Journal of Neuroinflammation最新文献

{"title":"Neuroglial P2Y₁ receptor signalling differentially contributes to inflammatory neurodegeneration.","authors":"Charlotte Schubert, Ricardo Lopes Fonseca, Alexandros Hadjilaou, Vanessa Vieira, Karoline Degenhardt, Anna Lena Seemann, Alice Hakimy, Jana K Sonner, Peter Ludewig, Tim Magnus, Marion Schneider, Christa E Müller, Daniela Hirnet, Manuel A Friese","doi":"10.1186/s12974-026-03904-1","DOIUrl":"10.1186/s12974-026-03904-1","url":null,"abstract":"<p><p>Extracellular adenosine triphosphate (ATP) and diphosphate (ADP) act as key signalling molecules in the central nervous system (CNS) and regulate neuroinflammatory responses through purinergic receptors. Although astrocytes and neurons undergo profound changes in signalling and metabolism during inflammation, the contribution of specific purinergic pathways to inflammation-induced neurodegeneration remains unclear. Here we show that the ADP/ATP-activated Gq-coupled receptor P2Y₁ drives astrocyte-mediated neurotoxicity in experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis (MS). Using plasma membrane-targeted luciferase reporter mice, we demonstrate that extracellular ATP levels are increased during acute EAE. This was accompanied by elevated astrocytic P2ry1 expression, which is also observed in inflammatory MS lesions. In vivo, pharmacological inhibition or astrocyte-specific deletion of P2Y₁ reduced disease severity, astrocytosis, and neuronal loss, whereas neuron-specific deletion exerted only modest effects. Mechanistically, astrocytic P2Y₁ signalling promoted cytokine-induced ERK activation, inflammatory gene expression, and metabolic reprogramming in vitro. In contrast to supernatants from stimulated P2Y₁-deficient astrocyte culture, supernatants derived from stimulated P2Y₁-proficient astrocytes reduced neuronal viability, demonstrating neurotoxic effects mediated by astrocyte-derived factors. In contrast, neuronal P2Y₁ signalling primarily contributed to oxidative stress and mitochondrial dysfunction. Together, these findings identify astrocytic P2Y₁ as a key regulator of neuroinflammatory damage and a potential therapeutic target.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":"23 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2026-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13263940/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148251845","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":"TREM2 restrains myeloid inflammasome activation to protect against photoreceptor degeneration.","authors":"Tianxi Wang, Liyun Su, Manon Szczepan, Xingyan Wang, Austin T Gregg, Jessica Guo, Lois E H Smith, Ye Sun","doi":"10.1186/s12974-026-03903-2","DOIUrl":"10.1186/s12974-026-03903-2","url":null,"abstract":"<p><p>Myeloid cells, including infiltrating macrophages and resident microglia, are critical regulators of retinal homeostasis and respond rapidly to photoreceptor stress. Dysregulated myeloid responses, however, can exacerbate retinal degeneration. Triggering receptor expressed on myeloid cells 2 (TREM2) modulates phagocytosis, metabolism, and inflammatory signaling, yet its role in retinal degeneration remains incompletely understood. Here, we investigated TREM2 function in the retinal degeneration 10 (rd10) mouse model of inherited retinal degeneration, characterized by progressive photoreceptor loss and robust myeloid cell activation. TREM2 expression was upregulated in degenerating retinas, and global TREM2-deficiency in rd10 mice exhibited accelerated photoreceptor cell death, reduced outer nuclear layer thickness, disrupted retinal pigment epithelium integrity, and altered microglial spatial dynamics. Single-cell transcriptomics revealed that TREM2-positive microglia express APOE-associated and interferon-primed programs. Global TREM2 deficiency was associated with increased inflammasome-related signaling in retinal myeloid cells, including elevated cleaved caspase-1, cleaved gasdermin D, and mature interleukin-1β, linking amplified immune priming to pyroptotic signaling. Genetic or pharmacological inhibition of gasdermin D significantly mitigated photoreceptor loss in global TREM2-deficient rd10 retinas, demonstrating a functional contribution of inflammasome-associated responses to disease exacerbation. Together, these findings support a protective role for TREM2-associated immune regulation in the degenerating retina and identify downstream inflammasome pathways as potential therapeutic targets in retinal degenerative diseases.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":" ","pages":""},"PeriodicalIF":11.5,"publicationDate":"2026-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13556085/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148251851","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 active role of pulmonary immunity in ischaemic stroke.","authors":"Junyi Wu, Yikun Gao, Yilin Li, Jiayan Gu, Xiaoting Li, Jin Wang, Xiaoxing Xiong, Lijuan Gu","doi":"10.1186/s12974-026-03907-y","DOIUrl":"10.1186/s12974-026-03907-y","url":null,"abstract":"<p><p>Previous stroke studies have mostly regarded the lungs as passively damaged target organs, and in clinical practice in the context of stroke, the role of the lungs has been habitually limited to secondary complications such as stroke-associated pneumonia or neurogenic pulmonary