Postoperative cognitive dysfunction (POCD) is a common complication after surgery, but its underlying mechanisms remain incompletely understood. Meningeal lymphatic vessels (MLV) regulate cerebrospinal fluid drainage, waste clearance, and immune surveillance; however, their role in POCD remains unclear. This study aimed to determine whether impaired meningeal lymphatic drainage contributes to POCD and to explore the underlying mechanisms. Meningeal lymphatic drainage was assessed by cisterna magna tracer injection in a mouse model of POCD and by contrast-enhanced MRI in a small exploratory clinical cohort of elderly surgical patients. To determine the functional role of MLV, mice received intracisternal VEGFC to enhance meningeal lymphatic drainage or VEGFR3d1–4 decoy receptor to disrupt meningeal lymphatic drainage. Single-cell RNA sequencing of meningeal tissues was performed to identify potential signaling pathways between macrophages and lymphatic endothelial cells. CXCL10 neutralization and CXCR3 blockade were further used to evaluate the functional role of this pathway in surgery-induced MLV dysfunction and cognitive impairment. Surgery impaired meningeal lymphatic drainage and induced postoperative cognitive deficits in aged mice. VEGFC-mediated enhancement of meningeal lymphatic drainage reduced neuroinflammation, p-tau217 accumulation, neuronal and synaptic injury, and cognitive impairment, whereas VEGFR3d1–4-mediated disruption of meningeal lymphatic drainage exacerbated these changes. Single-cell RNA sequencing identified the CXCL10–CXCR3 axis as a potential macrophage–lymphatic endothelial cell communication pathway. Neutralization of CXCL10 or blockade of CXCR3 improved meningeal lymphatic function and ameliorated postoperative cognitive deficits. In an exploratory clinical cohort, contrast-enhanced MRI-assessed meningeal lymphatic drainage was reduced in patients with early postoperative cognitive decline. Meningeal lymphatic dysfunction is associated with POCD and may contribute to postoperative cognitive decline by promoting neuroinflammation, p-tau217 accumulation, and neuronal and synaptic injury. Meningeal CXCL10–CXCR3 signaling may contribute to surgery-induced MLV dysfunction and may represent a potential therapeutic target for POCD.
Cognitive dysfunction is recognized as one of the most concerning complications in aging as well as in disease states such as neurodegenerative disorders and stroke. Although previous studies mainly focused on local brain pathology, growing evidence highlights neuroimmune crosstalk as a key regulator of cognitive function. In particular, bidirectional communication between peripheral adaptive immunity and the central nervous system (CNS) has emerged as an important mechanism underlying cognitive dysfunction. T- and B-cell subsets exert distinct effects on cognitive regulation, ranging from maintaining homeostasis to driving neuroinflammation and dysfunction. Following blood-brain barrier disruption, peripheral lymphocytes infiltrate the CNS and reshape the neuroinflammatory microenvironment through interactions with distinct glial cells. In parallel, meningeal immunity and lymphatic drainage have been identified as critical interfaces linking peripheral and central immune responses in cognitive regulation. In this review, we summarize the multifaceted roles of adaptive immune T and B cells in cognitive dysfunction, with particular emphasis on their subset-specific features, their crosstalk with glial cells, and the contribution of meningeal immunity. We further discuss the potential underlying mechanisms, with the aim of providing insights that may inform therapeutic strategies for cognitive dysfunction.
Microglia, the resident immune cells of the central nervous system, play pivotal roles in brain surveillance and injury responses through highly dynamic process motility. Here, we investigated the role of Ca2⁺ signaling in mediating microglial process motility under both physiological and pathological conditions in vivo. Using dual-laser two-photon microscopy in a transgenic mouse model expressing red fluorescent protein (mCherry) and the Ca2⁺ indicator (GCaMP6m) specifically in microglia, we observed autonomous Ca2⁺ microdomains that operate asynchronously within individual processes, exhibiting significantly more frequent and localized Ca2⁺ transients compared to non-motile structures. Upon focal laser-induced cortical injury, we observed rapid Ca2⁺ waves in microglia, with processes extending toward the lesion site displaying correlated Ca2⁺ activity. Attenuation of Ca2⁺ transients by BAPTA-AM, a Ca2⁺ chelator, impaired both homeostatic and laser-induced motility. Importantly, microglia-specific genetic overexpression of plasma membrane Ca2⁺ ATPase 2 in vivo markedly reduced both homeostatic surveillance and injury-induced motility. Together, our findings provide evidence that microglial intracellular Ca2⁺ signaling is required for process motility in vivo, supporting a model in which local Ca2⁺ dynamics enable surveillance and injury-directed remodeling.
