentate granule cells (DGC). Collectively, pharmacological inhibition of TLR4 in rats and cell-type-specific deletion of TLR4 in mice show that neuronal TLR4 mediates injury-driven increase in DGC excitatory input frequency and relies on downstream activation of Matrix Metalloproteinase-9 (MMP-9). In contrast, TLR4 signaling contributed to a decrease in inhibitory current frequency after injury, but independent of MMP-9, revealing a mechanistic divergence. Systemic inhibition of either TLR4 signaling or MMP-9 activity in rats within 24 h after injury reduced network hyperexcitability and improved long-term potentiation (LTP) in the DG measured in vivo one week after injury. Either TLR4 or MMP-9 inhibition early after injury effectively attenuated spatial memory deficits in a Barnes maze task one month post-injury. Paradoxically, in sham controls, inhibition of TLR4 increased the frequency of both excitatory and inhibitory inputs to DGCs and augmented network excitability, without altering MMP-9 levels, identifying context-dependent roles for TLR4 signaling. Together, these results identify a novel TLR4 -MMP-9 axis as a key driver of early post-TBI dentate gyrus circuit dysfunction and behavioral deficits.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":" ","pages":""},"PeriodicalIF":11.5,"publicationDate":"2026-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13474604/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148156896","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Multi-omics integration provides biological insight and prioritizes potential drug targets in multiple sclerosis progression.","authors":"Yuan Jiang, Jinyu Xiao, Ingrid Kockum, Pernilla Stridh, Qianwen Liu, Tomas Olsson, Lars Alfredsson, Xia Jiang","doi":"10.1186/s12974-026-03895-z","DOIUrl":"10.1186/s12974-026-03895-z","url":null,"abstract":"<p><strong>Introduction: </strong>Current therapies for multiple sclerosis (MS) primarily reduce relapse rates and delay disability by targeting inflammation, while have limited efficacy against disease progression driven by neurodegenerative processes. We sought to identify and validate proteins for MS progression by integrating a large genome-wide association study (GWAS) of MS progression with large-scale protein quantitative trait loci data from blood and brain.</p><p><strong>Methods: </strong>We conducted proteome-wide association studies (PWAS) to nominate proteins; applied summary-data Mendelian randomization and colocalization to evaluate association; and performed functional annotation (pathway enrichment, drug-target mapping, and protein-protein interaction networks) to prioritize therapeutic potential. Additionally, we performed external validation through bulk and cell-type-specific expression analyses and prioritized protein evaluation. The final key proteins were determined by triangulating evidence across all these streams.</p><p><strong>Results: </strong>We identified 48 genetically prioritized proteins. Functional annotation prioritized 14 with therapeutic potential and highlighted 13 non-MS drugs for repurposing. Triangulation of evidence with multi-omics external validation highlighted six key proteins: RRM2B (a Cladribine target), CBR1, and ETFA, which are linked to existing drugs; DNM3 (a GWAS-implicated locus), CAB39L, and NMRAL1, which emerged as validated novel proteins providing biological insight into MS progression.</p><p><strong>Conclusion: </strong>Our multi-omics integration prioritizes proteins implicated in MS progression, providing mechanistic insights into neurodegeneration and a foundation for future therapeutic exploration in progressive MS.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":" ","pages":""},"PeriodicalIF":11.5,"publicationDate":"2026-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13261964/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148150214","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"GPNMB modulates neutrophil extracellular trap formation: therapeutic implications for ischemic stroke.","authors":"Ningning Zong, Jian Chen, Yang Geng, Lixuan Yang, Shengnan Xia, Haiyan Yang, Xinyu Bao, Yun Xu","doi":"10.1186/s12974-026-03894-0","DOIUrl":"10.1186/s12974-026-03894-0","url":null,"abstract":"<p><p>Microglia are key immune-competent cells responding immediately to manipulate post-stroke neuroinflammation to shape the prognosis of stroke. GPNMB was reported to be upregulated after ischemic stroke and might influence the outcome. However, its detailed biological function and mechanism remain elusive. Here, we found that GPNMB was remarkably elevated in the ischemic brain and mainly distributed in microglia. Combining GPNMB knockout mice and recombinant GPNMB protein, we found that GPNMB could alleviate ischemic brain injury. Recombinant GPNMB (rGPNMB) administration could reduce neutrophil extracellular traps (NETs) formation, while knockout of GPNMB promoted NET formation in ischemic stroke. In addition, we found that CD44 functioned importantly in mediating the role of GPNMB inhibiting NET formation and alleviating ischemic brain injury. Depletion of neutrophils or inhibition of NET formation with DNase I could reduce the neuroprotective impact of GPNMB. Mechanistically, GPNMB might inhibit NET formation partly via modulating the Rac-ROS pathway after binding to the CD44 receptor. Finally, our data indicated that delayed rGPNMB administration retained neuroprotective impact in ischemic stroke. Our study revealed the importance of GPNMB in modulating NET formation and suggested a potential target for manipulating post-stroke neutrophil-associated neuroinflammation.