J Neuroinflammation [JOURNAL]
Sun
200 papers
Circadian gatekeepers of the gut-brain-immune axis: implications for neuroinflammation and neurodegeneration.
Cheng WY, Chan PL, Chan MK … +3 more , Xu J, Wong KH, Chang RC
J Neuroinflammation · 2026 Jun · PMID 42286650 · Full text
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 modul...
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.
The active role of pulmonary immunity in ischaemic stroke.
Wu J, Gao Y, Li Y … +5 more , Gu J, Li X, Wang J, Xiong X, Gu L
J Neuroinflammation · 2026 Jun · PMID 42277885 · Full text
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 s...
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.
Ischemic injury triggers a protective microglial phenotype in models of Aβ pathology.
Candlish M, Hofmann J, Brösamle D … +21 more , Haessler A, DeMeglio M, Skodras A, Tushev G, De Biasi ES, Günther S, Wiegandt R, Theis H, De Domenico E, Hermann NS, Breunig P, Sauerland C, Nilsson KPR, Beyer MD, Looso M, Windbergs M, Roeber S, Herms J, Neher JJ, Chiocchetti AG, Hefendehl JK
J Neuroinflammation · 2026 Jun · PMID 42265753 · Full text
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 b...
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.
The role of persistent inflammation in failed recovery after perinatal brain injury: is resolution the cure?
Helmbrecht H, Ardalan M, Kelly L … +7 more , Robinson S, Fleiss B, Doherty DG, Gressens P, Mallard C, Molloy EJ, Jantzie LL
J Neuroinflammation · 2026 Jun · PMID 42251420 · Full text
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 persisten...
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.
Microglial galectin-3 disrupts parvalbumin interneurons and hippocampal synchrony, driving cognitive deficits.
Jia M, Shao H, Ma SQ … +13 more , Liu WX, Cai M, Zhu T, Xu S, Li GZ, Lu SF, Shen JC, Chen J, Shi YS, Hashimoto K, Zhang GF, Ji MH, Yang JJ
J Neuroinflammation · 2026 Jun · PMID 42249483 · Full text
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...
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.
Neuronal toll-like receptor-4 regulation of matrix metalloproteinase-9 activity mediates dentate circuit dysfunction after traumatic brain injury.
Subramanian D, Contreras EM, Dovek L … +5 more , Jaberi R, Green E, Lao YK, Ethell IM, Santhakumar V
J Neuroinflammation · 2026 Jun · PMID 42237180 · Full text
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...
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.
Single-cell analysis of skin and blood reveals systemic immune responses to ultraviolet B and their impairment in MS.
Falk S, Krämer J, Leson S … +16 more , Pilo D, Deffner M, Ostkamp P, Lu IN, Schneider-Hohendorf T, Schulte-Mecklenbeck A, Wünsch C, Gross CC, Steinbrink K, Bischof A, Korsukewitz C, Meyer Zu Hörste G, Klotz L, Weishaupt C, Wiendl H, Schwab N
J Neuroinflammation · 2026 Jun · PMID 42237169 · Full text
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...
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.
TGR5 is essential for protecting from chronic stress-induced learning and memory impairments in mice by modulating inflammation associated with the gut-brain axis.
Zhang S, Liu X, Xu H … +10 more , Zhang W, Shi C, Wang M, Zhang G, Cheng X, Ding X, Tan H, Zhao Y, Fan H, Yang G
J Neuroinflammation · 2026 Jun · PMID 42231452 · Full text
BACKGROUND: 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 me...
BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
Placental and juvenile immune responses to maternal immune activation are differentially regulated by sex chromosomes and gonads across gestation.
Salia S, Burry NT, Hinks ME … +11 more , Sparkes KM, Randell AM, Maekawa AS, Reid N, Fowler LF, Kelly RQ, Francis JL, Youden MC, Pelley SHG, Walling SG, Swift-Gallant A
J Neuroinflammation · 2026 Jun · PMID 42231396 · Full text
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 fac...
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.
GPNMB modulates neutrophil extracellular trap formation: therapeutic implications for ischemic stroke.
Zong N, Chen J, Geng Y … +5 more , Yang L, Xia S, Yang H, Bao X, Xu Y
J Neuroinflammation · 2026 Jun · PMID 42231390 · Full text
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...
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.