oedema. However, recent studies have indicated that the lung plays a more active and central role in the pathophysiology of stroke. In this review, we propose and systematically elaborate on an emerging concept: the lung, as one of the largest immune organs in the body, functions as an active initiator and amplifier of systemic inflammation and neuroinflammation following stroke. Stroke \"remotely primes\" the unique immune reservoir of the lung (such as marginated pool neutrophils and resident macrophages) via neural and humoral pathways, leading to the rapid activation and release of these cells into the circulation. Activated pulmonary immune cells not only possess an enhanced capacity for brain homing but also produce large amounts of proinflammatory mediators, establishing a self-amplifying inflammatory cycle that significantly worsens neurological outcomes. Furthermore, we explore how advanced age and metabolic comorbidities, such as diabetes, pathologically remodel the pulmonary immune baseline, thereby increasing susceptibility to this self-amplifying cascade. By highlighting the current translational gap between preclinical models and human clinical cohorts, we propose that elevating the lung from a therapeutic bystander to a core intervention target provides a novel \"brain-lung coprotection\" strategy, which may offer a new perspective for optimizing the comprehensive clinical management of ischaemic stroke.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":" ","pages":""},"PeriodicalIF":11.5,"publicationDate":"2026-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13492031/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148226144","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":"C1q-CD44 interactions regulate microglial phagocytosis, proliferation, and migration.","authors":"Pooja S Sakthivel, Alyssa J Villegas, Anita Lakatos, Meghana Kaipa, Julian M Lopez, Ashley Ling, Zeina H Elrachid, Josh Karam, Aileen J Anderson","doi":"10.1186/s12974-026-03892-2","DOIUrl":"10.1186/s12974-026-03892-2","url":null,"abstract":"<p><p>Microglia, the immune cells of the central nervous system (CNS), quickly respond to neurodegeneration by proliferating and migrating to areas of disease, phagocytosing debris, and releasing cytokines to initiate inflammation. Critically, the mechanisms underlying these microglial functions remain only partly understood. One molecular regulator of interest is complement protein C1q, the initiator molecule of the complement cascade that increases 300-fold in healthy aging and accumulates with neurodegeneration. We have previously reported that exogenous C1q treatment alters inflammatory gene expression and cell function in human induced pluripotent stem cell-derived microglia (iMG). Here, we test the hypothesis that C1q induced cell changes are modulated by novel C1q receptor, CD44. We first confirmed expression of five novel C1q receptors at the RNA and protein levels, and then validated C1q-receptor binding on the iMG cell surface using proximity ligation assay. Based on these results, we selected CD44 as an initial target and generated CD44 knockout iMG to test the role of CD44 in the iMG response to C1q. We demonstrate that C1q-CD44 interactions regulate changes in microglial phagocytosis, proliferation, and migration. These data suggest C1q interacts with CD44 to modulate microglial functions that are critical to health and disease, thus informing future directions to test whether these interactions are altered in neurodegenerative disease.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":" ","pages":""},"PeriodicalIF":11.5,"publicationDate":"2026-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13483542/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148239503","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":"Circadian gatekeepers of the gut-brain-immune axis: implications for neuroinflammation and neurodegeneration.","authors":"Wai-Yin Cheng, Po-Lam Chan, Man-Ka Chan, Jiaying Xu, Ka-Hing Wong, Raymond Chuen-Chung Chang","doi":"10.1186/s12974-026-03899-9","DOIUrl":"10.1186/s12974-026-03899-9","url":null,"abstract":"<p><p>Circadian rhythms, primarily regulated by light-dark cycles, play a crucial role in maintaining physiological health, including metabolism and immune responses. Evidence shows that circadian rhythms are involved in modulating gut microbiota composition, peripheral and central immune systems, and neurodegenerative disease progression. Recent research has illuminated the complex interplay between circadian rhythms and the gut microbiota-immune-brain axis. This review examines the bidirectional relationship between circadian rhythms and gut microbiota, and explores how this interaction influences brain function through the gut-brain axis, with particular focus on neuroinflammation and neurodegeneration. We aim to provide novel insights that could inform therapeutic strategies to prevent or slow down the progression of neurodegenerative diseases through circadian rhythm modulation.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":" ","pages":""},"PeriodicalIF":11.5,"publicationDate":"2026-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13491710/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148239590","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":"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}