J Neuroinflammation [JOURNAL]
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200 papers
Butyrate-producing gut bacteria restrain PBAT microplastic-triggered brain microglial lipotoxicity via a microbiota-butyrate-mTORC1-ISR relay along the gut-brain axis.
Wang MZ, Du ZB, Xu WQ … +9 more , Xie YH, Wang LL, He XX, Wang YH, Zheng HY, Yao YL, Song YB, Lin ZN, Lin YC
J Neuroinflammation · 2026 May · PMID 42129837 · Full text
Eco-friendly poly(butylene adipate-co-terephthalate) (PBAT) is widely marketed as biodegradable, yet the neurotoxicity of derived PBAT microplastics (PBAT-MPs) and their underlying mechanisms remain poorly characterized....
Eco-friendly poly(butylene adipate-co-terephthalate) (PBAT) is widely marketed as biodegradable, yet the neurotoxicity of derived PBAT microplastics (PBAT-MPs) and their underlying mechanisms remain poorly characterized. Here we identify a previously unrecognized "gut microbiota-butyrate-neuro-lipid" axis linking intestinal PBAT-MPs exposure to hippocampal microglial lipotoxicity and cognitive impairment. By integrating fecal microbiota transplantation (FMT) with multi-omics analyses, we demonstrate that orally administered PBAT-MPs preferentially accumulate in the colon, impair epithelial barrier integrity, deplete butyrate-associated taxa, including Muribaculaceae and Alloprevotella, and enrich Escherichia-Shigella. Butyrate depletion elevates systemic lipopolysaccharide (LPS) levels and, via the gut-brain inflammatory route, activates mTORC1-integrated stress response (ISR) signaling in microglia. Consequently, microglia acquire a lipotoxic phenotype characterized by transcriptional up-regulation of DGAT- and ACSL-dependent lipid droplet (LD) biogenesis genes, accumulation of toxic lipids and inflammatory mediators, synaptic stripping, and memory loss. In vivo butyrate supplementation in PBAT-MP-exposed mice alleviates hippocampal pathology, normalizes microglial lipid accumulation, suppresses neuroinflammation, reduces ceramide levels, and improves cognitive performance. Mechanistically, butyrate inhibits mTORC1, attenuates eIF2α-ATF4-dependent ISR signaling, and represses DGAT/ACSL-dependent LD biogenesis, whereas microglial Rptor overexpression abolishes these protective effects, identifying mTORC1 as an upstream metabolic checkpoint. Collectively, our findings establish the microbiota-butyrate-mTORC1-ISR relay as a core driver of PBAT-MPs-induced neurotoxicity and highlight restoration of butyrate signaling as a promising microbiota-based strategy for preventing microplastic-induced brain lipotoxic injury.
A CSF disease-associated macrophage signature defines progressive multiple sclerosis.
Börsch AL, Riethues F, Schulte-Mecklenbeck A … +8 more , Wang X, Heming M, Lu IN, Müller-Miny L, Wiendl H, Gross CC, Bernard-Valnet R, Meyer Zu Hörste G
J Neuroinflammation · 2026 May · PMID 42129775 · Full text
OBJECTIVE: Progression in multiple sclerosis (MS) often corresponds to irreversible disability in MS patients. Cellular changes in the cerebrospinal fluid (CSF) have provided biomarkers and mechanisms in relapsing-remitt...
OBJECTIVE: Progression in multiple sclerosis (MS) often corresponds to irreversible disability in MS patients. Cellular changes in the cerebrospinal fluid (CSF) have provided biomarkers and mechanisms in relapsing-remitting MS (RRMS) but remain understudied in primary and secondary progressive MS (summarized herein as PMS). METHODS: We combined retrospective flow cytometry of CSF cells from RRMS (n = 169), PMS (n = 56), and non-inflammatory controls (n = 74) with prospective CSF single-cell transcriptomics of 35 individuals (11 controls, 12 RRMS, and 12 PMS) and with confirmatory CSF ELISA. Available CSF single-cell data from age-matched and Alzheimer's disease (AD) patients served as additional controls. RESULTS: Proportions of CD14 monocytes in CSF are increased in PMS and correlated with clinical surrogate markers of progression. Transcriptionally, these monocytes resembled border-associated macrophages (BAM)-like cells with a chronically activated antigen-presenting phenotype. Additionally, these monocytes shared some features with disease-associated microglia/macrophages (DAM), previously identified in neurodegeneration. Induction of DAM-associated molecules, including transcribed and soluble TREM2 (sTREM2), characterized secondary progressive MS (SPMS) and supported its differential diagnosis. INTERPRETATION: We thus identified MS stage-specific CSF signatures and shared cellular features of degeneration detectable in CSF of PMS patients.
SLC27A3-dependent lipid metabolic reprogramming by trilobatin suppresses microglial mtDNA/TLR9-driven inflammatory activation in traumatic brain injury.
Zhang HW, Wang XJ, Chu MM … +11 more , Xing GY, Qiu K, Zhang YG, Zhang WF, Zhang YT, Liu X, Li L, Lu XW, Huang XX, Zhang LY, Zhang ZY
J Neuroinflammation · 2026 May · PMID 42129771 · Full text
Peri-lesional microglia are particularly sensitive to traumatic brain injury (TBI)-induced disruption of brain lipid homeostasis. This disruption is characterized by elevated levels of acylcarnitines and phospholipids in...
