J Neuroinflammation [JOURNAL]
Sun
200 papers
Targeting the cGAS-STING pathway alleviates neuroinflammation and cognitive impairment induced by chronic infection of Toxoplasma gondii.
Xing Y, Lv H, He P … +10 more , Xu Y, Shen W, Gu Z, Zeng F, Zhang Y, Sui K, Shi Y, Yu Y, Pan W, He C
J Neuroinflammation · 2026 Jul · PMID 42401926 · Full text
Chronic infection of Toxoplasma gondii has been established as a contributor to cognitive impairment via inducing sustained neuroinflammation and synaptic damage. However, the underlying mechanisms remain poorly understo...
Chronic infection of Toxoplasma gondii has been established as a contributor to cognitive impairment via inducing sustained neuroinflammation and synaptic damage. However, the underlying mechanisms remain poorly understood. As a key regulator of both neuroinflammation and cellular senescence, Cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway is implicated in pathogenesis induced by T. gondii infection. Here, we found that cGAS-STING pathway was activated in the cerebral cortex of mouse chronically infected with T. gondii, as indicated by the elevated protein levels of cGAS and STING, and increased phosphorylation of TBK1 and IRF3. Pharmacological inhibition of this pathway with RU.521 and H151, specific inhibitors of cGAS and STING, significantly alleviated T. gondii-induced cognitive impairment and neuronal damage. Moreover, chronic T. gondii infection was shown to trigger senescence characterized by increased expression of senescence markers P16, P21 and P53, and senescence-associated secretory phenotypes (SASPs), including Il-1β, Il-6, Tnf-α, Cxcl1, Cxcl10 and Mmp9. In addition, elevated expression of β-galactosidase, a senescence marker, was predominantly observed in neurons compared to microglia and astrocytes, indicating a primary role for neurons in infection-associated senescence. Notably, these phenotypes of senescence were rescued by inhibition of the cGAS-STING pathway. Collectively, our findings demonstrate that chronic infection of T. gondii activates the cGAS-STING pathway, which in turn drives neuroinflammation and cognitive dysfunction in which neuronal senescence plays a contributory role. Targeting this pathway alleviates T. gondii-induced cognitive decline, highlighting its therapeutic potential against infection-triggered neurodegenerative diseases.
Dysregulated glia and periglomerular cells in the olfactory bulb and altered lipocalins in the olfactory epithelium underlie olfactory dysfunction in a murine model of eosinophilic chronic rhinosinusitis.
Kagoya R, Nishijima H, Horikiri K … +4 more , Ogawa K, Kishimoto-Urata M, Urata S, Kondo K
J Neuroinflammation · 2026 Jul · PMID 42401910 · Full text
BACKGROUND: Eosinophilic chronic rhinosinusitis (ECRS) is a chronic inflammatory disease. It is characterized by type 2 inflammation and olfactory dysfunction. Although olfactory dysfunction in patients with ECRS may hav...
BACKGROUND: Eosinophilic chronic rhinosinusitis (ECRS) is a chronic inflammatory disease. It is characterized by type 2 inflammation and olfactory dysfunction. Although olfactory dysfunction in patients with ECRS may have sensorineural and central components, the underlying mechanism remains to be elucidated. We aimed to investigate changes in the olfactory bulb (OB) and olfactory epithelium (OE) associated with sinonasal type 2 inflammation, using a murine model of ECRS. METHODS: We developed a murine model of ECRS based on the topical application of calcipotriol and ovalbumin for 14 days and subsequent daily intranasal challenge with ovalbumin for 5 days. Histopathological analyses were performed to assess glial cells and periglomerular cells (PGCs) in the OB. Bulk RNA sequencing was performed to determine the impact of sinonasal type 2 inflammation on the OB and OE. Differentially expressed genes were identified using a false discovery rate < 0.05 (Benjamini-Hochberg adjustment). For molecules exhibiting marked fluctuations at the gene expression level, the protein expression was evaluated using enzyme-linked immunosorbent assay (ELISA). RESULTS: In the ECRS group, a significant increase was noted in the number of microglia/macrophages and astrocytes in the OB. In addition, the number of tyrosine hydroxylase-positive PGCs was significantly reduced in the OB of mice with ECRS. Bulk RNA sequencing analysis revealed a significant decrease in the gene expression levels of the lipocalin family in both the OB and OE. Subsequent ELISA confirmed a significant reduction in the protein levels of lipocalin 4 and major urinary protein 5 in the OE; conversely, lipocalin 3 levels in the OE were significantly increased. No significant differences were observed in the protein expression levels of these molecules within the OB. CONCLUSION: Sinonasal type 2 inflammation causes various changes in the olfactory system. These changes may be involved in the pathogenesis of sensorineural and central olfactory dysfunction in ECRS.