Ischemic stroke elicits a sustained thromboinflammatory response that critically shapes secondary brain injury. The kallikrein-kinin system (KKS) has been identified as the interface of vascular injury and inflammatory processes; however, its role in adaptive immunity remains poorly defined. Here, we show that the KKS is associated with pathogenic CD4+ T cell activation and trafficking. In both ischemic stroke patients and mice subjected to transient middle cerebral artery occlusion (tMCAO), circulating CD4+ T cells exhibited a conserved, activated, and trafficking-competent phenotype characterized by upregulation of adhesion/migration markers, indicating a translationally preserved systemic adaptive immune response. Functionally, serum from stroke mice subacutely treated with a plasma kallikrein (PK)-neutralizing antibody (ɑPK) attenuated CD4+ T cell activation, proliferation, expression of adhesion/migration markers, and pro-inflammatory cytokine production in vitro. PK selectively enhanced CD4+ T cell adhesion and migration, while its downstream metabolite Des-Arg9-bradykinin (Des-Arg9-BK) induced a pronounced pro-inflammatory, pro-migratory phenotype and potentiated chemokine-driven transendothelial migration in vitro. Strikingly, delayed PK inhibition in vivo was associated with reduced T cell accumulation in the ischemic brain and increased circulating CD4+ T cell frequencies, suggesting impaired central nervous system (CNS) infiltration dynamics. Together, these findings support a role for KKS signaling in shaping neuroimmune interactions after ischemic stroke by enhancing endothelial adhesiveness and facilitating CD4+ T cell migration to the ischemic tissue. By linking thromboinflammation and adaptive immunity, the KKS emerges as a promising therapeutic target to selectively modulate neuroimmune interactions and potentially improve functional recovery after ischemic stroke.
Sleep disruption (SD) is increasingly recognized as a systemic stressor that worsens inflammatory disease, yet how it reshapes lung immunity remains poorly defined. To address this, we combined an ovalbumin (OVA)-induced allergic airway inflammation model with sleep disruption paradigms, together with transcriptomic profiling, in vivo pharmacological interventions, and in vitro RAW264.7 macrophage-like cells. In an OVA-induced allergic airway inflammation model, SD markedly increased methacholine responsiveness, aggravated peribronchial inflammation and mucus metaplasia, and promoted a more severe inflammatory airway phenotype. These changes were accompanied by enhanced pulmonary catecholaminergic signaling, reflected by increased tyrosine hydroxylase immunoreactivity and elevated norepinephrine levels. Mechanistically, SD induced mitochondrial dysfunction in the lung, characterized by ultrastructural injury, increased mitochondrial reactive oxygen species, and accumulation of cytosolic mtDNA, together with activation of the cGAS-STING pathway. Cell-type localization analysis showed that activated STING signaling was predominantly associated with F4/80-positive pulmonary macrophages, whereas overlap with Ly6G-positive neutrophils was limited. In vivo, chemical sympathectomy with 6-hydroxydopamine attenuated airway hyperresponsiveness and reduced pulmonary STING pathway activation. In RAW 264.7 cells, norepinephrine (NE) amplified lipopolysaccharide (LPS)-induced inflammatory responses, promoted mitochondrial oxidative stress, increased cytosolic mtDNA accumulation, and enhanced IRF3 activation, effects that were attenuated by adrenergic blockade and STING inhibition. Together, these findings support a model in which sleep disruption increases catecholaminergic exposure in allergic lungs, thereby driving macrophage mitochondrial stress and mtDNA-cGAS-STING dependent inflammatory amplification. This work identifies a brain-to-lung neuroimmune mechanism linking sleep loss to worsened airway disease and highlights sympathetic-macrophage signaling as a potential mechanism-informed therapeutic target. Sleep disruption enhances sympathetic nervous system activity, leading to increased norepinephrine (NE) release to the lung. NE acts on pulmonary macrophages, likely through adrenergic signaling pathways, inducing mitochondrial oxidative stress and structural disruption. This is characterized by elevated mitochondrial ROS, which promotes the release and cytosolic accumulation of mitochondrial DNA (mtDNA). The released mtDNA activates the cGAS-STING signaling pathway, leading to TBK1-IRF3 activation and downstream inflammatory gene expression, ultimately contributing to enhanced airway inflammation, mucus hypersecretion, and airway hyperresponsiveness under allergen challenge. Created in BioRender. Haotian, C. (2026) https://BioRender.com/xywyr61.