Multi-omics integration provides biological insight and prioritizes potential drug targets in multiple sclerosis progression.
Jiang Y, Xiao J, Kockum I … +5 more , Stridh P, Liu Q, Olsson T, Alfredsson L, Jiang X
J Neuroinflammation · 2026 Jun · PMID 42231304 · Full text
INTRODUCTION: 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 neurodegenerati...
INTRODUCTION: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.
Microbiota, systemic immunity, and extracellular vesicles in stroke: peripheral nodes as therapeutic leverage points.
Zhang L, Li J, Aldali F … +3 more , Li Y, Han X, Deng C
J Neuroinflammation · 2026 Jun · PMID 42226217 · Full text
BACKGROUND: 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 periphera...
BACKGROUND: 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. MAIN BODY: 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. CONCLUSION: 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.
Convergence of neuroinflammation across major neurotropic viral exposomes in AD and ADRD.
Harmouch J, Green R, Mayilsamy K … +3 more , Tosi K, Mohapatra S, Mohapatra SS
J Neuroinflammation · 2026 May · PMID 42215997 · Full text
BACKGROUND: Alzheimer's disease (AD) and Alzheimer's disease-related dementias (ADRD) are multifactorial neurodegenerative disorders driven by complex interactions among genetic susceptibility, aging, and environmental e...
BACKGROUND: Alzheimer's disease (AD) and Alzheimer's disease-related dementias (ADRD) are multifactorial neurodegenerative disorders driven by complex interactions among genetic susceptibility, aging, and environmental exposures. Growing epidemiological and mechanistic evidence implicates neurotropic viral exposomes, defined as cumulative lifetime viral infections, as significant contributors to AD risk. Viral encephalitis and common viral infections, including herpes simplex virus type 1 (HSV-1), human immunodeficiency virus (HIV), cytomegalovirus (CMV), SARS-CoV-2, and influenza, have been associated with an increased incidence of AD/ADRD; however, the molecular mechanisms underlying these associations remain incompletely understood. METHODS: A systematic literature review was conducted using PubMed, Web of Science, Scopus, and Google Scholar (1990-2025) to identify epidemiological, experimental, and mechanistic studies linking viral infections to AD-related pathology. Systems biology approaches were applied using Cytoscape, STRING, KEGG, WikiPathways, and Ingenuity Pathway Analysis to construct protein-protein interaction networks and identify convergent biological processes shared between AD and viral host-response pathways. Functional enrichment analyses focused on neuroinflammation, amyloid-β (Aβ) metabolism, tau pathology, autophagy, and blood-brain barrier (BBB) integrity. RESULTS: Across diverse viral infections, strong convergence was observed in innate immune activation pathways, including microglial priming and NLRP3 inflammasome signaling, accompanied by chronic production of proinflammatory cytokines (IL-1β, TNF-α, IFN-γ). Multiple viruses modulated amyloidogenic APP processing, impaired Aβ clearance, promoted tau hyperphosphorylation, disrupted autophagy-lysosomal systems, and compromised BBB integrity. Systems-level analyses revealed overlapping signaling hubs, including NF-κB, MAPK, PI3K-Akt, and cGAS-STING that amplify neurodegenerative cascades, with effects most pronounced in genetically susceptible populations such as APOE4 carriers. CONCLUSIONS: Collectively, current evidence supports a mechanistic link between viral exposomes and AD/ADRD mediated through convergent neuroinflammatory, and proteostatic pathways. Although viral infections alone are unlikely to be sufficient to cause AD, recurrent or persistent viral exposures may act as potent disease modifiers that accelerate neurodegenerative processes. Integrating viral biomarkers, genetic risk stratification, and systems biology approaches offers promising opportunities for early diagnosis, prevention, and development of mechanism-guided therapeutic strategies.
PRMT6 inhibition or deficiency attenuates diabetic neuropathic pain in male mice and is associated with reduced spinal neuroinflammation, microgliosis, and altered p53-p21 signaling.
Chu Y, Song H, Deng M … +9 more , Fang Y, Ding R, Huang K, Fan X, Peng L, Yang Y, Wei H, Han C, Yuan H
J Neuroinflammation · 2026 May · PMID 42215980 · Full text
Diabetic neuropathic pain (DNP) is a major contributor to chronic pain in adults, yet effective targeted therapies are still lacking, underscoring the need to elucidate its underlying mechanisms. Microglial proliferation...
