J Neuroinflammation [JOURNAL]
Sun
200 papers
An unrecognized mechanism of neuroprotection by microglial TIA1-mediated stress granules to prevent neuroinflammation and demyelination in experimental autoimmune encephalomyelitis mice through sequestering ApoE mRNA.
Fu Q, Liu Y, Li F … +10 more , Wang Y, Yue J, Chen Y, Wu S, Zhang J, Jia M, He Y, Wang J, Huang Z, Wang Y
J Neuroinflammation · 2026 May · PMID 42071235 · Full text
Microglia contribute to the pathogenesis of multiple sclerosis (MS) by promoting inflammatory cascades, mediating demyelination and regulating autoimmune responses, however, the molecular mechanisms connecting cellular s...
Microglia contribute to the pathogenesis of multiple sclerosis (MS) by promoting inflammatory cascades, mediating demyelination and regulating autoimmune responses, however, the molecular mechanisms connecting cellular stress to microglia-mediated immune responses in MS remain elusive. Stress granules (SGs) serve as an adaptive response of cells to various stressors such as viral infection and oxidative stress. In this study, we found that microglial T-cell intracellular antigen 1 (TIA1), a core SG component, was upregulated in MS patients and experimental autoimmune encephalomyelitis (EAE) mice. The neuroinflammation, demyelination and clinical deficits were exacerbated in Tia1-CKO (TIA1 knockout in microglia and monocyte-derived macrophages) EAE mice. Furthermore, TIA1 microglia exhibited the heightened activation characterized by increased proliferation, enhanced phagocytic activity, and a sustained polarization toward a pro-inflammatory phenotype. Notably, in an in vitro model of NaAsO-induced stress, TIA1 deficiency in BV2 cells and primary cultured microglia resulted in both enhanced phagocytic capacity and a pro-inflammatory phenotypic shift. Mechanistically, upon to stresses, microglial TIA1-mediated SGs formation was enhanced, leading to sequester ApoE mRNA into SGs to reduce ApoE expression, which in turn prevented excessive activation of microglia and inhibited demyelination in EAE mice. These findings uncover a previously unrecognized neuroprotective mechanism wherein TIA1-mediated SGs in microglia dynamically restrain neuroinflammation via post-transcriptional control of ApoE, revealing a new therapeutic avenue for MS.
The meningeal lymphatic vessel-peripheral immune axis: a novel therapeutic target in neurodegenerative diseases.
He Z, Sun J
J Neuroinflammation · 2026 May · PMID 42071213 · Full text
Meningeal lymphatic vessels serve as a direct anatomical conduit connecting the central nervous system and the peripheral immune system, fundamentally challenging the traditional view of the brain as an "immune-privilege...
Meningeal lymphatic vessels serve as a direct anatomical conduit connecting the central nervous system and the peripheral immune system, fundamentally challenging the traditional view of the brain as an "immune-privileged" organ. This review systematically examines, for the first time, the meningeal lymphatic vessel-peripheral immune axis as an integrated framework linking central proteinopathy, neuroinflammation, and systemic immune responses in neurodegenerative diseases. We highlight recent therapeutic advances, including lymphatic regeneration via the VEGF-C pathway, peripheral immune modulation, and combinatorial approaches. We also discuss current challenges and future translational directions, emphasizing the need for integrating lymphatic imaging with immune phenotyping to enable personalized interventions. While the majority of evidence discussed derives from preclinical models, we critically evaluate its translational relevance and highlight unresolved controversies. Based on the evidence, we propose that targeting this axis offers a dual opportunity to enhance CNS waste clearance and restore immune tolerance, providing a promising framework for clinical management.
Impaired suppressive effect of FoxP3 regulatory T cells on B cells in multiple sclerosis.
Greeck VB, Würthwein C, Mimura K … +9 more , Mattes K, Kutza M, Schirmer L, Fairless R, Williams SK, Jarius S, Haas J, Ruprecht K, Wildemann B
J Neuroinflammation · 2026 May · PMID 42069653 · Full text
BACKGROUND: B cells are key contributors to the pathogenesis of many autoimmune diseases (AID), including multiple sclerosis (MS), and appear to evade the peripheral tolerance checkpoints that normally maintain immune ho...
BACKGROUND: B cells are key contributors to the pathogenesis of many autoimmune diseases (AID), including multiple sclerosis (MS), and appear to evade the peripheral tolerance checkpoints that normally maintain immune homeostasis. The fate of B cells at these checkpoints is believed to be regulated by intracellular Ca signaling cascades triggered through engagement of B cell receptors (BCR), and by the suppressive effects of regulatory T cells (Tregs). However, most of the current knowledge about Treg-B cell interaction comes from animal studies, while data from human studies, particularly in the context of AID, are sparse. In contrast, impaired Treg-mediated inhibition of conventional T cells (Tcons) has already been described for several AID, including MS. OBJECTIVE: To assess the ability of Tregs to suppress activated B cells in healthy individuals and patients with MS. METHODS: B and T cell populations were isolated from 40 MS patients and 98 age- and sex-matched healthy donors (HD). Single-cell live Ca²⁺ imaging was used to assess early activation signals in B cells. In vitro proliferation assays and coculture experiments were employed to evaluate downstream responses, including proliferation, transcription factor activation (NFATc1, NF-ĸB), interleukin 6 (IL-6) release, and surface expression levels of antigen-presenting capacity (APC) markers both in anti-IgM/anti-CD40-stimulated B cells alone, and in the presence of Tregs. RESULTS: We demonstrate that Tregs exert a robust suppressive effect on B cell proliferation, IL-6 secretion and NFATc1 which is [1] independent of Ca signaling [2], dependent on direct cell contact, and [3] impaired in MS. In contrast, early Ca responses and downstream effects of anti-IgM/anti-CD40 stimulation, including activation of NFATc1 and NF-κB, as well as proliferation, did not differ between MS- and HD-derived B cells. CONCLUSION: This study provides new data on Treg-mediated suppression of B cells in humans, including at single-cell level. Our findings show that the Treg dysfunction in MS previously described in the context of Tcon regulation extends to B cell regulation. Given the critical role of B cells in MS pathogenesis, this impaired Treg-B cell interaction may represent a previously underappreciated disease mechanism with potentially important therapeutic implications.