Autophagy is a critical regulator of immune homeostasis, but the role of autophagy-related gene 7 (Atg7) in microglia during early postnatal brain development remains incompletely understood. Here, we investigated how Atg7 deficiency in Tmem119-Cre-targeted brain cells influences postnatal neuroimmune homeostasis and brain development. Conditional Atg7 knockout mice were generated by crossing Atg7flox/flox mice with Tmem119-Cre mice. Postnatal growth, survival, brain histology, ultrastructure, and transcriptomic changes in sorted microglia-enriched CD45+ cells were evaluated using molecular, histological, and ultrastructural analyses. Atg7 deficiency in Tmem119-Cre-targeted cells was associated with severe postnatal growth retardation, disproportionate brain retention, hair loss and shortened survival. In the brain, Atg7 deficiency was associated with progressive disruption of microglial homeostasis features, characterized by reduced microglial abundance, simplified morphology, and decreased expression of homeostatic markers. Transcriptomic analysis further revealed persistent inflammatory reprogramming enriched for type I interferon signaling, innate immune responses, and antigen processing and presentation pathways. These findings were supported by increased cortical expression of interferon-responsive genes and pro-inflammatory cytokines. These neuroimmune alterations were associated with astrogliosis, altered oligodendrocyte-lineage development, and dysregulated myelination, indicating impaired postnatal brain maturation. Our findings indicate that Atg7 deficiency in Tmem119-Cre-targeted brain cells is associated with disrupted neuroimmune homeostasis, accompanied by alterations in cortical development and myelination. These results support an important role for Atg7 in maintaining neuroimmune homeostasis during early postnatal brain maturation.
Sleep deprivation (SD) has become a critical global health concern, with consequences including cognitive decline. Transcranial alternating current stimulation (tACS) holds significant potential for improving cognitive impairment. This study aimed to evaluate the effects of tACS on SD-associated cognitive deficits. Male C57BL/6 mice were subjected to SD using the horizontal platform method. Cognitive function was assessed via multiple behavioral tests, and local field potential (LFP) signals were recorded. Untargeted metabolomics was employed to identify key metabolites and regulatory pathways in mouse brain tissue. Mouse models and co-culture systems were combined to investigate the regulatory relationships among microglia, synapses, and neurons. tACS significantly improved memory and cognitive function in SD-induced model mice, accompanied by inhibited microglial phagocytosis, increased synaptic density, and reduced neuronal apoptosis. Untargeted metabolomics revealed that tACS may regulate nervonic acid (NA) abundance and the Rap1 signaling pathway during SD. Further studies demonstrated that NA suppresses lipopolysaccharide (LPS)-induced microglial overactivation and synaptic loss via the Rap1 signaling pathway, thereby blocking neuronal apoptosis. Additionally, similar to the therapeutic effects of tACS, NA administration markedly alleviated cognitive impairment and neural damage in SD mice. These data support the regulatory roles of tACS and NA in neuronal activity and synaptic plasticity and propose novel therapeutic targets for SD-related cognitive deficits.