Human umbilical cord blood mononuclear cells ameliorate vascular dementia by modulating microglial myelin debris handling and white matter injury.
Wen X, He K, Huang C … +5 more , Shi C, Wei W, Zhang Y, Yang Z, Li K
J Neuroinflammation · 2026 Jul · PMID 42400069 · Full text
Vascular dementia (VaD), characterized by white matter damage and cognitive decline, currently lacks effective therapeutic options. Human umbilical cord blood mononuclear cells (hUCB-MNCs) have shown neuroprotective and...
Vascular dementia (VaD), characterized by white matter damage and cognitive decline, currently lacks effective therapeutic options. Human umbilical cord blood mononuclear cells (hUCB-MNCs) have shown neuroprotective and immunomodulatory properties; however, their therapeutic efficacy and underlying mechanisms in VaD remain incompletely understood. In this study, we investigated the effects of hUCB-MNCs treatment in a mouse model of VaD induced by bilateral common carotid artery stenosis (BCAS). Behavioral assessments showed that hUCB-MNCs treatment improved cognitive performance, affective-like behaviors, and motor coordination in BCAS mice. Histopathological analyses demonstrated that hUCB-MNCs treatment attenuated white matter injury, preserved myelin integrity, and mitigated neuronal and synaptic damage. Integrated transcriptomic and proteomic analyses of corpus callosum (CC) tissues revealed enrichment of immune-regulatory, phagocytosis-related, and phosphoinositide 3-kinase/protein kinase B (PI3K/AKT)-associated pathways after hUCB-MNCs treatment. In vivo and in vitro analyses further indicated that hUCB-MNCs helped preserve microglial homeostatic features and improved myelin debris-handling responses. Collectively, these findings suggest that hUCB-MNCs ameliorate VaD-associated pathology, at least in part, by modulating microglial myelin debris-handling responses and PI3K/AKT-related signaling, highlighting hUCB-MNCs as a promising cell-based therapeutic candidate for VaD.
Neuron-specific deletion of ADAR1 induces brain malformation and early postnatal lethality.
Todo H, Yang J, Vongpipatana T … +3 more , Shibuya T, Nakahama T, Kawahara Y
J Neuroinflammation · 2026 Jul · PMID 42400013 · Full text
Adenosine deaminase acting on RNA 1 (ADAR1), which mediates adenosine-to-inosine RNA editing, is expressed as two isoforms, p110 and p150. Deletion of Adar1 p150 in mice results in embryonic lethality caused by aberrant...
Adenosine deaminase acting on RNA 1 (ADAR1), which mediates adenosine-to-inosine RNA editing, is expressed as two isoforms, p110 and p150. Deletion of Adar1 p150 in mice results in embryonic lethality caused by aberrant activation of melanoma differentiation-associated protein 5 (MDA5)-mediated sensing of unedited endogenous transcripts, whereas Adar1 p110-specific deficient mice die postnatally through RNA editing-independent mechanisms. ADAR1 mutations cause Aicardi-Goutières syndrome (AGS), a congenital autoinflammatory disease accompanied by encephalopathy with a type I interferon (IFN) signature. However, the roles of ADAR1 in neurons remain elusive. Here, we show that neuron-specific deletion of Adar1 (both p110 and p150) in mice caused early postnatal lethality with elevated expression of type I IFN-stimulated genes (ISGs). Ventricular obstruction due to hypoplasia of the choroid plexus and ependymal cells, which was accompanied by gliosis, was observed. Of note, both selective restoration of ADAR1 p150 function and deletion of MDA5 largely normalized type I ISG expression and ameliorated ventricular obstruction but failed to rescue early postnatal lethality. Furthermore, selective restoration of RNA editing-independent function of ADAR1 p110 was also insufficient to rescue the early postnatal lethality, suggesting that both ADAR1 p110 and p150 in neurons are essential for postnatal survival.