Piezo1 in the central nervous system: decoding the mechanical signature of neuroinflammation.
Shi G, Tan R, Cao Y … +2 more , Zheng X, Zhan R
J Neuroinflammation · 2026 May · PMID 42069634 · Full text
Neuroinflammation has historically been viewed through a biochemical lens, governed by cytokines and danger signals. While this paradigm has provided foundational insights, integrating the physical dimension of tissue st...
Neuroinflammation has historically been viewed through a biochemical lens, governed by cytokines and danger signals. While this paradigm has provided foundational insights, integrating the physical dimension of tissue stiffening, hemodynamic shear stress, and compressive forces offers a more complete understanding of the pathological microenvironment of the central nervous system (CNS). In this Review, we examine Piezo1 as an important mechanosensitive channel that can translate such physical cues into neuroinflammatory responses. We synthesize emerging evidence showing that Piezo1-mediated calcium signaling can regulate activation, migration, and metabolic reprogramming in resident CNS cells and infiltrating immune populations. Importantly, the strength of evidence is not uniform across all cell types: genetic studies provide the strongest support in microglia, oligodendrocyte-lineage cells, and endothelial cells, whereas roles in astrocytes, dendritic cells, and T cells remain more context-dependent and emerging.Furthermore, we outline the distinct mechanical signatures across major CNS pathologies and discuss how Piezo1 may shape context-dependent outcomes-from plaque-associated microglial responses in Alzheimer's disease to mechanically restricted remyelination in multiple sclerosis, acute vascular or parenchymal injury in stroke and trauma, and emerging links to seizure-associated swelling and hyperexcitability in epilepsy. Finally, we propose an integrated "Mechanical Alterations-Piezo1-Immune Regulation" framework and discuss how mechano-therapeutic strategies might be used to modulate, rather than uniformly enhance or suppress, neuroinflammatory responses.
ALS-FTD-linked CCNF drives increased hippocampal astrocyte ramification and mitochondrial dysfunction and impairs motor neuron excitability.
Robinson L, Do-Ha D, Cheng F … +19 more , Stevens CH, Rosa Porto R, Coles M, Subachandran J, Kalajdzic P, Lui J, Balez R, Sanz Muñoz S, Cabral-da-Silva MC, Berg T, Morsch M, Lisowski L, Tan RH, Burgio G, Karl T, Lee A, Chung RS, Blair I, Ooi L
J Neuroinflammation · 2026 May · PMID 42069601 · Full text
Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are neurodegenerative diseases with overlapping pathology. Mutations in CCNF, encoding the E3 ubiquitin ligase, Cyclin F, can cause ALS, FTD, or both,...
Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are neurodegenerative diseases with overlapping pathology. Mutations in CCNF, encoding the E3 ubiquitin ligase, Cyclin F, can cause ALS, FTD, or both, even within the same family. Most prior studies of CCNF have relied on overexpression systems, potentially confounding outcomes through disruption of endogenous Cyclin F. Here, we generated the first knock-in mouse model of endogenous Ccnf using CRISPR/Cas9. Heterozygous and homozygous Ccnf mice showed no motor decline or neuronal loss after 18 months, however immunohistochemistry revealed increased hippocampal astrocyte ramification, with sex-, age, and subfield-dependent effects. These data indicate that endogenous Ccnf may prime early astrocyte alterations in the absence of overt neurodegeneration. Similar astrocyte morphological changes were observed in canonically affected regions of sporadic ALS and FTD-ALS patients post mortem, as well as in CCNF iPSC-derived astrocytes following inflammatory stimulation. Proteomics on Ccnf mice identified early dysregulation of pathways related to translation, mitochondrial function, cytoskeletal remodelling, synaptic transmission and neuroinflammation. Correspondingly, CCNF iPSC-derived astrocytes displayed impaired mitochondrial membrane potential and altered network morphology under both basal and inflammatory stimuli. As altered neuronal excitability is a hallmark of ALS, we examined astrocyte-driven changes to neuronal excitability. CCNF iPSC-derived motor neurons cultured alone were hyperexcitable, firing more action potentials than isogenic controls. Remarkably, co-culture with CCNF astrocytes, but not isogenic control astrocytes, abolished repetitive firing, increased the proportion of neurons unable to generate action potentials, and reduced voltage-gated sodium currents in CCNF and isogenic control neurons. Together, these findings identify astrocyte alterations as an early feature of CCNF-mediated disease, in the absence of neuronal loss. Moreover, the combination of astrocytic mitochondrial dysfunction and the ability of CCNF astrocytes to suppress repetitive neuronal firing suggests a critical astrocyte-driven non-cell autonomous mechanism that may contribute to an oligogenic role for CCNF in ALS/FTD pathogenesis.