Peri-lesional microglia are particularly sensitive to traumatic brain injury (TBI)-induced disruption of brain lipid homeostasis. This disruption is characterized by elevated levels of acylcarnitines and phospholipids in acute lipidomic profiling, reflecting global lipid alterations. Under physiological conditions, microglial lipid processing involves fatty acid uptake, storage, and mitochondrial oxidation. However, following TBI, excessive fatty acid uptake promotes lipid droplet accumulation, mitochondrial stress, and pro-inflammatory activation. In this study, we investigated whether modulating this process confers therapeutic benefits. Trilobatin (Tri), a natural flavonoid glycoside with potent immunometabolic modulatory activity, markedly reduced neuroinflammation and neuropathological damage while improving motor and cognitive performance in a mouse model of TBI. Integrated transcriptomic and metabolomic analyses revealed that Tri reduced excessive mitochondrial lipid accumulation, alleviated mitochondrial damage, and inhibited mitochondrial DNA release, thereby blocking the TLR9/MyD88/P-P65 pro-inflammatory pathway. Further screening and validation identified that Tri downregulates the lipid transporter SLC27A3, limits excessive lipid uptake, and consequently alleviates microglial pro-inflammatory responses driven by lipid overload. Collectively, these findings establish a link between microglial lipid metabolism and inflammatory activation and support trilobatin as a promising therapeutic agent targeting metabolic-inflammatory crosstalk in acute neural injury.
The lung-brain axis mediates the neuroprotective effects of nasally administered L. salivarius and its EV-delivered metabolite in vascular dementia.
Zheng C, Wang Z, Tang F … +9 more , Zhong Y, Zheng J, Xie J, Liu L, Pi Y, Wang X, Liu T, He Z, Luo J
J Neuroinflammation · 2026 May · PMID 42121153 · Full text
Neuroinflammation and impaired barrier function are two prominent pathological mechanisms contributing to cognitive impairment in patients with vascular dementia (VaD). Currently, effective treatments for VaD remain limi...
Neuroinflammation and impaired barrier function are two prominent pathological mechanisms contributing to cognitive impairment in patients with vascular dementia (VaD). Currently, effective treatments for VaD remain limited, underscoring the clinical significance of developing novel, multi-targeted therapeutic strategies. In recent years, more and more studies have shown the connection between lung and brain, so we used nasal administration of probiotics to observe the improvement of cognitive function in VaD rats. Because the safety of the organism is uncertain, the study develop a bacterial extracellular vesicles (EVs) drug delivery system that delivers the key bioactive metabolite asperuloside (ASP) by modulating the microbiota-lung-brain axis, aiming to improve brain targeting and therapeutic outcomes. The results show that nasal administration of L. salivarius significantly ameliorated cognitive impairment, mitigated neuroinflammation, restored blood-brain barrier and lung barrier function, and modulated lung flora in VaD rats. Metabolomics analysis identified ASP as the principal active metabolite, although its efficacy as a standalone agent was constrained. The EA system effectively facilitated ASP delivery to brain tissue, yielding neuroprotective and barrier-repair effects. Collectively, our study shows that L. salivarius can modulate the pathophysiological processes of VaD via the "microbiota-lung-brain axis." Its EVs serve as effective vehicles for delivering active metabolites, offering a novel integrated therapeutic approach for VaD involving microbial metabolism delivery.
Porcine plasma-derived extracellular vesicles orchestrate multi-target neuroimmune reconfiguration to alleviate Alzheimer's disease pathology in a 5×FAD mouse model.
Lu X, Jiang Y, Lin X … +3 more , Zhang Y, Liu Q, Chen S
J Neuroinflammation · 2026 May · PMID 42120990 · Full text
BACKGROUND: Systemic factors found in young blood possess the capacity to revitalize the aging brain, yet the clinical translation of human-derived therapeutics is severely limited by donor scarcity. We hypothesized that...
BACKGROUND: Systemic factors found in young blood possess the capacity to revitalize the aging brain, yet the clinical translation of human-derived therapeutics is severely limited by donor scarcity. We hypothesized that porcine plasma-derived small extracellular vesicles (PpSEVs) could serve as a scalable, cross-species alternative by leveraging evolutionarily conserved bioactive cargoes. RESULTS: In this study, we demonstrate that PpSEVs efficiently penetrate the blood-brain barrier and show relative enrichment in the hippocampus CA3 region of 5×FAD mice. Transcriptomic profiling and functional assays reveal that PpSEVs reverse AD pathology by reconfiguring the dysregulated neuroimmune network rather than through broad immune suppression. Specifically, PpSEVs exert a dual-action effect on microglia by blocking caspase-1/GSDMD axis-mediated pyroptosis, while simultaneously enhancing CD68-dependent amyloid-β clearance. This microglial modulation occurs in tandem with the reprogramming of reactive astrocytes, characterized by the downregulation of neurotoxic C3 and the upregulation of neuroprotective S100A10. Furthermore, we identify a direct, glia-independent neurotrophic pathway in which PpSEVs activate neuronal BDNF signaling to rescue synaptic integrity and cognitive function. CONCLUSIONS: By demonstrating robust cross-species efficacy without provoking immunotoxicity, our study positions PpSEVs as a potent, multi-target intervention that decouples therapeutic benefits from human donor reliance, paving the way for sustainable, xenogeneic exosome-based AD therapies.
IFI204 drives gasdermin D-mediated mitochondrial permeabilization to amplify neuronal pyroptosis in ischemic stroke.