Regional mapping of CSF1R-positive microglia in neurodegenerative diseases and progressive MS, with exploratory presynaptic marker analyses.
Bavarsad MS, Pereira FL, Reinhardt MM … +7 more , Satpati A, Spina S, Seeley WW, Jagust W, Rabinovici GD, Green A, Grinberg LT
J Neuroinflammation · 2026 Jul · PMID 42399983 · Full text
BACKGROUND: Microglial colony-stimulating factor-1 receptor (CSF1R) is a therapeutic and imaging target, yet the regional, disease-specific distribution of CSF1R-positive microglia in the human brain remains incompletely...
BACKGROUND: Microglial colony-stimulating factor-1 receptor (CSF1R) is a therapeutic and imaging target, yet the regional, disease-specific distribution of CSF1R-positive microglia in the human brain remains incompletely defined, limiting interpretation of emerging CSF1R-PET signals. We sought to build a cross-disease, multi-region, quantitative map of CSF1R-positive microglia in neurodegenerative conditions and progressive multiple sclerosis (MS) lesions, with an exploratory comparison to presynaptic marker burden. METHODS: CSF1R mRNA‑positive microglia were quantified by RNAscope across six cortical regions (MFG, IFG, ITG, AG, CA1, EC) in early‑onset Alzheimer's disease (EOAD), late‑onset AD (LOAD), progressive supranuclear palsy (PSP), and frontotemporal lobar degeneration with TDP-43 inclusions due to progranulin mutation (FTLD‑GRN), and in primary and secondary progressive MS (PPMS, SPMS) within cortical gray‑matter plaques, plaque-adjacent gray matter and white matter. Positivity was defined a priori as ≥ 3 puncta with housekeeping‑probe pass and negative‑control verification, counting blinded, and densities were cortical‑thickness corrected. Iba-1 immunolabeling verified microglial identity. Western blot provided protein‑level verification. We explored ROI‑level associations of CSF1R with SV2A and synaptophysin previously measured in the same regions/cases. RESULTS: In neurodegeneration, increases were smaller and region‑specific (e.g., EOAD-ITG/CA1; LOAD-AG; PSP-AG; FTLD‑GRN-IFG/ITG/AG/EC), with minimal white‑matter change. In progressive MS, gray-matter CSF1R-positive microglia densities did not differ from controls, whereas SPMS white matter was increased. Exploratory analysis showed that CSF1R and SV2A were positively associated across ROIs in neurodegenerative diseases (e.g., PSP approximately ρ = 0.66), and weakest in LOAD; synaptophysin showed similar patterns, suggesting that regions with higher CSF1R-positive microglia density can coincide with relative preservation of presynaptic markers. CONCLUSIONS: A cross‑disease, region‑resolved map reveals region‑specific changes in CSF1R + cell density in neurodegeneration, but only white matter in MS. These findings provide the histological context needed to interpret future CSF1R‑PET. Prospective studies pairing CSF1R‑PET with SV2A‑PET and multiplex tissue profiling are warranted to define microglial states and synaptic outcomes in vivo.
Microglial checkpoint collapse in Alzheimer's disease: a tri-axial framework for biomarker-informed neuroimmune therapy.