Acarbose modulates microglial Pkm2 acetylation to reshape immunometabolism and preserve retinal neurons after ischemia-reperfusion.
Wen Y, Dou YN, Chen X … +8 more , Liu X, Yang Z, Zhu Y, Li Z, Deng C, Deng Y, Su W, Zhuo Y
J Neuroinflammation · 2026 May · PMID 42069589 · Full text
Retinal ischemia-reperfusion (IR) elicits microglia-driven neuroinflammation and mitochondrial failure that led to retinal ganglion cell (RGCs) loss, yet effective disease-modifying therapies remain limited. Acarbose (AC...
Retinal ischemia-reperfusion (IR) elicits microglia-driven neuroinflammation and mitochondrial failure that led to retinal ganglion cell (RGCs) loss, yet effective disease-modifying therapies remain limited. Acarbose (ACA), an α-glucosidase inhibitor widely used for diabetes, has recently been recognized for its dual regulatory potential on immune metabolism and aging-associated neurodegeneration. Here, we demonstrate that intravitreal ACA administration attenuates retinal inflammation and improves RGCs survival following IR injury. Single-cell RNA sequencing revealed extensive inflammatory activation and metabolic reprogramming across the retina, characterized by enhanced nicotinamide adenine dinucleotide (NAD) catabolism, particularly in microglia. ACA treatment was associated with reversal of these alterations, replenished NAD levels, and restored mitochondrial integrity. Integrative proteomic and biochemical analyses identified pyruvate kinase, muscle-type 2 (Pkm2) as a candidate regulatory node affected by ACA. Intravitreal delivery of siPkm2 partially protected against IR injury, and co-administration with ACA produced an additive trend in neuroprotection. Mechanistically, ACA upregulated sirtuin 1 (Sirt1) and reduced Pkm2 acetylation at lysine 270 (K270), which was linked to pro-inflammatory microglial activation. Structure-based virtual screening further identified HY-113082, a small molecule targeting Pkm2-K270, which synergized with ACA to suppress inflammation and enhance retinal protection. Moreover, Pkm2Cx3cr1-Cre mice conferred partial resistance to IR injury, but blunted the additional benefit of HY-113082 when combined with ACA, consistent with on-target engagement. Our findings support that ACA exerts retinal protection through the Sirt1-Pkm2-NAD axis, suggesting a metabolic checkpoint that integrates immune and mitochondrial regulation. This study provides mechanistic insight into ACA's dual immunometabolic and neuroprotective actions, holding promise for therapeutic insights into neuroinflammation.
Retraction Note: Omega-3 polyunsaturated fatty acid attenuates traumatic brain injury-induced neuronal apoptosis by inducing autophagy through the upregulation of SIRT1-mediated deacetylation of Beclin-1.
Chen X, Pan Z, Fang Z … +7 more , Lin W, Wu S, Yang F, Li Y, Fu H, Gao H, Li S
J Neuroinflammation · 2026 May · PMID 42067910 · Full text
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SGK1 inhibition supports neuroprotection in spinal cord injury by suppressing oxidative stress and AIM2 activation via FoxO1 mediated mitophagy.
Chen Y, Wang Y, Fang N … +9 more , Xu J, Teng Y, Wang K, Huang L, Ni H, Wang Y, Zhou K, Lin Y, Li Y
J Neuroinflammation · 2026 May · PMID 42067867 · Full text
Spinal cord injury (SCI) is accompanied by a significant microglia-associated inflammatory response that is associated with secondary tissue damage and poorer functional outcomes. Serum and glucocorticoid-regulated kinas...
Spinal cord injury (SCI) is accompanied by a significant microglia-associated inflammatory response that is associated with secondary tissue damage and poorer functional outcomes. Serum and glucocorticoid-regulated kinase 1 (SGK1) has been implicated in the regulation of cell survival and neuronal excitability in various diseases. However, the role and cell-specific mechanism of SGK1 in SCI remain to be elucidated. In this study, we observed that SGK1 was predominantly expressed in microglia located at the lesion margin during the early phase of SCI in a mouse contusion model. Inhibition of SGK1 by GSK650394 has been shown to promote neural repair while simultaneously suppressing neuroinflammation and mitochondrial oxidative stress. Mechanistically, the inhibition of SGK1 results in a reduction of FoxO1 phosphorylation and the promotion of nuclear import, consequently inducing microglial mitophagy and promoting mitochondrial homeostasis, leading to the suppression of absent in melanoma 2 (AIM2) related pyroptosis and the conversion of microglia into a neuroprotective M2 phenotype. In particular, AIM2 overexpression or deletion effectively interfered with the influence of SGK1-FoxO1 on the modulation of SCI. In conclusion, the present findings provide a potential therapeutic strategy for the treatment of SCI.
MSC-EVs attenuate subretinal fibrosis in choroidal neovascularization through miR-21-5p-mediated inhibition of EMT and MMT and suppression of inflammation.
Yuan XL, Hughes D, Cui X … +10 more , Zhou R, Qi J, Yi C, Liu J, McFetridge S, Silva JD, Naderi-Meshkin H, Krasnodembskaya AD, Xu H, Chen M
J Neuroinflammation · 2026 Apr · PMID 42063159 · Full text
BACKGROUND: Subretinal fibrosis causes irreversible vision loss in neovascular age-related macular degeneration (nAMD). Sustained macular inflammation drives the initiation and progression of fibrosis by activating profi...