Diabetic neuropathic pain (DNP) is a major contributor to chronic pain in adults, yet effective targeted therapies are still lacking, underscoring the need to elucidate its underlying mechanisms. Microglial proliferation and activation are key drivers of central sensitization and pain hypersensitivity. In a type 2 diabetes mouse model, protein arginine methyltransferase 6 (PRMT6) was markedly upregulated in spinal dorsal horn microglia in male mice, and high-glucose stimulation similarly increased PRMT6 expression in BV-2 cells, accompanied by enhanced proliferation and inflammatory activation. Genetic deletion of Prmt6 or pharmacological inhibition with EPZ020411 alleviated pain hypersensitivity and reduced spinal microgliosis and inflammation in male mice. Transcriptomic analysis revealed enrichment in cell proliferation-related processes and the p53 signaling pathway. In BV-2 cells, PRMT6 knockdown induced G0/G1 arrest and attenuated high-glucose-induced proliferation and inflammatory activation, whereas PRMT6 overexpression exerted opposite effects. Mechanistically, PRMT6 methylated p53 and decreased its transcriptional activity, leading to reduced p21 mRNA expression and enhanced cell-cycle progression. In contrast, in female DNP mice, spinal microgliosis was limited, PRMT6 expression remained unchanged, and Prmt6 deficiency did not significantly alter spinal microglial density, inflammatory markers, or nociceptive hypersensitivity. Collectively, our results uncover a previously unrecognized PRMT6-p53-p21 regulatory axis that may contribute to microglial proliferation and neuroinflammation under hyperglycemic conditions in male mice, highlighting PRMT6 as a potential therapeutic target for microglia-associated DNP.
Epigenetic brain reprogramming rejuvenates neuro-immune circuits to reverse Alzheimer's disease pathology and systemic bone loss.
Wan MD, Liu XX, Wan TF … +16 more , Liu YW, Jiang YL, Zou JT, Jiao B, Liu QQ, Jin L, Duan R, Wang Z, Hong CG, Wang X, Hu XY, Liao XX, Cao J, Shen L, Xie H, Wang ZX
J Neuroinflammation · 2026 May · PMID 42210397 · Full text
Alzheimer's disease (AD) is characterized by progressive neurodegeneration, neuroinflammation, and systemic comorbidities, yet disease-modifying therapies remain elusive. Here, we show that partial epigenetic reprogrammi...
Alzheimer's disease (AD) is characterized by progressive neurodegeneration, neuroinflammation, and systemic comorbidities, yet disease-modifying therapies remain elusive. Here, we show that partial epigenetic reprogramming via brain-restricted expression of Oct4, Sox2, and Klf4 (OSK) restores neuronal and neuroimmune homeostasis without loss of cellular identity. In APP/PS1 mice, OSK reprogramming improves cognitive performance across disease stages, reduces amyloid-β deposition, attenuates microglial activation, preserves synaptic integrity, and limits neuronal apoptosis. Mechanistically, reduced representation bisulfite sequencing reveals widespread reversal of AD-associated DNA methylation patterns, which is dependent on Tet2-mediated demethylation, establishing epigenetic rejuvenation as a key driver of functional recovery. Unexpectedly, brain-restricted OSK reprogramming also ameliorates systemic bone loss by reshaping brain-derived extracellular vesicle signaling, including modulation of miR-483-5p, thereby restoring osteogenic capacity. Together, these findings identify partial epigenetic reprogramming as a strategy to rewire neuro-immune circuits and link central nervous system rejuvenation to peripheral tissue homeostasis, providing a conceptual framework for targeting both neurodegeneration and its systemic consequences in AD.
Inflammatory blood-based biomarkers to aid in the assessment and prognostication of traumatic brain injury: a TRACK-TBI study.