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":" ","pages":""},"PeriodicalIF":11.5,"publicationDate":"2026-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13483522/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148150243","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"TGR5 is essential for protecting from chronic stress-induced learning and memory impairments in mice by modulating inflammation associated with the gut-brain axis.","authors":"Shuai Zhang, Xiaoyang Liu, Hao Xu, Wenqian Zhang, Chenchen Shi, Meimei Wang, Guangmin Zhang, Xin Cheng, Xuanpan Ding, Haoyang Tan, Yuan Zhao, Honggang Fan, Guiyan Yang","doi":"10.1186/s12974-026-03898-w","DOIUrl":"10.1186/s12974-026-03898-w","url":null,"abstract":"<p><strong>Background: </strong>CS impairs brain function, causing long-term changes in neural systems linked to anxiety, depression, and cognition. TGR5 is a key receptor crucial for modulating various physiological processes, impacting metabolic homeostasis and inflammation. However, the role of TGR5 in regulating CS-induced learning and memory impairments along the gut-brain axis remains incompletely understood.</p><p><strong>Methods: </strong>WT and TGR5 KO male C57BL/6J mice underwent 21-day chronic restraint stress to model stress-induced memory deficit. Stress severity and cognitive function were evaluated by behavioral tests. Hippocampal and intestinal integrity were assessed by H&E, Nissl, AB-PAS staining, and TEM ultrastructural analysis. CORT and 5-HT levels were quantified by ELISA. BAs and gut microbiota were profiled by UPLC-MS/MS and 16S rRNA sequencing. Hippocampal and colonic transcriptomes were analyzed by RNA-seq. Electrophysiological LTP was recorded in hippocampal CA1. Inflammatory cytokines were detected by qPCR. Fkbp51, TGR5, and LCN2 proteins were quantified by Western blot, while TGR5 and LCN2 were localized by IHC/IF.</p><p><strong>Results: </strong>This study found that 21 days of CRS suppressed body weight gain, triggered anxiety-like behaviors, and impaired spatial learning and memory in mice. CS induced significant damage to the hippocampal CA1 region and colon, accompanied by elevated TGR5 expression in both tissues. Moreover, CS altered gut microbiota composition and BAs metabolism (most notably increasing TCDCA levels) potentially contributing to neuroinflammation along the gut-brain axis. Using TGR5 KO mice, this study demonstrated that TGR5 deficiency exacerbated CS-induced hippocampal neuroinflammation, as evidenced by increased expression of pro-inflammatory markers including IL-1β, IL-6, TNF-α, and LCN2. CS also induced decreased 5‑HT levels and severely impaired LTP, disrupting synaptic plasticity and neurotransmission, which ultimately led to learning and memory deficits. In the colon, TGR5 deficiency similarly worsened CS-induced tissue injury. These findings highlight a protective role of TGR5 in both the hippocampus and the colon.</p><p><strong>Conclusions: </strong>In summary, TGR5 is essential for protecting from CS-induced learning and memory impairments in mice by modulating inflammation associated with the gut-brain axis.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":" ","pages":""},"PeriodicalIF":11.5,"publicationDate":"2026-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13483826/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148150205","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Placental and juvenile immune responses to maternal immune activation are differentially regulated by sex chromosomes and gonads across gestation.","authors":"Stephanie Salia, Nadine T Burry, Meagan E Hinks, Kerri M Sparkes, Alison M Randell, Alexandre S Maekawa, Nicole Reid, Lucas F Fowler, Rachel Q Kelly, Jai-Lynn Francis, Madison C Youden, Stephanie H G Pelley, Susan G Walling, Ashlyn Swift-Gallant","doi":"10.1186/s12974-026-03881-5","DOIUrl":"10.1186/s12974-026-03881-5","url":null,"abstract":"<p><p>Sex differences are a defining feature of neurodevelopmental disorders (NDDs), with males diagnosed up to four times more frequently than females. Gestational maternal immune activation (MIA) is an environmental risk factor for NDDs that produces stronger behavioral alterations among male offspring. To identify the contributions of sex chromosomes (XX vs. XY) and gonadal development (ovaries vs. testes) in this sex bias, we