BACKGROUND: Subretinal fibrosis causes irreversible vision loss in neovascular age-related macular degeneration (nAMD). Sustained macular inflammation drives the initiation and progression of fibrosis by activating profibrotic cells and perpetuating tissue damage. This study investigated the therapeutic potential of mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) in mitigating nAMD-associated subretinal fibrosis. METHODS: MSC-EVs were prepared from human bone marrow-derived MSCs and characterized using nanoparticle tracking analysis, transmission electron microscopy, and Western Blotting. Subretinal fibrosis was induced in C57BL/6J mice using the two-stage laser-induced model. MSC-EVs were injected either intravitreally (1 × 10 particles/eye, single injection) or retro-orbitally (1 × 10 particles, two injections four days apart) immediately after the second laser. Eyes were collected 10 days post-second laser for immunostaining of collagen-1 and CD31 or iso-lectin B4. In vitro, primary human RPE and ARPE-19 cells were treated with TGF-β2 (10 ng/mL) to induce epithelial-mesenchymal transition (EMT); peritoneal macrophages were treated with TGF-β1 (10 ng/mL) to induce macrophage-to-myofibroblast transition (MMT). After 48 h, cells were treated with MSC-EVs (cell-to-MSC-EV ratio = 1:2000) for 3 days. Myofibroblast markers (αSMA, fibronectin, and collagen-1) were examined by immunocytochemistry and quantitative PCR (qPCR). Human iPCS-derived macrophages (iMACs), bone-marrow-derived macrophages, peritoneal macrophages, and BV2 microglia were treated with LPS (100 ng/mL) and IFN-γ (20 ng/mL) for 24 h with or without MSC-EVs (1:2000). Small RNA sequencing was used to identify specific functional molecules within MSC-EVs. Immune-related gene expressions were evaluated by qPCR. RESULTS: Intravitreal and retroorbital administration of MSC-EVs reduced collagen-1 fibrotic lesions by 46% and 30%, respectively, and significantly inhibited infiltrating Iba-1 cells. In vitro, MSC-EVs attenuated TGF-β2-induced upregulation of αSMA, fibronectin, and collagen-1 at both protein and mRNA levels in RPE cells. Similarly, the expression of Acta2, Fn1, and Col1a1 in TGF-β1-treated macrophages was also significantly reduced following MSC-EV treatment. In LPS + IFN-γ-stimulated immune cells, MSC-EVs significantly suppressed the expression of Il6 and Il1b in all cell types, and reduced the expression of Inos, Tnfa, and Cd86 in iMACs, peritoneal macrophages, and BV2 cells. Enriched hsa-miR-21-5p was identified in MSC-EVs and involved in the TGF-β-related signaling pathway. Overexpression of miR-21-5p mimic abrogated the TGF-β1-driven upregulation of pro-fibrotic markers in RPE and macrophages. CONCLUSIONS: Local administration of MSC-EVs effectively mitigated subretinal fibrosis and reduced inflammation in the mouse model of nAMD, potentially via miR-21-5p-mediated attenuation of EMT and MMT, and suppression of inflammation. MSC-EVs represent a novel cell-free therapeutic strategy for macular fibrosis in nAMD.
PTP1B in astrocytes drives pathogen-induced neurodegeneration.
He Z, Xing Y, Gu J … +16 more , Xu D, He P, Lin X, Cui W, Lv H, Ding H, Sui K, Hao W, Zheng Y, Yang X, Huang X, Yin K, He C, Zheng K, Yu Y, Pan W
J Neuroinflammation · 2026 Apr · PMID 42057007 · Full text
Mounting evidence implicates pathogen infections in the pathogenesis of Alzheimer's disease (AD), yet the cellular mechanisms underlying infection-induced neurodegeneration remain poorly understood. Central to this proce...
Mounting evidence implicates pathogen infections in the pathogenesis of Alzheimer's disease (AD), yet the cellular mechanisms underlying infection-induced neurodegeneration remain poorly understood. Central to this process is the dysfunction of astrocyte-neuron interactions, which are critical for maintaining neuroinflammatory balance and synaptic homeostasis. Here, we demonstrate that astrocytic protein tyrosine phosphatase 1B (PTP1B) acts as a key regulator of astrocyte reactivity during infection, leading to impaired neuroglial communications and cognitive decline. In a murine model of chronic Toxoplasma gondii (T. gondii) infection, elevated PTP1B levels in astrocytes were closely associated with neuroinflammation and cognitive impairments. Conditional deletion of astrocytic PTP1B or its pharmacological inhibition mitigated neuroinflammation, restored synaptic integrity, and rescued cognitive function. Mechanistically, astrocytic PTP1B induced the polarization of A1-like neurotoxic reactive astrocytes, enhanced glutamate-mediated excitotoxicity, and triggered neuronal senescence, collectively contributing to synaptic damage and cognitive deficits. Notably, elevated levels of PTP1B, GAFP and cellular senescence markers were observed in the serum samples from T. gondii IgG-seropositive individuals and in hippocampal transcriptomes from AD patients, underscoring the translational relevance. Together, our findings reveal that PTP1B-mediated disorder of astrocyte-neuron crosstalk represents a novel mechanism of pathogen-driven neurodegeneration.
Short-chain fatty acids mitigate inflammation and associated metabolic programming of human stem cell-derived enteric glial cells.
Markidi A, Zaal EA, de Wit LHC … +5 more , Mavrogeni ME, Caiazzo M, Kraneveld AD, Perez Pardo P, Berkers CR
J Neuroinflammation · 2026 Apr · PMID 42050556 · Full text
BACKGROUND: The enteric nervous system (ENS) plays a pivotal role not only in gastrointestinal function but also in neurodegenerative diseases through bidirectional communication with the central nervous system along the...