Yue JK, Fu AY, Jain S … +39 more , Puccio AM, Eagle SR, Korley FK, van Essen TA, Samanta R, Li LM, Roberts CJ, Caldwell DJ, Elguindy MM, Vassar MJ, Belton PJ, Bhattacharyay S, Nelson LD, Tracey JX, Etemad LL, Gotthardt CJ, Satris GG, Wang MB, Demos C, Sigal GB, Amorim E, Madhok DY, Radabaugh HL, Ferguson AR, Markowitz AJ, Robertson CS, Valadka AB, Mukherjee P, Yuh EL, McCrea MA, Hinson HE, Schneider ALC, Sun X, Okonkwo DO, Kobeissy FH, Manley GT, Diaz-Arrastia R, Wang KKW, TRACK-TBI Investigators
J Neuroinflammation · 2026 May · PMID 42210282 · Full text
BACKGROUND: Inflammatory proteins detectable in blood reflect pathoanatomic injury patterns after traumatic brain injury (TBI). Identifying biomarkers of secondary neurologic and systemic injury may improve detection of...
BACKGROUND: Inflammatory proteins detectable in blood reflect pathoanatomic injury patterns after traumatic brain injury (TBI). Identifying biomarkers of secondary neurologic and systemic injury may improve detection of patients at risk for clinical decline and chronic disability. This study examined the utility of acute and subacute inflammatory biomarkers to differentiate TBI diagnosis and severity, and predict 6-month outcomes. METHODS: The Transforming Research and Clinical Knowledge in Traumatic Brain Injury (TRACK-TBI) Study prospectively enrolled TBI patients presenting to 18 United States trauma centers with head computed tomography (CT) on day 1 (D1; < 24-h post-injury). Data were extracted from TRACK-TBI subjects with D1 and 2-week (W2) plasma samples and 6-month functional outcomes, yielding 369 TBI subjects, 100 orthopedic trauma controls (OC), and 69 healthy controls. Twenty-seven inflammatory biomarkers were analyzed (MesoScale Diagnostics). TBI severity was defined using Glasgow Coma Scale (GCS; 3-12/13-15) and radiographic intracranial injury (CT-positive/CT-negative). Multivariable logistic regressions examined biomarkers as predictors of 6-month unfavorable outcomes (Glasgow Outcome Scale-Extended = 1-4 (death/severe-disability)), and adjusted for clinico-demographic factors and multiple comparisons. Adjusted odds ratios (AOR [95% confidence interval]) per log-unit increase in biomarker level were reported. RESULTS: Ten biomarkers (c-reactive protein (CRP), serum amyloid A (SAA), interleukin (IL)-1ꞵ, IL-2, IL-4, IL-6, IL-10, IL-15, IL-17A, tumor necrosis factor (TNF)-α) differed significantly between GCS 3-12 vs. 13-15 TBI, CT-positive vs. CT-negative TBI, and GCS 3-12 TBI vs. OC, at both D1 and W2 (p < 0.001). IL-6, CRP, and SAA showed good discrimination of clinical TBI severity (D1/W2 area under-the-curve (AUC): 0.87/0.87, 0.82/0.88, 0.80/0.85, respectively), and moderate-to-good discrimination of radiographic TBI severity (D1/W2 AUC: 0.81/0.82, 0.78/0.83, 0.77/0.79, respectively). Five W2 biomarkers emerged as multivariable predictors of 6-month unfavorable outcomes (IL-15: AOR = 2.26 [1.14-4.49]; SAA: AOR = 1.91 [1.37-2.67]; IL-6: AOR = 1.80 [1.25-2.61]; IL-17A: AOR = 1.72 [1.24-2.39]; CRP: AOR = 1.40 [1.06-1.85]). CONCLUSIONS: Ten circulating inflammatory proteins were associated with TBI diagnosis and severity at D1 and W2. Of these, five biomarkers expressed subacute (W2) levels predictive of 6-month death/severe-disability, underscoring their potential for validation as a novel biomarker class and integration into TBI prognostic models. Distillation of pro- and anti-inflammatory biomarker cascades in TBI could facilitate precision medicine approaches for risk stratification and therapeutic modulation.
Integrated imaging and molecular profiling reveals APOE4-associated neurovascular and glial disruptions in young adult mice.
Guan Y, Cheng CH, Khanna SD … +4 more , Fader C, Ohene Y, Wells JA, Koo BB
J Neuroinflammation · 2026 May · PMID 42210271 · Full text
BACKGROUND: The Apolipoprotein-E ε4 (APOE4) allele is the strongest genetic risk factor for late-onset Alzheimer's disease (LOAD) and may contribute to neurodegeneration through a multi-hit hypothesis, in which vascular...