The excitability imbalance in the lateral septum (LS) has been recognized as a critical neural basis for chronic pain-anxiety comorbidity. However, the downstream molecular mechanisms triggered by this imbalance, as well as the bidirectional crosstalk between neurons and glia within the LS, remain poorly understood. Employing a complete Freund’s adjuvant model, we identified enhanced excitability of LS GABAergic neurons as a direct driver of chronic inflammatory pain and comorbid anxiety. Neuronal activation directly increases tau expression in the LS. Neuronal tau overexpression or tau ablation exacerbated or alleviated pain hypersensitivity and anxiety-like behaviors, respectively. The anterior cingulate cortex tau manipulation exhibited no effect, confirming the specificity of LS. Mechanistic studies have revealed that hyperactive neurons release tau proteins, which was internalized by microglia through CX3CR1 receptors. Internalized tau induced NF-κB phosphorylation and upregulated NLRP3 inflammasomes, resulting in the secretion of IL-1β. Extracellular IL-1β then bound to neuronal IL-1R1, enhancing neuronal excitability and forming a positive feedback loop, where neuronal activation drove tau release, microglial inflammation, and reciprocal neuronal sensitization. Systemic clonidine administration disrupted this neuroimmune axis and concurrently alleviated pain and anxiety. These findings reveal a novel neuroimmune circuit mechanism that bridges neuronal hyperactivity and glial inflammation in pain-affective comorbidities, providing a therapeutic framework for dual-target intervention strategies.
Cognitive impairment in schizophrenia is inadequately treated. The molecular link between oxidative stress and neuroinflammation in its pathophysiology remains unclear. We measured CB2R in circulating microglia‑derived exosomes from schizophrenia patients and healthy controls. In a maternal separation rat model, we assessed brain reactive oxygen species, microglial activation, and the 2‑AG/CB2R signaling axis. A microglia‑targeted hydrogen‑releasing nanoplatform (PdH0.12@CM) was administered to maternal separation rats, followed by behavioural, histological and transcriptomic analyses. In primary microglia, we examined the effects of hydrogen peroxide on CB2R, 2‑AG and inflammatory responses, and tested rescue with a CB2R agonist or exogenous 2‑AG. CB2R was reduced in patient-derived microglia exosomes and correlated with cognitive performance and symptom severity. Maternal separation rats showed elevated brain reactive oxygen species, microglial activation, and selective decreases in microglial 2-AG and CB2R, with reduced CB2R expression observed in the hippocampal CA1 region. PdH0.12@CM treatment scavenged reactive oxygen species, restored 2‑AG/CB2R signaling, suppressed pro‑inflammatory cytokines, and rescued cognitive and sensorimotor deficits. In vitro, hydrogen peroxide directly reduced CB2R and 2‑AG levels, increased CD86 and cytokine release; these effects were reversed by a CB2R agonist or 2‑AG. Elevated oxidative stress is associated with disruption of the microglial 2‑AG/CB2R axis, which correlates with neuroinflammation and cognitive deficits. Targeted ROS scavenging restores this pathway, identifying the 2‑AG/CB2R axis as a potential therapeutic target in schizophrenia.
Activated microglia-mediated aberrant synaptic phagocytosis is an important contributor to neurological deficits following traumatic brain injury (TBI). Galectin-3 (Gal-3), a pivotal regulator of microglial activity, is increased after TBI. However, its role in microglia-mediated synaptic phagocytosis and associated neuroinflammation remains unclear. Microglial phagocytic activity post-TBI was analyzed using public single-cell RNA sequencing datasets from GEO. The function of Gal-3 was investigated in a mouse model of controlled cortical impact by intraperitoneal administration of the selective inhibitor TD139. Sensorimotor and cognitive functions, microglial heterogeneity, synaptic engulfment, and neuroinflammation were assessed using behavioral tests, immunostaining, western blotting, and RT-qPCR. Gal-3 expression was specifically upregulated in phagocytic microglia following TBI. Pharmacological inhibition of Gal-3 by TD139 alleviated long-term sensorimotor and cognitive dysfunction and reduced cerebral tissue loss. Additionally, TD139 treatment promoted microglial heterogeneity, elevated the expression of anti-inflammatory factors, and inhibited excessive microglial synaptic engulfment, thereby attenuating synapse loss and preserving synaptic integrity. Microglial Gal-3 drives neuroinflammation and aberrant synaptic phagocytosis, contributing to neurological deficits following TBI. These findings identify Gal-3 as a promising therapeutic target for TBI intervention.