Xu P, Shen N, Qiu T … +5 more , Zhou M, Li R, Tao C, Zhu Y, Hu W
J Neuroinflammation · 2026 May · PMID 42116053 · Full text
Gasdermin D (GSDMD)-mediated pore formation on mitochondrial membranes is known to exacerbate pyroptosis. The cytosolic DNA sensor interferon activated gene 204 (IFI204) can activate the inflammasome to induce pyroptosis...
Gasdermin D (GSDMD)-mediated pore formation on mitochondrial membranes is known to exacerbate pyroptosis. The cytosolic DNA sensor interferon activated gene 204 (IFI204) can activate the inflammasome to induce pyroptosis. However, whether and how IFI204 regulates mitochondrial membrane permeabilization to drive pathological outcomes in ischemic stroke remains unclear. Here, using a mouse model of middle cerebral artery occlusion (MCAO), we demonstrate that IFI204 was predominantly expressed in neurons and increased to peak at 24 h after ischemic injury. Neuron-specific deletion of IFI204 alleviated cerebral infarction, reduced neuronal degeneration, and restored long-term sensorimotor coordination and cognitive function. These protective effects correlated with attenuated neuronal pyroptosis and mitochondrial dysfunction, as evidenced by decreased levels of GSDMD N-terminal fragment (GSDMD-N) and reduced mitochondrial colocalization. Conversely, adeno-associated virus-mediated re-expression of IFI204 in knockout mice restores these pathological features. In vitro, IFI204 is both necessary and sufficient to trigger this cascade. Transcriptomic profiling revealed a significant downregulation of the stimulator of interferon genes (STING) within the NOD-like receptor signaling pathway in IFI204-deficient neurons. Mechanistically, glutathione S-transferase (GST) pull-down assays confirmed a direct interaction between the pyrin domain (PYD) of IFI204 and STING. This interaction triggers caspase-1 activation and GSDMD cleavage, generating GSDMD-N, which subsequently forms pores specifically on mitochondrial membranes. These pyroptotic pores disrupted mitochondrial integrity, exacerbating dysfunction, and facilitating the cytosolic release of mitochondrial DNA (mtDNA), cytochrome c, and aconitase 2. Notably, the released mtDNA further activated IFI204, establishing a pathogenic feed-forward cycle that exacerbates mitochondrial damage and inflammatory neuronal death. Genetic ablation of STING partially abrogated the pyroptosis-promoting effect of IFI204. Collectively, these findings demonstrate that IFI204-driven cytosolic mtDNA sensing underlies a neuronal inflammatory mechanism responsible for pyroptosis and mitochondrial damage in ischemic stroke.
Pulmonary microbiota-associated formononetin modulates microglial activation in asthma-related anxiety.
Liu Y, Zhang H, Zhou Y … +7 more , Chen H, Pan X, Zhi J, Wang Q, Zhao K, Xia W, Yang D
J Neuroinflammation · 2026 May · PMID 42108470 · Full text
Asthma is frequently accompanied by anxiety disorders, yet the mechanisms linking asthma to neuropsychiatric symptoms remain poorly defined. Here, we investigated the contribution of the pulmonary microbiota and its meta...
Asthma is frequently accompanied by anxiety disorders, yet the mechanisms linking asthma to neuropsychiatric symptoms remain poorly defined. Here, we investigated the contribution of the pulmonary microbiota and its metabolites to anxiety-like behavior in an ovalbumin-induced asthma mouse model. Behavioral testing and resting-state functional magnetic resonance imaging revealed anxiety-like phenotypes and altered hippocampal function in a subset of asthmatic mice that were susceptible to anxiety-like behavior. These mice exhibited hippocampal neuroinflammation and neuronal damage, accompanied by dysbiosis of the pulmonary microbiota. Intratracheal transplantation of lung microbiota from anxiety-susceptible donors induced similar behavioral changes in recipient mice, indicating a causal role of the pulmonary microbiota. Untargeted metabolomics identified formononetin as a candidate metabolite positively correlated with the relative abundance of Acidobacteria. Intratracheal administration of formononetin alleviated anxiety-like behaviors, reduced hippocampal inflammation and injury, and restored hippocampal BDNF/TrkB signaling. However, these effects were abolished by the TrkB antagonist ANA-12. Transcriptomic and immunofluorescence analyses suggested that formononetin acts through modulation of hippocampal microglia. In vitro and small RNA sequencing analyses further demonstrated that formononetin promotes BDNF production by downregulating miR-1912-3p, thereby relieving its translational repression in microglia. Together, these findings reveal a lung-brain axis in which a pulmonary microbiota-associated metabolite modulates microglial function to alleviate asthma-related anxiety.
β-oxidation-mediated differentiation of effector CD4 T cells in the lung enhances neuroinflammation.
Jiang Q, Zhu G, Ma X … +2 more , Si W, Yang G
J Neuroinflammation · 2026 May · PMID 42106839 · Full text
Although the lung-brain axis has emerged as a potential regulator of central nervous system (CNS) autoimmunity, the cellular and molecular mechanisms by which the lung microenvironment influences pathogenesis of multiple...