BACKGROUND: The enteric nervous system (ENS) plays a pivotal role not only in gastrointestinal function but also in neurodegenerative diseases through bidirectional communication with the central nervous system along the gut-brain axis. Enteric glial cells are central to ENS function, acting as key regulators of neuroimmune interactions. Enteric glial cell metabolism likely plays an important role in these functions. However, how pro- or anti-inflammatory stimuli influence enteric glial cell metabolism remains largely unexplored. METHODS AND RESULTS: Here, we established a human embryonic stem cell (hESC)-derived ENS model, incorporating both enteric neurons and glial cells, to investigate pro-inflammatory cytokine-induced metabolic adaptations in enteric glial cells. Cytokine exposure triggered a pro-inflammatory response associated with a metabolic shift towards glycolysis, TCA cycle and glutathione metabolism. Short-chain fatty acids (SCFAs) exhibited strong anti-inflammatory properties and reversed the observed metabolic shift. Tracer-based metabolomics further revealed that both pro-inflammatory cytokine and SCFA treatment alter glucose metabolism in hESC-derived enteric glial cells, driving them into distinct flux phenotypes. CONCLUSION: By integrating immune and metabolic perspectives, our findings identify condition-dependent glucose metabolism programs and reveal pathways that may be exploited to modulate glial activity, providing new insights into enteric glial cell biology, under homeostatic, pro-inflammatory and SCFA-rescued conditions. Overall, our findings enhance our understanding of ENS pathophysiology and lay the groundwork for identifying novel therapeutic strategies aimed at mitigating ENS inflammation in gastrointestinal and neurodegenerative disease.
Glioblastoma radiomics can delineate systemic immune activity states like blood abundance of T cell populations or transcription factors.
Heugenhauser J, Visus C, Buchroithner J … +7 more , Marosi C, Rössler K, Felzmann T, Widhalm G, Iglseder S, Nowosielski M, Erhart F
J Neuroinflammation · 2026 Apr · PMID 42050553 · Full text
BACKGROUND: Glioblastoma, the most frequent and most malign brain cancer, not only cultivates a local immunosuppressive milieu but also causes systemic immunological dynamics. Radiomics is an advanced, automated imaging...
BACKGROUND: Glioblastoma, the most frequent and most malign brain cancer, not only cultivates a local immunosuppressive milieu but also causes systemic immunological dynamics. Radiomics is an advanced, automated imaging analysis approach that harnesses data point patterns not readily visible for the human eye. It has been shown that radiomics can differentiate glioblastoma from other tumors, that it can recognize molecular features and that it can identify local immune infiltration in the tumor. However, whether radiomics can also indicate systemic, i.e. peripheral blood, immune states has not been investigated so far. METHODS: Therefore, we retrospectively analyzed magnetic resonance images of a comprehensively immunophenotyped clinical cohort (n = 34) and performed radiomics feature extraction from three morphological segments of the tumor: the necrotic core, the contrast-enhancing margin and the T2/FLAIR hyperintensive peritumoral zone. 321 radiomics dimensions were then integrated with 67 peripheral blood immunology markers (from flow cytometry and PCR). Via machine learning methods like t-SNE dimensionality reduction and hierarchical clustering, as well as regression modelling, we integrated the highly multidimensional data. RESULTS: A radiomics variable of the T2 hyperintensity zone seemed to predict T helper 17 blood levels. Radiomics variables of the necrotic core were apparently correlated with blood immune cell RORγT levels and CD15 + myeloid cell abundance. Major immune activation parameters like the number of naïve and activated CD8 + T cells, early-differentiated CD8 + T cells, CD56 + natural killer cells or levels of the T helper 1-polarizing transcription factor T-bet could be delineated by integrated multivariable modelling of radiomics features. CONCLUSIONS: In an exploratory study on a modestly-sized but immunologically well-characterized glioblastoma cohort we provide first hypothesis-generating evidence that data-driven radiomics approaches could delineate systemic immune states. In the future, non-invasive, radiomics-based blood immunology prediction could e.g. be helpful for patient stratification or immunotherapy research. Before that, however, additional confirmatory studies are needed given the inherent limitations of this work.
Lactate metabolism links reactive microglia, amyloid pathology, and Aβ dynamics.
Ashley CC, Constantino NJ, Pettit-Mee RJ … +10 more , Snipes JA, Saito K, Irmen RE, Zhang R, Neary EM, Lanning MJ, Karch CM, Johnson LA, Morganti JM, Macauley SL
J Neuroinflammation · 2026 Apr · PMID 42035056 · Full text
Alzheimer’s disease (AD) is increasingly recognized as a disorder of early immunometabolic dysfunction, yet how amyloid-β (Aβ) pathology reshapes brain metabolism and neuroinflammation remains poorly defined. Here, we de...