Zhang J, Yang N, Zou P … +1 more , Zong X
J Neuroinflammation · 2026 Jul · PMID 42393750 · Full text
BACKGROUND: Anti-amyloid antibodies have validated amyloid-β (Aβ) as a disease-relevant target in Alzheimer's disease (AD), but their modest clinical effect, efficacy largely restricted to early disease, and amyloid-rela...
BACKGROUND: Anti-amyloid antibodies have validated amyloid-β (Aβ) as a disease-relevant target in Alzheimer's disease (AD), but their modest clinical effect, efficacy largely restricted to early disease, and amyloid-related imaging abnormalities (ARIA) indicate that Aβ removal alone does not resolve the glial, lipid, and inflammatory programmes that sustain neurodegeneration. Microglia sit at the centre of this therapeutic gap. Single-nucleus and spatial profiling has resolved several AD-associated microglial states, yet state labels remain descriptive and do not explain why adaptive engagement becomes maladaptive. MAIN BODY: We frame AD-relevant microglial dysfunction as checkpoint collapse: progressive failure of regulatory nodes that coordinate lipid sensing, lysosomal competence, neuronal restraint, and inflammatory threshold control. The central nodes are TREM2-mediated lipid and apolipoprotein sensing, progranulin-associated lysosomal regulation, CX3CR1-dependent neuron-microglia restraint, and CD33/Siglec-3 inhibitory tone. When these controls destabilise, downstream pathology can be organised around three coupled effector axes: a lipid axis centred on APOE-biased cholesterol trafficking, ACSL1/DGAT2-driven lipid-droplet accumulation, and impaired lysosomal flux; an iron/ferroptosis axis involving labile iron, phospholipid peroxidation, and insufficient GPX4/FSP1 defences; and an inflammation/complement axis linking NLRP3 activation, type-I interferon signalling, and C1q/C3-dependent synaptic engulfment to tau pathology and synapse loss. White-matter injury, astrocyte-microglia crosstalk, and cGAS-STING-linked senescence are integrated as cross-axis amplifiers. CONCLUSIONS: This framework is proposed as a hypothesis-generating scaffold for biomarker-informed translational studies, rather than as a validated clinical stratification system. It may help organise stage-aware therapeutic hypotheses, including regulatory-node preservation in early disease, lipid-handling restoration and ferroptosis control at intermediate stages, and complement- or senescence-directed modulation in later disease. Current glial, iron, inflammatory, and imaging biomarkers remain insufficiently specific to assign individual patients reliably to discrete pathological axes in clinical practice.
SGK1-mediated deficits in microglial phagocytosis drive pathological progression in amyotrophic lateral sclerosis.
He M, Wu C, Hu M … +6 more , Shi X, Liu R, Tong Y, Wang H, Hu H, Liao H
J Neuroinflammation · 2026 Jul · PMID 42387584 · Full text
Alterations in microglial function and transcriptomic profiles are major pathological hallmarks of amyotrophic lateral sclerosis (ALS). However, the dynamics and regulatory mechanisms underlying microglial phagocytic act...
Alterations in microglial function and transcriptomic profiles are major pathological hallmarks of amyotrophic lateral sclerosis (ALS). However, the dynamics and regulatory mechanisms underlying microglial phagocytic activity during disease progression remain unclear. In this study, we observed stage-dependent alterations in microglial phagocytic activity during disease progression in SOD1 mice. Single-cell RNA sequencing suggested that this change was associated with a reduced abundance of microglial subpopulations enriched for phagocytosis-related pathways. Transcriptomic analysis identified serum- and glucocorticoid-regulated kinase 1 (SGK1) as a potential mediator of this process. Notably, sgk1 knockout in SOD1 mice was associated with improved microglial clearance of myelin debris and reduced aberrant engulfment of neuronal material after disease onset. Our results further showed that, after disease onset, the accumulation of myelin debris and apoptotic neurons induced SGK1 upregulation in microglia from SOD1 mice. Mechanistically, SGK1 appeared to promote lipid accumulation in microglia by suppressing lipophagy, thereby impairing the ability of microglia to clear cellular debris. Moreover, pharmacological inhibition of SGK1 with GSK650394 attenuated motor deficits and prolonged survival in SOD1 mice. Together, our findings provide evidence for a previously unrecognized role of SGK1 in regulating microglial phagocytosis in ALS models and support SGK1 as a potential therapeutic target in SOD1 mutation-associated ALS models.