Microglia are central regulators of brain homeostasis and synaptic architecture, but whether they, like astrocytes, act as reservoirs and handlers of glutamate and GABA is unknown. Using post-embedding immunogold electron microscopy, we provide the first ultrastructural evidence that individual microglial processes contain GABA and glutamate. At the nanoscale, glutamate-positive microglial processes were preferentially apposed to glutamatergic terminals, whereas GABA-positive processes showed no consistent spatial relationship to GABAergic boutons. At the microscale, spatial transcriptomics revealed that microglial somata expressing GABA-handling genes are enriched in GABAergic neuron-rich regions, while microglia expressing glutamate-handling genes are enriched in glutamatergic neuron-rich regions. Analysis of four single-cell and single-nucleus RNA-sequencing datasets (6,594,428 cells, including 320,683 microglia) demonstrated conserved expression of glutamate and GABA transport and metabolism genes in microglia across species, corroborated at the protein level by proteomics and in situ by confocal microscopy. Functionally, acute neuroinflammation selectively depleted microglial GABA content by 57
Parkinson's disease (PD) is a common neurodegenerative disease characterized by the loss of dopaminergic (DAergic) neurons in the substantia nigra pars compacta (SNpc) and the formation of Lewy bodies composed of misfolded alpha-synuclein (α-syn). A growing number of studies indicate that microglia-mediated neuroinflammation and autoimmune responses are important pathological features of PD. Thioredoxin-1 (Trx-1), a multifunctional redox-regulatory protein, exerts neuroprotective effects in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD models, but its impact on microglia-mediated autoimmune responses in PD remains unexplored. In the present study, we demonstrated that Trx-1 suppressed microglial accumulation and the increase of pro-inflammatory cytokines. Furthermore, Trx-1 suppressed the increase of α-syn and major histocompatibility complex class II (MHC-II)-mediated antigen presentation in microglia induced by MPTP. Additionally, MPTP promoted T helper 17 (Th17) cell differentiation, inhibited forkhead box P3 (FOXP3) protein level and regulatory T (Treg) cell differentiation, and enhanced forkhead box O1 (FOXO1) phosphorylation and nuclear exclusion in the SNpc. All these pathological alterations induced by MPTP were effectively restored by Trx-1 overexpression. Our findings highlight the pivotal role of Trx-1 in microglia-mediated autoimmune responses, thereby providing a potential therapeutic target for PD.
Efficient clearance of myelin debris is essential for white matter repair in vascular cognitive impairment (VCI) caused by chronic cerebral hypoperfusion, but the underlying cell-specific mechanisms remain poorly defined. Here, we investigated the role of astrocytic Caveolin-1 (Cav-1) in regulating this process. Chronic cerebral hypoperfusion was induced by bilateral carotid artery stenosis in mice and CoCl2-induced hypoxia in primary astrocytes. Myelin uptake and degradation were assessed by immunofluorescence and flow cytometry. Lysosomal function was evaluated using DQ-BSA assays and lipid staining. Human relevance was examined using single-nucleus RNA sequencing of vascular dementia (VaD) white matter. Corpus callosum integrity was assessed by immunofluorescence and transmission electron microscopy, and cognitive function was evaluated using the Morris water maze. Astrocyte-specific Cav-1 knockout and cathepsin D (Ctsd) knockdown were used to define molecular mechanisms. Chronic cerebral hypoperfusion induced progressive demyelination, accompanied by a shift from microglial to astrocytic myelin clearance. Under hypoxia, astrocytes displayed enhanced myelin uptake but impaired degradation, characterized by reduced lysosomal proteolysis and increased inflammatory signaling. Cav-1 was markedly upregulated in reactive astrocytes, and human VaD transcriptomic data revealed activation of caveolin-mediated endocytosis and lysosomal alterations. While Cav-1 did not affect early myelin uptake, its deletion restored lysosomal proteolysis, reduced neuroinflammation, and improved cognitive performance. Mechanistically, the scaffolding domain of Cav-1 interacts with proCTSD and promotes its secretion, thereby limiting CTSD maturation and lysosomal proteolytic capacity. Blocking this secretory pathway restored intracellular CTSD and enhanced myelin degradation. Notably, Ctsd knockdown abolished the beneficial effects of Cav-1 deletion, establishing a Cav-1/proCTSD-dependent mechanism. These findings identify a Cav-1–proCTSD axis that impairs astrocytic lysosomal proteolysis by redirecting CTSD from maturation to secretion, thereby driving neuroinflammation and white matter injury in VCI. Targeting this pathway may represent a therapeutic strategy for hypoperfusion-related white matter disorders.