Alzheimer’s disease (AD) is increasingly recognized as a disorder of early immunometabolic dysfunction, yet how amyloid-β (Aβ) pathology reshapes brain metabolism and neuroinflammation remains poorly defined. Here, we demonstrate interstitial fluid (ISF) lactate levels progressively increase with amyloid plaque accumulation in APPswe/PSEN1dE9 (APP/PS1) mice, a model of cerebral amyloidosis. Stable isotope-resolved metabolomics revealed metabolic reprogramming in APP/PS1 mice, characterized by increased glycolysis at the expense of TCA cycle intermediates and neurotransmitter biosynthesis. Spatial interrogation of lactate production demonstrated lactate dehydrogenase A (Ldha), the enzyme required for lactate generation, is highly enriched in the peri-plaque microenvironment. Approximately 98% of cortical amyloid plaques were Ldha + , with Ldha preferentially localized to diffuse Aβ deposits rather than the dense core of amyloid plaques. Although most plaque-associated Ldha appeared extracellular, higher-resolution analyses demonstrated a pronounced enrichment of Ldha within peri-plaque microglia, identifying microglia as a key cellular source of plaque-associated lactate. Consistent with this, single-cell and single-nucleus transcriptomic analyses in both mouse and human brains identified microglia as the highest expressers of LDHA, with expression further increased in AD and enriched within specific microglial populations. Notably, LDHA was concentrated within a subset of glycolytic microglia (MG7) associated with cytokine production and innate immune signaling, which emerge early with amyloid pathology and decline with disease progression. Functionally, in vitro Aβ42 aggregation assays demonstrated that lactate alters Aβ aggregation kinetics and fibril stability. Critically, this immunometabolic signature was reversible; pharmacologic inhibition of lactate dehydrogenase (LDH) with stiripentol, an FDA-approved anti-seizure medication, reduced ISF Aβ levels by approximately 50% and selectively depleted peri-plaque microglia, including Cd68⁺ and Clec7a⁺ populations. Together, these data demonstrate that amyloid pathology drives early metabolic reprogramming in microglia that elevates brain lactate levels, sustains neuroinflammation, and modulates Aβ dynamics, identifying lactate metabolism as a tractable therapeutic target in presymptomatic Alzheimer’s disease.
Neural impairments caused by energy storage material NCM811 via aberrated synaptic pruning: role of Th17 cells in microglia polarization.
Dong C, Cui J, Bi Y … +3 more , Huang N, Li B, Li X
J Neuroinflammation · 2026 Apr · PMID 42032721 · Full text
INTRODUCTION: With the development of green energy technology, the Nickel (Ni)0.8Cobalt(Co)0.1Manganese(Mn)0.1(OH)₂ (NCM811) precursor has been used as a cathode material for lithium batteries due to its high energy dens...
INTRODUCTION: With the development of green energy technology, the Nickel (Ni)0.8Cobalt(Co)0.1Manganese(Mn)0.1(OH)₂ (NCM811) precursor has been used as a cathode material for lithium batteries due to its high energy density. However, this raises a concern about the risk of NCM811 exposure during raw material processing, battery production, and recycling. OBJECTIVES: This study aimed to investigate the neurotoxic effects of NCM811 particle exposure and the underlying mechanism. METHODS: C57BL/6J mice were intranasally exposed to NCM811 particles. Then, spatial memory ability was assessed using the Morris water maze. Metal accumulation and distribution in brain regions were analyzed by laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS), and histopathological changes were examined by histological staining. The proportion of peripheral T helper type 17 (Th17) cells was measured by flow cytometry, and the concentration of IL-17A in brain tissue was determined by ELISA. The effect of IL-17A on microglia was further verified in il17ra knockout mice. Furthermore, an agonist of the cAMP pathway was administered to examine its protective effects against NCM811 exposure. RESULTS: NCM811exposure resulted in spatial memory impairment in mice, accompanied by increased Mn²⁺ deposition in the hippocampus and microglial M1 polarization. NCM811 exposure also increased the proportion of Th17 cells in the periphery, accompanied by enhanced Th17 cell infiltration and elevated IL-17A levels in brain tissues. Mechanistically, IL-17A activated microglia via the IL-17RA, suppressed the cAMP-CREB pathway, and promoted M1 polarization, subsequently leading to aberrant synaptic pruning and neurotransmitter dysregulation. Administration of a cAMP agonist blocked microglial M1 polarization induced by NCM811. Il17ra knockout mice effectively resisted these neural effects. CONCLUSION: Our findings elucidate a novel mechanism by which NCM811 induces neurotoxicity through Th17 cell-mediated microglial polarization, providing potential therapeutic targets for cognitive dysfunction associated with battery material exposure in the context of green energy and sustainable development.
Glymphatic dysfunction contributes to thalamic iron retention and secondary thalamic injury after stroke: evidence from primates and rodents.
Wei J, Chen X, Lei Q … +8 more , Xie J, Long X, Xiong Z, Yang M, Zha L, Huang W, Ouyang F, Zeng J
J Neuroinflammation · 2026 Apr · PMID 42032717 · Full text
BACKGROUND: Secondary neurodegeneration, characterized by neuronal loss and neuroinflammation, in the remote thalamus is associated with post-stroke cognitive impairment (PSCI). This study aimed to elucidate common patho...