Although the lung-brain axis has emerged as a potential regulator of central nervous system (CNS) autoimmunity, the cellular and molecular mechanisms by which the lung microenvironment influences pathogenesis of multiple sclerosis (MS) remain unclear. Here, using experimental autoimmune encephalomyelitis (EAE), a murine model of MS, we found a marked expansion of effector CD4⁺ T cells in the lungs of EAE mice. The EAE lung microenvironment promoted metabolic reprogramming in CD4⁺ T cells, characterized by enhanced fatty acid uptake and upregulation of carnitine transporters. Metabolomic profiling further demonstrated enrichment of carnitine-related metabolites in the EAE lungs, with a strong correlation between metabolic profiles in the lungs and brains, suggesting coordinated metabolic remodeling along the lung-brain axis. Mechanistically, the EAE lung microenvironment significantly enhanced effector CD4⁺ T cell differentiation in vitro through a β-oxidation-dependent pathway. Importantly, pharmacological inhibition of β-oxidation in the lungs significantly attenuated EAE severity, reduced CD4⁺ T cell infiltration into the CNS, and impaired effector CD4⁺ T cell differentiation in the lungs. Collectively, these findings demonstrate that β-oxidation-mediated differentiation of effector CD4⁺ T cells in the lung exacerbates neuroinflammation, highlighting the lung-brain axis as a potential therapeutic target for MS.
Mechanistically informed circulating biomarkers are associated with acquired epilepsy after neonatal brain injury.
Numis AL, Shellhaas RA, Soul JS … +16 more , Gardner MA, Wusthoff CJ, Benedetti GM, Di Germanio C, Bammler TK, Erle DJ, Eckalbar WL, McCulloch CE, Heagerty PJ, Wood TR, Wu YW, Juul SE, Lowenstein DH, Glass HC, Neonatal Seizure Registry Study Group, HEAL Consortium
J Neuroinflammation · 2026 May · PMID 42106818 · Full text
BACKGROUND: Acute provoked neonatal seizures are a major risk factor for acquired epilepsy, yet clinicians lack reliable tools to identify neonates at highest risk. Preclinical data implicate innate immune activation and...
BACKGROUND: Acute provoked neonatal seizures are a major risk factor for acquired epilepsy, yet clinicians lack reliable tools to identify neonates at highest risk. Preclinical data implicate innate immune activation and neuronal injury as key drivers of epileptogenesis, suggesting blood-based biomarkers could provide mechanistic insight and prognostic utility. We sought to identify biomarkers of epileptogenesis in neonates with acute provoked seizures after brain injury using multicenter cohorts. METHODS: We conducted a prospective, multi-cohort analysis across two independent studies. NSR-RISE enrolled neonates with EEG-confirmed acute provoked seizures of diverse etiologies. The HEAL trial enrolled neonates with hypoxic-ischemic encephalopathy; analyses were limited to those with seizures. Plasma proteins were quantified 48-96 h after seizure onset. Associations with acquired epilepsy by 24-months were evaluated using log-link models with robust standard errors and false-discovery rate correction (FDR < 0.05). Significant proteins were added to models including established clinical predictors (≥ 3 days of EEG seizures and abnormal neurological examination at discharge). Exploratory pathway enrichment used KEGG databases. NSR-RISE participants also underwent plasma microRNA (miRNA) sequencing with integrative pathway analyses. RESULTS: Among 35 neonates in NSR-RISE, 7 (20%) developed epilepsy; among 40 neonates in HEAL, 6 (15%) developed epilepsy. Across both cohorts, neonates with epilepsy had higher concentrations of the pro-inflammatory cytokine IL-1β and the neuronal injury marker UCHL1 compared to those without epilepsy. Growth hormone (GH), measured only in NSR-RISE, was decreased in neonates with epilepsy. Incorporation of biomarkers improved prognostic accuracy for epilepsy beyond clinical features alone (Area under the precision-recall curve (AUPRC) 0.30 (95%CI, 0.28-0.32) versus 0.91 (95%CI, 0.89-0.92); p < 0.001). Pathway enrichment analyses implicated innate immune signaling, including TLR/IL1/NF-κB-related and MAPK-associated IL-17 signaling. miRNA profiling identified 11 species differentially expressed between neonates with and without epilepsy, including brain-enriched miRNAs. Network analysis identified a co-expression module enriched for let-7f-5p and miR-146a-5p targeting TLR/IL1/NF-κB, MAPK, and JAK/STAT pathways. CONCLUSIONS: Across two cohorts, mechanistically informed biomarkers were associated with acquired epilepsy after neonatal seizures. IL-1β, UCHL1, and GH reflect inflammation, neuronal injury, and impaired trophic signaling, while circulating miRNAs provide complementary mechanistic insight. Findings support a translational biomarker panel and highlight inflammation as a biologically plausible therapeutic target.
Mechanical regulation of microenvironment remodeling in brain tumors: from mechanism to therapy.
Fan H, Xu C, He S … +3 more , Wang J, Zhu H, Shu K
J Neuroinflammation · 2026 May · PMID 42106743 · Full text
Aberrant mechanical signaling is a hallmark of solid tumors. Given that the brain is one of the softest tissues in the body, brain tumors develop within a unique mechanical microenvironment, where mechanical cues extensi...
Aberrant mechanical signaling is a hallmark of solid tumors. Given that the brain is one of the softest tissues in the body, brain tumors develop within a unique mechanical microenvironment, where mechanical cues extensively regulate malignant behaviors and brain-tumor associated neuroinflammation. Growing evidence indicates that mechanical signals promote brain tumor progression by symbiotically regulating various immune cells and canonical neuroimmune pathways. Thus, targeting mechanical cues has emerged as a promising strategy in overcoming immunotherapy resistance. This review outlines the distinct characteristics of the mechanical microenvironment in brain tumors and the regulatory roles of mechanical forces in tumor progression, highlighting the key functions of mechanical force-mediated immune microenvironment remodeling in brain tumor immunosuppression and treatment resistance. Furthermore, we summarize mechano-targeting methods in cancer therapy, aiming to provide insights into the mechanisms and therapeutic opportunities of mechanical signaling in the brain tumor microenvironment.