BACKGROUND: The Apolipoprotein-E ε4 (APOE4) allele is the strongest genetic risk factor for late-onset Alzheimer's disease (LOAD) and may contribute to neurodegeneration through a multi-hit hypothesis, in which vascular dysfunction, glial activation, and impaired lipid metabolism play central roles. Alterations in neurovascular unit (NVU) have emerged as an early APOE4-related phenotype, independent of amyloid and tau pathology. Astrocytes, as the primary source of APOE in the brain and key regulators of NVU homeostasis, may play a central role in these processes. This study investigates APOE4-associated NVU water exchange dynamics and astrocyte-vascular interactions using integrated in vivo MRI, ex vivo histology, and transcriptomic profiling. METHODS: Non-contrast multimodal MRI, including multi-echo time arterial spin labeling (multi-TE ASL), T1-weighted imaging, and diffusion-weighted MRI, were applied in 6-9-month-old APOE3-KI and APOE4-KI mice. Multi-TE ASL was used to estimate regional NVU water exchange dynamics, while diffusion MRI assessed tissue microstructural alterations. Immunohistochemistry evaluated perivascular matrix metalloproteinase-9 (MMP9) activity, vascular-associated markers, astrocytic AQP4 expression, and glial reactivity. Single-nucleus RNA sequencing (snRNAseq) characterized cell-type-specific transcriptional profiles, and inferred cell-cell communication analysis between astrocytes, pericytes, and other NVU components. Integrated analyses compared MRI-derived measures with molecular and cellular findings. RESULTS: APOE4-KI mice showed regionally specific alterations in NVU water exchange dynamics, particularly in the hippocampus, accompanied by trends toward altered microstructural complexity. Immunohistochemistry demonstrated increased perivascular MMP9 expression and evidence of extracellular matrix remodeling without prominent structural disruption of blood-brain barrier (BBB) markers in APOE4 mice. Astrocytes showed increased AQP4 expression, heightened proinflammatory gene signatures, and morphological reactivity. Molecular findings aligned with MRI, supporting the sensitivity of non-contrast MRI to early NVU alterations. Exploratory snRNAseq suggested an APOE4-enriched astrocyte subpopulation associated with immune activation and matrix-related pathways and suggested potential glial-vascular interactions that require validation in larger samples. CONCLUSIONS: This integrated imaging and molecular analysis suggests that non-contrast multimodal MRI detects early APOE4-related changes in NVU exchange dynamics and glial-vascular interactions. By providing converging multiscale neuroimaging and cellular observations, this work provides a foundation for developing non-invasive biomarkers to monitor neurovascular vulnerability and guide early intervention strategies in individuals at risk for LOAD.
Repeated head impacts establish a senescent cranial bone marrow niche that impairs brain metabolism.
Devlin PJ, Khan R, Do TH … +13 more , West BE, Korf JM, Guzman GU, Ahn J, Saltzman A, Jain A, Tan C, Flores R, Maniskas ME, Marrelli SP, Malovannaya A, Underwood E, Ritzel RM
J Neuroinflammation · 2026 May · PMID 42204700 · Full text
BACKGROUND: Traumatic brain injury (TBI) of any severity is associated with long-term systemic inflammation and increased risk of peripheral comorbidities, yet the mechanisms driving immune dysregulation and accelerated...
BACKGROUND: Traumatic brain injury (TBI) of any severity is associated with long-term systemic inflammation and increased risk of peripheral comorbidities, yet the mechanisms driving immune dysregulation and accelerated aging after repeated sub-concussive head impacts remain poorly defined. Here, we investigated the acute and chronic effects of repetitive head impacts (RHI) on distal and proximal bone marrow compartments in the femur and calvaria, respectively. METHODS: Using a modified weight-drop mouse model delivering rotational and acceleration-deceleration forces (3 hits/week for up to 16 weeks), RHI produced no mortality, skull fracture, hemorrhage, or brain leukocyte infiltration. Bone marrow stem and progenitor cell proliferation, senescence, and output were assessed using flow cytometry, senescence-associated assays, telomere analysis, and secretome profiling. RESULTS: One day after three consecutive impacts, RHI induced robust proliferation of LSK stem/progenitor cells in both femoral and calvarial marrow, evidenced by Ki67 expression, BrdU incorporation, and increased monocyte output. By 8 weeks (24 impacts), injury-induced proliferation subsided and LSK cells exhibited increased senescence-associated β-galactosidase activity and upregulation of tumor suppressor genes. At 16 weeks (48 impacts), LSK populations were depleted at both sites, displaying reduced proliferative capacity, telomere shortening, and pancytopenia in otherwise young adult mice. Calvarial bone marrow cells exposed to RHI released a distinct cytokine and proteomic secretome marked by elevated IL-6, suppressed mitochondrial and metabolic signaling, and enhanced DNA repair pathways. Notably, skull-derived secretome factors impaired cortical and hippocampal mitochondrial metabolism, and reduced microglial mitochondrial membrane potential. CONCLUSIONS: Together, these findings identify replicative senescence of the brain-adjacent bone marrow niche as an early and progressive consequence of repeated mild head injury, linking RHI to long-lasting metabolic dysfunction, impaired immunity, and accelerated aging.