BACKGROUND: Secondary neurodegeneration, characterized by neuronal loss and neuroinflammation, in the remote thalamus is associated with post-stroke cognitive impairment (PSCI). This study aimed to elucidate common pathological mechanism of the secondary neurodegeneration in both primates and rodents. METHODS: Thalamic amyloid-β (Aβ), iron deposition and glymphatic dysfunction was assessed across primate and rodent stroke models in different time points, using histopathological, and magnetic resonance imaging methods. Proteomic analysis was performed to explore the molecular mechanisms underlying the secondary thalamic damage. Neuronal loss and neuroinflammation were assessed through histopathological methods. Using aquaporin-4 (AQP4) inhibitor, we investigated whether glymphatic inhibition aggravated thalamic iron deposition and PSCI. RESULTS: Aβ accumulated in the remote thalamus of mice but was absent in cynomolgus monkeys by imaging and histology, and Aβ40/42 remained unchanged in plasma and cerebrospinal fluid in monkeys following stroke. Instead, quantitative susceptibility mapping MRI and Prussian blue staining uncovered progressive iron deposition in the remote thalamus shared by both species, alongside ferroptosis activation. Glymphatic imaging and AQP4 analyses showed impaired glymphatic clearance and loss of AQP4 perivascular polarization, which worsened along with time. Both stroke monkeys and mice exhibited neuronal injury and increased neuroinflammation in the remote thalamus, with cognitive impairment. Glymphatic inhibition with TGN-020 exacerbated iron deposition and ferroptosis, leading to more severe neuronal loss and microglial proliferation, ultimately aggravating PSCI. In addition, CD31 and ZO-1 co-immunostaining demonstrated blood-brain-barrier damage, with reduced ZO-1 colocalization with CD31. CONCLUSIONS: Iron deposition and ferroptosis-related changes were consistently observed in the remote thalamus across both rodent and primate models, whereas Aβ accumulation appeared to be species-dependent. Glymphatic dysfunction and blood-brain barrier damage in the remote thalamus may jointly facilitates iron accumulation and ferroptosis.
Blood vessel-associated inflammatory microglia and astrocytes are associated with molecular and cellular markers of blood-brain barrier permeability in neonatal mice infected with the respiratory pathogen Bordetella pertussis.
O'Neill E, Lynch MA, Mills KHG
J Neuroinflammation · 2026 Apr · PMID 42032708 · Full text
Severe infection with the respiratory pathogen Bordetella pertussis during infancy has been associated with neurological complications, but the underlying mechanisms are not fully understood. Here we examined the impact...
Severe infection with the respiratory pathogen Bordetella pertussis during infancy has been associated with neurological complications, but the underlying mechanisms are not fully understood. Here we examined the impact of infection of neonatal mice with B. pertussis on the blood-brain barrier (BBB) by assessing pericytes, endothelial cells and tight junctions in cortex. We report that B. pertussis infection was associated with altered spatial distribution of brain pericytes, together with cerebral vasodilation and changes in endothelial cell tight junctions, as well as enhanced vascular deposition of the alarmin S100β. We demonstrate that, while there was an increase in the number of GFAP+ blood vessel-associated astrocytes, expression of the end foot marker, aquaporin 4 (AQP4), was decreased in these astrocytes. Microglia from the cortex of infected mice adopted a reactive morphology, migrated towards blood vessels and internalised AQP4 to a greater extent than microglia in un-infected mice. This study indicates that disruption of the BBB, inferred from structural and molecular alterations, during infection of neonatal mice with B. pertussis is linked to activation of vessel-associated microglia and astrocytes. Our findings suggest that the neurological sequelae associated with critical pertussis in infancy may be due, at least in part, to breakdown of the BBB.
Microglial cholesterol reprogramming drives cognitive impairment under hypobaric hypoxia.
Cao S, Ni W, Fang Y … +4 more , Luo Q, Zhu L, Dong Z, Wang X
J Neuroinflammation · 2026 Apr · PMID 42026659 · Full text
BACKGROUND: High-altitude cognitive impairment (HACI) is an irreversible neurological disorder with limited treatment options. Dysregulation of cholesterol homeostasis is an established mechanism of cognitive impairment....
BACKGROUND: High-altitude cognitive impairment (HACI) is an irreversible neurological disorder with limited treatment options. Dysregulation of cholesterol homeostasis is an established mechanism of cognitive impairment. However, whether cholesterol dysregulation is involved in HACI remains unknown. OBJECTIVE: This study aims to investigate the role of cholesterol in HACI pathogenesis and elucidate the molecular mechanisms through which high-altitude hypoxia disrupts cholesterol homeostasis. METHODS: Mice were exposed to hypobaric hypoxia (HH, 7000 m) followed by recovery assays. Cholesterol levels and cognitive function were monitored over time. Microglial depletion (PLX5622), RNA-seq/ATAC-seq, JASPAR analysis, Cut&Tag, and microglia-specific NRF1 knockout were used to dissect molecular pathways. RESULTS: HH exposure in mice induced intracranial cholesterol accumulation, which preceded cognitive decline. Microglial depletion abolished HH-induced intracranial cholesterol accumulation. Multi-omics analyses revealed that hypoxia triggers NRF1-mediated transcriptional activation of HSP90 subunits (Hsp90aa1/Hsp90ab1), leading to SREBP2 nuclear translocation and subsequent activation of cholesterol synthesis. Notably, microglia-specific NRF1 knockout reversed these pathological changes, normalizing cholesterol levels, preventing synaptic loss, and preserving cognitive function under HH. CONCLUSION: HH exposure upregulates NRF1 in microglia, which induces HSP90 expression and activates the SREBP2-mediated cholesterol synthesis. This cascade promotes pro-inflammatory microglial activation and synaptic pruning, culminating in cognitive impairment. Targeting NRF1 represents a potential therapeutic strategy for HACI.
Polyhexamethylene guanidine phosphate exposure induces abnormal behaviors by disrupting synaptic formation and activity in the cerebral cortex.
Ko MY, Choi J, Min E … +9 more , Kim M, Song MK, Kim DI, Park J, Park H, Lee BS, Lee K, Hyun SA, Ka M
J Neuroinflammation · 2026 Apr · PMID 42026629 · Full text
BACKGROUND: Polyhexamethylene guanidine phosphate (PHMG-p), a commonly utilized ingredient in humidifier disinfectants, has emerged as a primary factor contributing to pulmonary damage, asthmatic conditions, and prenatal...