LAPF enhances lysosomal acidification to promote TLR9 and cGAS-STING-mediated antiviral immunity and attenuate HSV-1-induced neuroinflammatory pain.
Kong E, Deng M, Ding R … +8 more , Yang M, Li Y, Feng X, Song H, Wei H, Jiang X, Yuan H, Han C
J Neuroinflammation · 2026 May · PMID 42104430 · Full text
Postherpetic neuralgia (PHN) is characterized by neural injury and neuroinflammation resulting from viral infection and reactivation. Herpes simplex virus type 1 (HSV-1) is capable of inducing virus-associated PHN-like n...
Postherpetic neuralgia (PHN) is characterized by neural injury and neuroinflammation resulting from viral infection and reactivation. Herpes simplex virus type 1 (HSV-1) is capable of inducing virus-associated PHN-like neuropathic pain and has been widely used as a model for studying virus-induced neuroinflammatory pain. However, the immune mechanisms underlying virus-induced neuroinflammation and pain remain incompletely understood. In this study, we used an HSV-1-induced neuroinflammatory pain model and observed reduced Lapf expression following HSV-1 infection through transcriptome sequencing, which was further confirmed to be localized in microglia of the spinal dorsal horn by immunofluorescence staining. Lapf microglia-specific deficiency aggravated neuroinflammation and promoted mechanical allodynia by impairing antiviral innate immunity both in vivo and in vitro. Overexpression of Lapf in microglia strengthened antiviral innate immunity and suppressed HSV-1 replication. Mechanistically, transcriptome sequencing of Lapf microglia-specific deficient mice identified lysosomal endocytosis as a critical pathway in LAPF-mediated antiviral innate immunity. Lapf deficiency decreased lysosomal acidity, resulting in reduced TLR9 activation, thereby impairing viral DNA sensing and IFN-I production. Lapf deficiency also reduced lysosomal membrane stability, facilitating the escape of HSV-1 DNA into the cytoplasm, where it could amplify and reactivate. Conversely, Lapf overexpression enhanced lysosomal acidity and membrane stability, promoting TLR9 activation and antiviral innate immunity. Furthermore, Lapf deficiency markedly reduced the phosphorylation of STING, TBK1, and IRF3, whereas Lapf overexpression restored cGAS-STING signaling. This effect was abolished by lysosomal acidification inhibitor chloroquine (CQ), supporting that LAPF promotes lysosomal acidification-dependent antiviral immunity via TLR9 and cGAS-STING pathways. Pharmacological enhancement of LAPF activity using the dephosphorylation inhibitor SHP099 alleviated neuroinflammation and mechanical allodynia in HSV-1-induced neuroinflammatory pain model mice, suggesting potential therapeutic implications. In conclusion, our findings demonstrate that LAPF enhances lysosomal acidification to promote dual antiviral innate immune responses via TLR9 and cGAS-STING pathways in HSV-1 infection, thereby attenuating HSV-1-induced neuroinflammatory pain. These results provide mechanistic insights and potential therapeutic targets for virus-associated neuroinflammatory pain.
TNF-α and IFN-γ impair neural oscillations and induce neurodegeneration by microglial nitric oxide, metabolic and oxidative stress.
Malorny N, Chausse B, Khodaie B … +5 more , Elgez A, Söder L, Lewen A, Egorov AV, Kann O
J Neuroinflammation · 2026 May · PMID 42104415 · Full text
BACKGROUND: The cytokine tumor necrosis factor-alpha (TNF-α) regulates inflammatory responses in infectious and neurodegenerative diseases and also affects neuronal function. The role of TNF-α in the activation of microg...
BACKGROUND: The cytokine tumor necrosis factor-alpha (TNF-α) regulates inflammatory responses in infectious and neurodegenerative diseases and also affects neuronal function. The role of TNF-α in the activation of microglial cells (resident central nervous system macrophages), including the impact on neuronal survival, excitability, and synaptic transmission is incompletely defined, however. We explored the effects of chronic TNF-α exposure (72 h) on microglia and neurons in organotypic hippocampal slice cultures from male and female rats, i.e., postnatal cortex tissue lacking leukocyte invasion and adaptive immunity. METHODS: We applied gene expression analysis, biochemical assays, immunohistochemistry, electrophysiology by extracellular (local field potential) and intracellular (intrinsic membrane properties) recordings, and pharmacological ablation of the microglial cell population. We mainly focused on carbachol-induced neural network oscillations (brain waves) in the gamma frequency band (30-70 Hz) that underlie higher cognitive functions such as perception, attention, and memory. RESULTS: TNF-α induced microglial proliferation and upregulation of genes related to inflammation and oxidative stress such as Il6 (interleukin-6), Nos2 [inducible nitric oxide (NO) synthase, iNOS] and Sod2 (superoxide dismutase 2), which was accompanied by a decreased number of slices showing gamma oscillations in extracellular recordings. Notably, a fraction of slices presented neural bursting reflecting hyperexcitability in the tissue. Neuronal dysfunction was absent during acute TNF-α exposure (30 min). When paired with the lymphocyte cytokine interferon-gamma (IFN-γ), TNF-α induced an amplified neuroinflammation response dominated by bursting or loss of electrical activity. In intracellular recordings, neurons showed a brief burst of action potentials followed by slowing of spiking with pronounced afterhyperpolarization (switch from regular to burst firing behavior) during depolarizing current injection. Notably, the impairments could be attenuated by inhibition of iNOS and NADPH oxidase, glucose supplementation, microglial depletion or blockade of TNF receptor 1 (TNFR1) signaling with small molecule drugs, RIPA-56 and ICCB-19. CONCLUSIONS: Our data provide mechanistic insight into TNF-α- and IFN-γ-induced neuronal impairments mediated by microglial NO, metabolic and oxidative stress, and demonstrate functional neuroprotection by pharmacology. Our study extends the pathophysiological understanding of diseases such as sepsis, multiple sclerosis, Alzheimer's disease, depression and schizophrenia featuring activated microglia, infiltrating monocytes and T cells, and/or blood-brain barrier leakage.