HSV-1 reactivation as an emergent property of neuronal stress: implications for traumatic brain injury.
Stewart AR, Saucedo AB, Beauregard LL … +3 more , Link CD, Niemeyer CS, Rowe RK
J Neuroinflammation · 2026 Jul · PMID 42387516 · Full text
Herpes simplex virus type 1 (HSV-1) establishes lifelong latency in neurons, with reactivation driven by multiple molecular, cellular, and systemic stressors. While several individual mechanisms of reactivation have been...
Herpes simplex virus type 1 (HSV-1) establishes lifelong latency in neurons, with reactivation driven by multiple molecular, cellular, and systemic stressors. While several individual mechanisms of reactivation have been well characterized, there are potentially other unresolved vulnerabilities that drive HSV-1 reactivation. Traumatic brain injury (TBI) has emerged as a potential trigger of HSV-1 reactivation and represents a complex and clinically relevant perturbation that disrupts neuronal homeostasis, immune surveillance, and inflammatory signaling, processes that are also central to HSV-1 latency and reactivation. However, the mechanisms linking TBI to HSV-1 reactivation remain poorly understood.In this review, we examine whether known mechanisms of TBI-induced cellular stress overlap with pathways implicated in HSV-1 latency and reactivation. We synthesize shared mechanisms, including stress signaling, neuroinflammation, and immune dysregulation during TBI that may create conditions permissive for HSV-1 reactivation in the injured brain. This integrated perspective reframes TBI as a context in which established drivers of HSV-1 reactivation converge and may increase reactivation susceptibility.We propose that HSV-1 reactivation is an emergent property of dysregulated neural systems and that TBI may engage many of these processes. In this framework, viral reactivation is inseparable from the broader neuronal and systemic context in which it occurs. This perspective highlights the importance of integrating neural state, injury, and immune dynamics into models of HSV-1 latency and reactivation. Advancing this multidimensional view will be critical for developing therapeutic strategies that not only suppress viral reactivation but also address neuroinflammation following brain injury.
Neuropsychiatric disorders in pulmonary fibrosis: from brain network alterations to inflammatory mechanisms and therapeutic implications.
Li C, Wang L, Wang F … +9 more , Wang L, Xu L, Lyu W, Shan K, Li J, Zhou H, Rong F, Kong X, Wei P
J Neuroinflammation · 2026 Jun · PMID 42380891 · Full text
Pulmonary fibrosis encompasses a spectrum of chronic lung diseases characterized by progressive scarring of lung tissue, ultimately leading to respiratory failure. Emerging clinical evidence indicates that pulmonary fibr...
Pulmonary fibrosis encompasses a spectrum of chronic lung diseases characterized by progressive scarring of lung tissue, ultimately leading to respiratory failure. Emerging clinical evidence indicates that pulmonary fibrosis patients frequently experience comorbid neuropsychiatric disorders, including cognitive impairment, anxiety, and depression. These complications significantly impact patients' quality of life and treatment outcomes. However, the mechanisms underlying this comorbidity remain incompletely understood, and there is a lack of effective interventions. This review summarizes the latest clinical evidence linking pulmonary fibrosis to neuropsychiatric complications and contributes to the understanding of the underlying mechanisms through the lung-brain axis theory. Studies indicate that various pulmonary fibrosis subtypes, including idiopathic pulmonary fibrosis and pneumoconiosis, exhibit high prevalence of neuropsychiatric disorders and abnormal brain networks, indicating a close pathophysiological connection between pulmonary fibrosis and neuropsychiatric complications. At the mechanistic level, accumulating experimental evidence suggests that pulmonary fibrosis may induce central nervous system damage through three interrelated pathways: (1) Systemic dissemination of pulmonary inflammation leads to blood-brain barrier disruption and microglial activation; (2) Chronic hypoxia exacerbates neuroinflammation and synaptic dysfunction; (3) The inhaled particulate matter enters the brain from the olfactory mucosa through the olfactory bulb or crosses the damaged alveolar capillary barrier, enters the circulation, and then passes through the already damaged blood-brain barrier, inducing local neurotoxicity. Furthermore, we advocate for actively exploring a comprehensive treatment model that shifts from "lung-focused therapy" to "lung-brain co-therapy". This approach employs multiple interventions-including medication, pulmonary rehabilitation training, and cognitive training-to prevent or delay systemic complications, including neuropsychiatric damage, in pulmonary fibrosis patients. Elucidating the lung-brain axis in pulmonary fibrosis may open new avenues for a more comprehensive understanding, early intervention, and holistic management of this devastating disease.