Systemic inflammation is increasingly recognised as a key modifier of Alzheimer’s disease (AD) progression, yet the mechanisms linking inflammatory acute-phase responses to Amyloid-β (Aβ)-driven neurotoxicity remain incompletely defined. Here, we report that amyloidogenic acute-phase peptide fragment SAA19–45 (SAA27), derived from Serum Amyloid A (SAA), modulates Aβ aggregation and amplifies downstream oxidative and inflammatory stress responses in neuronal and microglial systems. Immunofluorescence analysis of human AD brain tissue revealed plaque-associated SAA-positive cellular structures within or adjacent to Aβ-positive pathological microenvironments across all range of Braak stages. In vitro, co-incubation of SAA27 with Aβ accelerated Thioflavin T-positive aggregation kinetics and altered fibrillar organisation. In SH-SY5Y neurons, Aβ induced marked cytotoxicity and oxidative stress, and SAA27 selectively enhanced intracellular reactive oxygen species without a proportional increase in cell death. In HMC3 microglia, Aβ triggered oxidative stress and inflammatory activation, both of which were further amplified by SAA27, as reflected by increased reactive oxygen species and elevated IL-6 secretion. Similarly, SAA27 enhanced Aβ-induced IL-1β release in monocyte-derived microglia-like cells. In zebrafish larvae, Aβ and SAA27 co-injection produced a stronger ThT-positive amyloid signal and synaptic degeneration, compared with Aβ alone, supporting enhanced amyloid accumulation and synaptic disruption in vivo. Quantitative proteomics revealed Aβ-driven stress and proteostasis-related reprogramming in both neurons and microglia, with SAA27 biasing these responses toward oxidative and activation-associated pathways consistent with microglial remodelling and immune engagement. The polyphenol epigallocatechin gallate (EGCG) suppressed fibrillar aggregation in vitro and in zebrafish larvae, preserved synaptic integrity in vivo, attenuated oxidative and inflammatory responses, and differentially modulated cellular proteomic states, promoting near-restoration in neurons while inducing a distinct, less stress-associated state in microglia. Together, these findings identify SAA27 as an inflammation-associated co-factor that accelerates Aβ assembly and amplifies oxidative and innate immune stress responses. The observed partial overlap with human AD proteomic signatures further supports the disease relevance of these pathways. This work provides mechanistic insight into how systemic inflammatory states may exacerbate amyloid-driven neuroinflammation in AD and highlights inflammation-amyloid crosstalk as a pharmacologically modifiable axis.