Otilonium bromide ameliorates paclitaxel-induced peripheral neuropathy by targeting phosphatase PPM1A.
Liu X, Zhang M, Zhang Y … +4 more , Hao Y, Lu D, Li W, Shen X
J Neuroinflammation · 2026 May · PMID 42098844 · Full text
Paclitaxel (PTX)-induced peripheral neuropathy (PIPN) is a severe side effect lacking effective treatment, largely due to its complex and poorly understood pathogenesis. Here, we observed the pathological inhibition of p...
Paclitaxel (PTX)-induced peripheral neuropathy (PIPN) is a severe side effect lacking effective treatment, largely due to its complex and poorly understood pathogenesis. Here, we observed the pathological inhibition of phosphatase PPM1A activity in the dorsal root ganglia (DRG) tissues of PIPN mice. We also found that otilonium bromide (OB), as a PPM1A activator, ameliorated the PIPN-like pathology in mice, as evidenced by the alleviation of sensory dysfunction, myelin sheath injury, intraepidermal nerve fiber loss and vascular lesions. Using PPM1A-specific knockdown mice, we demonstrated that OB suppresses pro-inflammatory M1 macrophage polarization in the DRG through the PPM1A/NF-κB/NLRP3/IL-1β pathway, thereby alleviating axonal degeneration and neuronal apoptosis. In vitro experiments revealed that PTX-damaged DRG neurons release high-mobility group box 1 (HMGB1) to promote pro-inflammatory macrophage polarization, while OB disrupts this neuron-macrophage interaction by limiting HMGB1 release and subsequent macrophage activation. Together, our findings highlight PPM1A activation as a promising therapeutic strategy for PIPN and identify OB as a potential agent for treating this clinical side effect.
Iba1 deficiency impairs microglial synaptic remodeling and neuronal survival after axonal injury.
Sekiguchi K, Shoji H, Shindo T … +5 more , Sasabe J, Tokuyasu D, Nakahara J, Miyakawa T, Ito D
J Neuroinflammation · 2026 May · PMID 42098744 · Full text
BACKGROUND: Microglia remodel neuronal circuits in pathological conditions; however, the molecular requirements for these responses and their consequences for motoneuron survival remain unclear. METHODS: Aif1 (Iba1) knoc...
BACKGROUND: Microglia remodel neuronal circuits in pathological conditions; however, the molecular requirements for these responses and their consequences for motoneuron survival remain unclear. METHODS: Aif1 (Iba1) knockout mice were generated using CRISPR/Cas9-mediated deletion, and baseline phenotypes and responses to unilateral facial nerve axotomy were assessed using immunohistochemistry, transmission electron microscopy, and single-nucleus RNA sequencing of the facial motor nucleus. Motoneuron survival and nuclear γH2AX foci were evaluated 28 days post-axotomy. FINDINGS: Under baseline conditions, Iba1 mice had reduced body weights and mild behavioral abnormalities compared to wild-type mice. After axotomy, microglial ensheathment of ChAT-positive facial motoneurons was reduced, with fewer neurons showing extensive perisomatic microglial coverage than in Iba1 mice. Ultrastructurally, somatic synapse loss observed after injury in wild-type mice was not detected in Iba1 mice, and fewer injured motoneurons were in contact with microglial processes. Single-nucleus transcriptomics showed an exaggerated expansion of an interferon-responsive microglial state in Iba1-/- mice after axotomy, whereas injured motoneurons displayed altered transcriptional programs related to synapse organization and neurotransmission. At 28 days, Iba1-/- mice showed reduced motoneuron survival, lower ChAT expression, and increased nuclear γH2AX foci. INTERPRETATION: Iba1 supports microglia-neuron cross-talk that enables effective perisomatic remodefling after axonal injury; disruption of this response is accompanied by inflammatory-state shifts and compromised motoneuron survival.
Loss of astrocytic Bmal1 promotes blood-brain barrier disruption and synaptic dysfunction during systemic inflammation.
Lee C, Lee Y, Jeong WC … +6 more , Hwang I, Bae H, Shim DW, Jung H, Um JW, Yu JW
J Neuroinflammation · 2026 May · PMID 42093016 · Full text
Circadian rhythm disruption has been associated with the exaggerated inflammatory responses in peripheral tissues; however, its impact on neuroinflammation and blood-brain barrier (BBB) integrity remains unclear. Here, w...