BACKGROUND: Polyhexamethylene guanidine phosphate (PHMG-p), a commonly utilized ingredient in humidifier disinfectants, has emerged as a primary factor contributing to pulmonary damage, asthmatic conditions, and prenatal complications in South Korea. Nevertheless, the extended neurological impacts resulting from PHMG-p exposure have not been adequately investigated. Our objective was to examine the fundamental mechanisms underlying PHMG-p-triggered neurological dysfunction in a murine model after biocide exposure. METHODS: Adult mice aged eight weeks underwent intratracheal instillation (ITI) with either PHMG-p solution (0.9 mg/kg) or saline solution (serving as controls). After a four-week recuperation interval, we examined histopathological features including inflammatory responses and fibrotic alterations in lung tissue. Behavioral performance was assessed through open field testing, Y-maze evaluation, and Rotarod performance tests. Brain tissue molecular characteristics were investigated via RNA sequencing, RT-PCR analysis, and western blot techniques. Cellular composition in neural tissues was determined using immunofluorescence methods. RESULTS: Four weeks after the exposure, the brains of the mice displayed abnormal neuronal and astrocyte populations owing to activated neuronal death. Notably, exposure to PHMG-p impaired synaptic formation and altered behavioral patterns in the mice. The observed changes appeared to be associated with transfer RNA (tRNA)-mediated neuronal death and synaptic formation, as RNA sequencing-based gene ontology analysis revealed the downregulation of tRNA expression following PHMG-p exposure. CONCLUSION: These findings enhance our understanding of the pathophysiological mechanisms triggered by PHMG-p exposure.
Dopamine signaling governs macrophage-mediated acute lung injury through JAML/IL-10-coupled mitochondrial regulation.
Wu D, Liao X, Gao J … +8 more , Wang M, Meng L, Xu W, He Y, Zhang Q, Li Q, Wang K, Gao W
J Neuroinflammation · 2026 Apr · PMID 42026623 · Full text
Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) remain devastating clinical entities characterized by uncontrolled pulmonary inflammation driven by dysregulated macrophage activation, with limited...
Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) remain devastating clinical entities characterized by uncontrolled pulmonary inflammation driven by dysregulated macrophage activation, with limited therapeutic options and high mortality. Emerging evidence implicates neuroimmune crosstalk as a pivotal regulator in inflammatory disorders, yet the role of dopaminergic signaling in orchestrating macrophage function during ALI remains ill-defined. Herein, we systematically characterized the dynamic perturbations of pulmonary dopaminergic signaling during ALI/ARDS progression and delineated the anti-inflammatory and cytoprotective properties of dopamine (DA) D1-like receptor (D1R) signaling in ALI mouse model and targeted macrophages. Mechanistically, DA-D1R activation mitigated macrophage hyperactivation by reversing lipopolysaccharide-induced mitochondrial dysfunction, thereby curbing excessive M1 polarization and maintaining cellular homeostasis. Transcriptomic profiling identified junctional adhesion molecule-like protein (JAML) as a critical downstream effector of the D1R agonist SKF38393 (SKF) in macrophages. SKF downregulated JAML expression and its interaction with interleukin (IL)-10, thus enhancing IL-10 bioavailability to sustain mitochondrial integrity and limit oxidative damage. Notably, the anti-inflammatory capacity of DA bioactivity system was validated in macrophages from ARDS patients and healthy controls, underscoring its translational potential. Collectively, our findings unravel a previously unrecognized DA-D1R-JAML/IL-10-mitochondria axis that governs macrophage-mediated ALI, positioning dopaminergic signaling as a promising therapeutic target for ARDS and other inflammatory disorders involving neuroimmune dysfunction.
Tryptophan-kynurenine metabolic reprogramming along the gut-brain axis alleviates Alzheimer's pathology.
Choi H, Hong SB, Kim Y … +11 more , Joung H, Choi Y, Cha J, Park JY, Lee YS, Choi H, Han JW, Kim KH, Shin CH, Lee DY, Mook-Jung I
J Neuroinflammation · 2026 Apr · PMID 42026585 · Full text
The gut–brain axis influences neuroinflammation and metabolic homeostasis in Alzheimer’s disease (AD). Disruption of gut microbiota and barrier function promotes amyloid and tau pathology via immune and metabolic dysregu...
The gut–brain axis influences neuroinflammation and metabolic homeostasis in Alzheimer’s disease (AD). Disruption of gut microbiota and barrier function promotes amyloid and tau pathology via immune and metabolic dysregulation. In this study, Limosilactobacillus fermentum SRK414 (SRK414) was orally administered to ADLPAPT mice, resulting in reduced Aβ and tau pathology and improved cognition. Multi-omics analysis revealed that SRK414 altered gut microbial composition and increased hippocampal kynurenic acid (KYNA), a metabolite linked to neuroimmune regulation. Increased hippocampal KYNA was associated with metabolic changes consistent with enhanced neuronal fatty acid oxidation, reduced lipid accumulation, and suppressed microglial activation, suggesting improved hippocampal homeostasis. In vitro studies further showed that KYNA attenuated tau-related and inflammatory phenotypes. These findings support a link between gut microbial modulation and brain resilience, and suggest that KYNA may contribute to the neuroprotective effects associated with SRK414 treatment. This study highlights metabolites modulated by SRK414 administration as potential mediators of microbiota-based therapeutic effects in AD.
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