Hereditary spastic paraplegia (HSP) gene 11 (Spg11) attenuates lipid accumulation in myeloid cells and neuroinflammation in the midbrain without affecting α-synuclein pathology.
Hayne M, Lipka J, Lucas TA … +10 more , Soung AL, Adrian M, Ghosh S, Lin H, Chu S, Stark K, Ngu H, Foreman O, Kaminker J, Hoogenraad CC
J Neuroinflammation · 2026 Jun · PMID 42374481 · Full text
Hereditary spastic paraplegia type 11 (SPG11-HSP) is a neurodegenerative disorder caused by mutations in SPG11, which encodes the large scaffolding protein spatacsin, involved in lysosomal and autophagosomal trafficking....
Hereditary spastic paraplegia type 11 (SPG11-HSP) is a neurodegenerative disorder caused by mutations in SPG11, which encodes the large scaffolding protein spatacsin, involved in lysosomal and autophagosomal trafficking. A portion of patients with SPG11 mutations present with parkinsonism features. While spatacsin dysfunction is linked to neurodegeneration, the underlying cellular mechanisms, especially in the midbrain, remain largely unclear. Here, we demonstrate that loss of Spg11 in mice results in neuroinflammation and lipid accumulation in myeloid cells. Bulk RNA sequencing revealed a strong upregulation of microglial genes in the midbrain of Spg11 knockouts, supported by increased CD68 and CLEC7A expression and morphological changes consistent with microglial activation. Spg11 depletion in two in vivo models of synucleinopathy revealed no enhancement of phosphorylated α-synuclein-positive inclusions or dopaminergic neuron loss; however, the mice did exhibit Spg11-dependent microglial reactivity. Further in vitro studies using primary bone-derived macrophages revealed increased phagocytic capacity and neutral lipid accumulation under basal and stress conditions. These findings support a model where SPG11 is a critical regulator of microglial activation and myeloid lipid metabolism, contributing to neurodegeneration through pathways distinct from α-synuclein-mediated pathology.
N-Acetylcysteine protects the developing brain in neonatal sepsis-like inflammation via a redox-neurovascular pathway.
Cheng P, Zhang S, Zhang X … +11 more , Li W, Du M, Li M, Yu Z, Zhu J, Zeng G, Xu Y, Sun H, Kang W, Wang X, Zhu C
J Neuroinflammation · 2026 Jun · PMID 42374475 · Full text
BACKGROUND: Neonatal sepsis can disrupt brain development through oxidative stress, blood-brain barrier (BBB) dysfunction, peripheral leukocyte infiltration, and white matter injury. N-acetylcysteine (NAC), a glutathione...