Circadian rhythm disruption has been associated with the exaggerated inflammatory responses in peripheral tissues; however, its impact on neuroinflammation and blood-brain barrier (BBB) integrity remains unclear. Here, we identify the astrocytic circadian clock as a key regulator of BBB homeostasis during systemic inflammation. In a mouse model, circadian rhythm disruption for three weeks markedly increased BBB permeability in male mice, as evidenced by Evans blue leakage and myeloid cell infiltration into the brain parenchyma following lipopolysaccharide (LPS) challenge. Transcriptomic analyses using public datasets revealed that astrocytes exhibit the highest expression of core circadian clock genes among brain cell types. Accordingly, we generated tamoxifen-inducible, astrocyte-specific Bmal1-knockout (KO) mice. Deletion of Bmal1 in astrocytes significantly enhanced BBB leakage, astrogliosis and pericyte loss after LPS administration. Mechanistically, Bmal1-deficient astrocytes produced elevated levels of the chemokine CXCL5, which promoted CXCR2-dependent neutrophil recruitment into the brain. Pharmacological blockade of CXCR2 with SB225002 restored pericyte coverage and attenuated BBB disruption in astrocytic Bmal1 KO mice. Functionally, these mice exhibited impaired excitatory synaptic transmission following systemic inflammation, suggesting that astrocytic Bmal1 loss compromises neurovascular and synaptic integrity. Taken together, our findings demonstrate that astrocytic Bmal1 maintains BBB integrity and synaptic stability under inflammatory stress. This work also highlights astrocyte-intrinsic circadian regulation as a critical mechanism linking chemokine production to neurovascular vulnerability.
Mechanistic insights and therapeutic potential of targeting the cGAS-STING pathway in neurodegenerative diseases.
Liu H, Hu C, Liu H … +8 more , Gong Z, Jiang S, Xie J, Li Y, Liu C, Wang Y, Zou C, Yang G
J Neuroinflammation · 2026 May · PMID 42092970 · Full text
The cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway is a central cytosolic DNA-sensing module that links DNA damage and mitochondrial dysfunction to innate immune activation. Here, we focus on...
The cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway is a central cytosolic DNA-sensing module that links DNA damage and mitochondrial dysfunction to innate immune activation. Here, we focus on canonical cGAS-STING signaling in the central nervous system (CNS) and discuss non-canonical branches only when directly relevant to neurodegeneration. We summarize structural and activation-termination mechanisms and synthesize cell-type-biased outputs across microglia, astrocytes, neurons, and oligodendroglial lineage cells. We then integrate Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease by mapping shared DNA-stress triggers to multicellular amplification loops and by grading causal evidence from genetic perturbation, pharmacological pathway interference, and correlative human datasets. Finally, we classify inhibitor modalities and emerging enabling technologies while emphasizing translational constraints, including blood-brain barrier (BBB) delivery, long-term safety, human STING-allele diversity, and pharmacodynamic biomarkers. Collectively, we propose an evidence-calibrated framework for judging when cGAS-STING is most plausibly positioned as a causal node, a permissive amplifier, or a secondary correlate in neurodegenerative disease, and where therapeutic translation should proceed cautiously.
Hyperactive basolateral amygdala mediates comorbid anxiety in chronic rhinosinusitis.
Zhang X, Wu W, Zhao H … +9 more , Chang Y, Ma X, Shi X, Li W, Tang B, Wang P, Duan C, Jin M, Feng X
J Neuroinflammation · 2026 May · PMID 42092937 · Full text
RATIONALE: Anxiety disorder is a common but often overlooked comorbidity in patients with chronic rhinosinusitis (CRS). However, it remains unclear which specific brain regions are involved in CRS-related anxiety-like be...
RATIONALE: Anxiety disorder is a common but often overlooked comorbidity in patients with chronic rhinosinusitis (CRS). However, it remains unclear which specific brain regions are involved in CRS-related anxiety-like behaviors, as well as how neural-immune interactions contribute to the progression of comorbid anxiety in CRS. METHODS: Anxiety symptoms in CRS patients were evaluated using the Hospital Anxiety and Depression Scale (HADS). A papain-induced CRS mouse model was established to examine anxiety-like behaviors and associated neural and immunological alterations. Behavioral assays were combined with immunohistochemistry, in vivo fiber photometry, electrophysiology, viral tracing, and chemogenetic manipulation to identify brain regions and circuits. Peripheral inflammation, sympathetic activity, blood-brain barrier (BBB) integrity and the effects of IL-33 neutralization on peripheral inflammation, anxiety-like behaviors, and neuronal excitability were also examined. RESULTS: Persistent anxiety was observed in CRS patients and mice, even after improvement of sinonasal inflammation. In CRS mice, anxiety-like behaviors were linked to selective hyperactivation of BLA CaMKIIα-positive neurons, with increased intrinsic excitability and excitatory synaptic input shifting the excitation-inhibition balance toward excitation. Chemogenetic inhibition of BLA neurons alleviated anxiety-like behaviors and reduced sympathetic nerve fiber density, norepinephrine release, and nasal eosinophilic inflammation, whereas activation produced the opposite effects. Functional analyses implicate a BLA-centered network involving the vHPC and premammillary nucleus (PMN) in regulating peripheral sympathetic and immune responses. Additionally, CRS mice exhibited impaired BBB integrity, and IL-33 neutralization mitigated peripheral inflammation, improved anxiety-like behaviors, and decreased BLA hyperexcitability. CONCLUSIONS: Dysregulated excitatory activity in the BLA underlies anxiety comorbidity in CRS. Our findings support the involvement of a BLA-centered functional network encompassing the vHPC and PMN in the regulation of sympathetic activity and peripheral inflammation.