Monocytes and monocyte-derived macrophages are increasingly recognized as key contributors to the initiation and progression of inflammatory conditions, in part through metabolic reprogramming that drives pathogenic inflammatory phenotypes. However, the upstream mechanisms that coordinate these early metabolic transitions in multiple sclerosis (MS) remain largely undefined. We previously identified extracellular matrix metalloproteinase inducer (EMMPRIN/CD147), a chaperone of monocarboxylate transporter 4 (MCT4), as a regulator of lactate efflux and glycolysis-dependent activation in murine macrophages. Here, we investigate the role of EMMPRIN in circulating CCR2+ monocytes during experimental autoimmune encephalomyelitis (EAE), a mouse model for MS. Using the newly generated CCR2CreERT2:EMMPRINfl/fl (CCR2:EMMP−/−) mice, we demonstrate that presymptomatic deletion of EMMPRIN prevents or significantly attenuates clinical disability and is associated with a marked reduction in CNS infiltration by CD45+ leukocytes, including macrophages and T cells. Single cell RNA-sequencing of blood monocytes during pre-onset EAE, combined with proteomic profiling of bone marrow–derived macrophages from CCR2:EMMP−/− mice, reveals coordinated metabolic reprogramming characterized by reduced glycolytic activity, enhanced mitochondrial electron transport, and increased fatty acid oxidation. These data identify EMMPRIN-mediated lactate export as a pivotal regulator of immunometabolic programming in monocytes and monocyte-derived macrophages and implicate this pathway as an upstream driver of early neuroinflammatory pathology in MS. Targeting this pathway during presymptomatic phases may therefore represent a promising strategy to prevent disease progression by modulating early inflammatory metabolism. Multiple sclerosis (MS) develops long before neurological symptoms, in part due to early inflammatory activation of circulating monocytes. Our study shows that metabolic reprogramming, mediated by EMMPRIN-dependent lactate export and enhanced glycolysis, primes monocytes for CNS infiltration and early immune activation. Deleting EMMPRIN in CCR2+ monocytes during the presymptomatic phase markedly reduced or prevented disease, highlighting a critical window for early intervention. The newly generated CCR2CreERT2:EMMPRINfl/fl mice provide a versatile tool to manipulate monocyte metabolism in vivo, enabling detailed studies of monocyte-driven inflammation and immunometabolic regulation. These findings will inform strategies for targeting metabolic pathways in other inflammatory and neurodegenerative disorders.
Meningeal enhancement is observed on cranial and spinal magnetic resonance image in a subset of patients with multiple sclerosis (MS) and is associated with a higher risk of future disease progression, however, the underlying mechanisms by which it promotes such progression remain elusive. By cross-validating clinical MRI datasets with the experimental autoimmune encephalomyelitis model (EAE), we revealed a meningeal lymphatics-innate immune axis that orchestrates a localized signaling cascade driving and promoting the pathogenesis of inflammatory demyelination. We show that the earliest phase of the disease is characterized by a rapid, selective influx of neutrophils recruited directly from the vertebral bone marrow via specialized osteo-channels. Crucially, we identify the glycosphingolipid hexosylceramide (Hex1Cer), which is derived from meningeal lymphatic vessels after drainage of myelin debris and triggers neutrophil extracellular trap (NET) formation. These meningeal NETs utilized a SELPLG-SELL axis to recruit pathogenic lymphocytes, promoting their infiltration into the spinal cord parenchyma. Both pharmacological targeting of the Hex1Cer or NETs formation pathway significantly reduced downstream T cell infiltration and clinical severity. Finally, we demonstrate that low-dose intrathecal repurposing of Sivelestat to target this meningeal niche provides superior protection compared to systemic delivery. Our findings define the meningeal lymphatic endothelial cells (mLECs) as active metabolic gatekeepers of neuroinflammation and establish the mLEC-myelin-Hex1Cer-NETs formation axis as a high-priority therapeutic target for intercepting MS.