used the Four Core Genotypes (FCG) mouse model. We assessed placental, fetal, and juvenile brain immune responses, along with juvenile behavioral outcomes, following early (E12.5) or late (E17.5) gestational exposure to Poly(I: C), eliciting a robust systemic maternal immune response. Placental immune profiling revealed distinct sex-specific strategies: XX gonadal females mounted coordinated pro- and anti-inflammatory responses, whereas XY offspring and gonadal males exhibited relative immune suppression, particularly in late gestation, coinciding with the testicular androgen surge. Conversely, fetal brain chemo-cytokine responses 24 h post-MIA were similar across XX females and XY males. However, XY offspring juvenile neuroimmune alterations were associated with increased social avoidance. Early MIA eliminated the typical social advantage of gonadal females, shifting behavior toward male-typical patterns. Together, we identify the placenta as a key site of sex-specific immune responses to MIA and demonstrate that gestational timing, sex chromosome complement, and gonadal signals interact to shape long-term neuroimmune and behavioral outcomes relevant to sex-bias in NDDs.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":" ","pages":""},"PeriodicalIF":11.5,"publicationDate":"2026-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13560310/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148150218","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Microbiota, systemic immunity, and extracellular vesicles in stroke: peripheral nodes as therapeutic leverage points.","authors":"Lilei Zhang, Jinghong Li, Fatima Aldali, Yajie Li, Xiaohua Han, Chunchu Deng","doi":"10.1186/s12974-026-03896-y","DOIUrl":"10.1186/s12974-026-03896-y","url":null,"abstract":"<p><strong>Background: </strong>Stroke is increasingly understood as a systemic disorder rather than a brain-only lesion. Beyond the initial cerebral ischemic insult, rapid autonomic and neuroendocrine stress responses destabilize peripheral organ homeostasis and promote widespread immune and metabolic remodeling. Subsequent barrier failure and peripheral immune dysregulation can generate a sustained \"second hit\" in which circulating microbial products, damage-associated signals, and inflammatory mediators feedback to amplify neuroinflammation in a blood-brain barrier-vulnerable state. Meanwhile, post-stroke immunity is temporally plastic: inflammatory programs that worsen acute injury can later support resolution and repair, indicating that outcomes depend on immune balance and timing, not simply inflammatory magnitude.</p><p><strong>Main body: </strong>Stem cell-derived extracellular vesicles (EVs) are emerging as multi-cargo biologics with consistent preclinical benefit across functional, histological, and inflammatory endpoints. However, clinical translation has progressed slowly, in part because development has largely prioritized strategies to enhance central nervous system delivery even though systemically administered vesicles typically show low exposure in brain parenchyma. Here, we propose a \"periphery-first\" therapeutic strategy that reframes this pharmacokinetic profile as an advantage. By leveraging the natural sequestration of systemically delivered vesicles by reticuloendothelial and barrier-associated organs-particularly the liver, spleen, and gut-this approach aims to reprogram peripheral immune trajectories, strengthen barrier integrity, and suppress humoral amplification loops that sustain secondary brain injury. We synthesize evidence for stroke-driven multi-organ dysfunction and phase-dependent immune remodeling and integrate mechanistic plausibility for EVs acting through complementary routes: peripheral immune and metabolic rebalancing, actions at the blood-brain barrier interface and limited but potentially meaningful effects within central nervous system immune niches. We also summarize the emerging clinical landscape of EV interventions in stroke and highlight key translational constraints, including product heterogeneity and potency-linked quality control, comorbidity-relevant modeling aligned with systemic pathology, dosing and safety limitations imposed by hepatic clearance, and the need for artifact-resistant biodistribution methods and causal necessity/sufficiency study designs to quantify route-to-efficacy.</p><p><strong>Conclusion: </strong>A periphery-first framework positions EV therapy as a systems-level intervention that targets peripheral drivers of secondary brain injury. Establishing quantitative causal mechanisms and translation-ready manufacturing and dosing principles will be essential to accelerate clinical development beyond a primarily brain-delivery paradigm.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":" ","pages":""},"PeriodicalIF":11.5,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13439792/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148143640","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}