Microglial state transitions dominate the brain immune response in the subacute phase after cardiac arrest.
Dang L, Zhang R, Zhang J … +9 more , He P, Yu X, Rehman AU, Del Águila Á, Jain V, Tian J, Xu E, Sheng H, Yang W
J Neuroinflammation · 2026 May · PMID 42204534 · Full text
Cardiac arrest (CA) is a life-threatening medical emergency, and most victims are elderly. Despite advances in resuscitation, post-CA morbidity and mortality remain high, and this is thought to result largely from brain...
Cardiac arrest (CA) is a life-threatening medical emergency, and most victims are elderly. Despite advances in resuscitation, post-CA morbidity and mortality remain high, and this is thought to result largely from brain injury in which neuroinflammation plays a key role. Yet, how individual immune cell populations contribute to the immune response in the post-CA brain is still poorly understood. Here, using single-cell RNA-sequencing (scRNA-seq), we revealed the first immune landscape of the young and aged brain on day 3 after CA. Our data demonstrate that transitions in microglial states constituted a dominant immune change in the post-CA brain. We identified 5 CA-associated microglial states that included 3 major clusters defined by pro-inflammatory signatures, a proliferative phenotype, and high Spp1 expression. These 3 states exhibited age-dependent differences: the inflammatory subset was markedly expanded in aged mice, whereas the proliferative and Spp1⁺ clusters were more prominent in young mice. Such divergent responses likely underpin age-related disparities in neurologic outcome after CA. Notably, Spp1 microglia displayed unique spatiotemporal dynamics. These cells were robustly induced by CA, and were enriched in selective brain regions including the basal ganglia where they were associated with a microinfarct-like injury pattern. Lastly, we found that microglial depletion worsened functional outcome after CA, suggesting an overall protective role for microglia. Together, these findings provide novel insights into microglial heterogeneity and age-dependent immune responses in the brain after CA, and highlight the central role of microglia in shaping post-CA recovery.
A reparative neutrophil subpopulation accelerates spinal cord regeneration in zebrafish by controlling macrophage inflammation via Il-4.
Tian 田晓波 X, Docampo-Seara A, Heilemann K … +5 more , Kessel F, Zöller D, Bretschneider A, Becker T, Becker CG
J Neuroinflammation · 2026 May · PMID 42192435 · Full text
In mammals, a dysregulated immune response is detrimental to spinal cord repair. In zebrafish, which are capable of spinal cord regeneration, the immune response promotes regeneration. Neutrophils are the first immune ce...
In mammals, a dysregulated immune response is detrimental to spinal cord repair. In zebrafish, which are capable of spinal cord regeneration, the immune response promotes regeneration. Neutrophils are the first immune cells to arrive at a spinal cord injury site, but their role in successful regeneration is not fully understood. Here we show that ablating neutrophils, including a subpopulation that expresses the cytokine il4, increases expression of il1b (coding for Il-1β) mainly in macrophages/microglia and delays anatomical and functional recovery after a spinal cord injury in larval zebrafish. Experimentally reducing Il-1β levels rescues axonal regeneration. Disruption of il4 mimics the detrimental effect of neutrophil ablation for axonal regeneration and this is also rescued by reducing Il-1β levels. Moreover, after ablation of neutrophils, axonal regeneration and il1b expression levels are both rescued by over-expression of il4. Hence, after spinal cord injury, a pro-regenerative neutrophil subpopulation accelerates spinal cord regeneration in larval zebrafish by controlling expression of il1b mainly in macrophages/microglia. For this neutrophil action, il4 expression is necessary and sufficient.
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