NLRC5 is a known activator of MHC class I genes and a regulator of type I interferon activity. Although its expression increases in brains infected with Japanese encephalitis virus (JEV), its specific contribution to JEV pathogenesis and neuroinflammation remains unclear. We utilised in vitro cell cultures, in silico modelling, and in vivo mouse knockdown models of NLRC5 to investigate its impact on JEV replication, antiviral immune responses, central nervous system (CNS) inflammation, and overall disease progression. JEV infection upregulated NLRC5 expression in the brain, microglia, and non-neuronal cells, but not in neuronal cells. However, NLRC5 expression could be induced in neuroblastoma cells via IFN-γ treatment. Experimental modulation demonstrated that the typical antiviral restriction of JEV replication by IFN-γ is lost in NLRC5-deficient cells. Evaluation of stable cell lines expressing different NLRC5 variants showed that cytoplasmic retention and NLRC5 leucine-rich repeats (LRRs) are essential for viral restriction. Mechanistically, in silico modelling, co-immunoprecipitation, and immunofluorescence confirmed that NLRC5 binds directly to the viral NS3 protein in an LRR-dependent manner. In mouse models, in vivo knockdown of NLRC5 in the brain significantly accelerated clinical disease progression, heightened mortality, and triggered uncontrolled viral replication, indicated by elevated viral titers and NS3/NS1 expression. This viral surge induced severe neuroinflammation, as evidenced by significantly elevated levels of ASC and cleaved caspase-3 in NLRC5-deficient brains. These findings demonstrate that NLRC5 functions as a cell-type-specific antiviral regulator during JEV infection. It suppresses viral replication by directly binding to and degrading the viral NS3 protein. Loss of NLRC5 impairs IFN-γ-mediated antiviral restriction, leading to enhanced viral replication, severe neuroinflammation, and accelerated disease progression in vivo.
General anesthesia exposure in early life may disrupt the normal progression of developmental myelination, but the underlying mechanisms remain unclear. Early postnatal microglia in developing white matter exhibit diverse transcriptional and functional states, including a population with pronounced phagocytic activity. This study aims to investigate whether sevoflurane impairs oligodendrocyte myelination by promoting microglial phagocytosis of oligodendrocyte precursor cells (OPCs). Mice received either a single 2-h exposure to 3.3
Substantial evidence from human studies and experimental mouse models highlights a key role for dysregulated Th17 cell responses in the pathogenesis of chronic inflammatory disorders, including neuroinflammatory conditions such as multiple sclerosis (MS). Th17 cell biology is closely linked to neutrophils, with Th17 cells promoting optimal neutrophil effector functions and conversely, neutrophils propagating Th17 responses, indicating bi-directional Th17 neutrophil crosstalk is necessary for optimal type 17 immunity. Importantly, recent studies demonstrate communication networks between neutrophils and Th17 cell responses in numerous chronic inflammatory disorders suggesting that dysregulation of this interplay contributes to disease pathogenesis. This review discusses the current understanding of Th17-neutrophil bi-directional crosstalk and focusses specifically on how dysregulation of this interplay may drive chronic inflammation during central nervous system (CNS) autoimmunity. Furthermore, we consider how evolving therapeutics could exploit these interactions for the development of new treatment strategies.
Neuroinflammation plays a central role in the progression of tauopathy via the glial activation and T cell accumulation in the brain parenchyma. However, the key molecular mediators that link these processes to tau pathology remain poorly understood. Here, we identify C-X-C motif chemokine ligand 10 (CXCL10) as a critical inflammatory mediator that is markedly upregulated in the brains of P301S-mutant tau transgenic mice and associated with regions of severe tau pathology. Spatial transcriptomics revealed that CXCL10 is mainly expressed by disease-associated astrocytes, defining an astrocytic CXCL10-rich inflammatory niche within the tauopathy brain. Genetic ablation of Cxcl10 significantly attenuated soluble and insoluble tau accumulation selectively in 9-month-old female mice, whereas no attenuation of tau accumulation was observed at 11–12 months of age. In addition, Cxcl10 deficiency significantly prolonged survival specifically in female tauopathy mice. Although Cxcl10 deficiency reduced the number of parenchymal T cells in both sexes, this reduction did not explain the female-specific effects. Furthermore, Cxcl10 deficiency did not alter neurodegeneration and motor dysfunction, suggesting that downstream sex-dependent regulatory mechanisms govern tauopathy progression. Moreover, CXCL10-dependent inflammatory activation within the local microenvironments was observed in both sexes. Although the molecular mechanisms underlying the sex-dependent effects of CXCL10 remain unclear, these findings suggest that CXCL10 contributes to tau pathology through multiple inflammatory pathways. In summary, our findings identify CXCL10 as a key inflammatory mediator of sex specific tau-associated pathology.