SARS-CoV-2 infection is associated with hypothalamic orexin suppression and persistent cortical NeuN attenuation.
Yoon GY, Chung YC, Choi JH … +11 more , Ha Y, Seo SY, Ku KB, Kim DY, Hwang WY, Jeong GU, Ahn DG, Kim KD, Rhee JK, Shin WH, Kwon YC
J Neuroinflammation · 2026 May · PMID 42087199 · Full text
Long COVID frequently presents with persistent neurological symptoms, including cognitive impairment, fatigue, and sleep disturbances; however, its underlying mechanisms remain unclear. Here, we show that SARS-CoV-2 infe...
Long COVID frequently presents with persistent neurological symptoms, including cognitive impairment, fatigue, and sleep disturbances; however, its underlying mechanisms remain unclear. Here, we show that SARS-CoV-2 infection induces lasting cortical neuronal injury and hypothalamic orexin (hypocretin) dysfunction in vivo. In K18-hACE2 and wild-type BALB/c mice, viral RNA persisted in the brain and coincided with focal loss of Neuronal Nuclei (NeuN)-positive cortical neurons beyond acute infection. SARS-CoV-2, but not the influenza A virus, triggered rapid and sustained suppression of hypothalamic orexin expression, defining a virus-specific neuropathological signature. Considering the downregulation of orexin and focal cortical NeuN attenuation, we found that exogenous orexin-A/B supplementation increased NeuN abundance in vitro and in vivo under the tested conditions. Overall, these findings identify the orexin system as a candidate neural vulnerability to SARS-CoV-2 and suggest that orexinergic dysfunction may contribute to the neurological manifestations of Long COVID.
Sex-dependent interferon signaling contributes to female-biased vulnerability in Alzheimer's disease.
López-López V, Iniesta G, Galán-Ganga M … +10 more , Expósito-Coca A, Durán-Laforet V, Bhojwani-Cabrera AM, Navarrón CM, Guillot-Fernández M, Venero JL, Sánchez-Mut JV, Barco A, Giralt A, López-Atalaya JP
J Neuroinflammation · 2026 May · PMID 42083037 · Full text
Alzheimer's disease (AD) disproportionately affects women, yet the biological basis of this sex bias remains unclear. Here, we identify sex-dependent interferon signaling as a contributor to this disparity. Transcriptomi...
Alzheimer's disease (AD) disproportionately affects women, yet the biological basis of this sex bias remains unclear. Here, we identify sex-dependent interferon signaling as a contributor to this disparity. Transcriptomic profiling of postmortem AD tissue and APP/PS1 mice revealed preferential enrichment of interferon-responsive gene programs in females. In APP/PS1 mice, heightened interferon responses were associated with increased neurodegenerative features, and single-cell transcriptomic analyses identified microglia as a major cellular compartment engaging interferon responses. To test causality, we manipulated interferon signaling in vivo. Acute systemic interferon activation promoted AD-like neuropathological alterations. Genetic amplification of interferon signaling in microglia exacerbated neuroinflammatory and neurodegenerative features in APP/PS1 mice, whereas pharmacological inhibition through cGAS-STING blockade suppressed interferon responses, reduced neuropathology, and preserved cognitive performance in female APP/PS1 mice. Together, these findings identify microglial interferon signaling as a modifiable contributor to AD-associated neuropathology and suggest a neuroimmune mechanism underlying the increased vulnerability of females to the disease.
Feasibility of multimodal metabolic analysis for detecting early changes in acute neuroinflammation.
Grist JT, Evstafev I, Olesova D … +5 more , Nynäs SE, Orešič M, Dickens AM, Tyler DJ, Couch Y
J Neuroinflammation · 2026 May · PMID 42071250 · Full text
Given the prevalence of metabolic perturbations in a variety of neurological and neurodegenerative diseases, understanding and monitoring brain metabolism is a key step in our advancement of therapies. The details of the...
Given the prevalence of metabolic perturbations in a variety of neurological and neurodegenerative diseases, understanding and monitoring brain metabolism is a key step in our advancement of therapies. The details of the citric acid cycle were established at the beginning of the last century but only recently have its metabolic intermediates been observed in vivo in the brain. In this study, we employed orthogonal analyses to investigate metabolic alterations in response to acute neuroinflammation in vivo, demonstrating a multi-technique approach that could be used for future studies.Hyperpolarized [1-C] pyruvate spectroscopy revealed an early decline in pyruvate metabolism via pyruvate dehydrogenase (PDH), leading to reduced C-bicarbonate formation. This metabolic disruption occurred despite the absence of structural or perfusion changes on conventional MRI. Further analysis of polar metabolites in the ipsilateral hemisphere confirmed ongoing inflammatory processes. These findings highlight the potential of this dual technique approach to inform upon metabolic changes due to neuroinflammation.Combining methods to probe metabolism in invasive (metabolomics) and non-invasive (hyperpolarized MRI) manners, this represents a promising translational approach for real-time metabolic assessments in an area of the body, the brain, where studying processes such as metabolism has traditionally been challenging. This study has demonstrated the approach to monitor changes in metabolism in response to inflammation in the brain.
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