BACKGROUND: Neonatal sepsis can disrupt brain development through oxidative stress, blood-brain barrier (BBB) dysfunction, peripheral leukocyte infiltration, and white matter injury. N-acetylcysteine (NAC), a glutathione precursor with antioxidant and immunomodulatory properties, is a promising neuroprotective candidate, but its effects in neonatal sepsis-like brain injury remain incompletely defined. The purpose of this study was to investigate whether early NAC pretreatment, followed by continued treatment, was associated with protection in a neonatal LPS model and examine the principal mechanisms associated with its effects. METHODS: In this study, neonatal C57BL/6J mice received lipopolysaccharide (LPS; 3 mg/kg, subcutaneously) on postnatal day (PND) 3 to model sepsis-like injury. NAC was administered intraperitoneally 2 h before LPS (200 mg/kg), followed by daily treatment (100 mg/kg/day) through PND14. Survival was monitored to PND21. Acute outcomes at PND4 included oxidative stress, glial/inflammatory markers, MPO-positive cell accumulation, apoptosis, and BBB-related injury. Longer-term outcomes included myelination, dentate gyrus proliferation, and behavior. RESULTS: NAC improved survival after neonatal LPS exposure, with exploratory sex-stratified analyses suggesting greater benefit in males. NAC partially restored cortical glutathione levels and reduced lipid peroxidation, indicating improved redox balance. Although it did not significantly alter galectin-3, GFAP, or NLRP3 at the time point examined, NAC reduced cortical MPO-positive cell burden and attenuated markers associated with neurovascular injury and BBB-associated pathology, including matrix metallopeptidase-9 expression and albumin extravasation. NAC also decreased apoptosis in selected brain regions and partly improved white matter-related outcomes, including oligodendrocyte precursor cell abundance, myelination, and early sensorimotor performance. However, long-term behavioral performance in the open field and novel object recognition tests was not significantly improved at PND60. CONCLUSIONS: Overall, early NAC pretreatment followed by continued treatment mitigated neonatal LPS-induced sepsis-like brain injury and improved survival, with protection associated with restoration of redox homeostasis and reduction of MPO-positive leukocyte and markers associated with neurovascular injury and BBB-associated pathology rather than broad suppression of measured inflammatory mediators. These findings are consistent with a potential role for a redox-neurovascular-leukocyte pathway in NAC-associated neuroprotection and support further evaluation of NAC in prevention-oriented experimental paradigms relevant to high-risk preterm populations.
Hypoxic CA9-high mesenchymal-like glioma stem cells promote ANXA1-FPR1-dependent macrophage polarization in recurrent glioblastoma.
Gao H, You G, Huang J … +4 more , Lin Y, Huang J, Liang R, Lin C
J Neuroinflammation · 2026 Jun · PMID 42374432 · Full text
BACKGROUND: Recurrent glioblastoma (rGBM) is characterized by marked myeloid remodeling and a profoundly immunosuppressive microenvironment. Although carbonic anhydrase 9 (CA9) is a canonical hypoxia-inducible molecule l...
BACKGROUND: Recurrent glioblastoma (rGBM) is characterized by marked myeloid remodeling and a profoundly immunosuppressive microenvironment. Although carbonic anhydrase 9 (CA9) is a canonical hypoxia-inducible molecule linked to aggressive glioblastoma (GBM) behavior, its cell-state-specific distribution in rGBM and its role in glioma stem cell (GSC)-macrophage crosstalk remain incompletely understood. METHODS: We integrated public transcriptomic cohorts, single-cell RNA sequencing, quantitative proteomics, paired clinical specimens, and in vitro/in vivo functional assays to define the role of CA9 in rGBM. Malignant-cell states and tumor-associated macrophage (TAM) subpopulations were resolved at single-cell resolution, and intercellular communication was inferred computationally. CA9 gain- and loss-of-function models were established in GBM cell lines and patient-derived GSCs. ANXA1 expression and secretion were assessed by qRT-PCR, Western blotting, ELISA, and promoter-reporter assays. Macrophage polarization was evaluated using conditioned-medium transfer, recombinant ANXA1 rescue, and pharmacological FPR1 blockade with cyclosporin H. RESULTS: CA9 was upregulated in GBM, further enriched in mesenchymal and recurrent tumors, and associated with inferior survival. Single-cell analysis localized CA9 predominantly to a hypoxia-associated MES-like GSC subpopulation that expanded in recurrent samples and exhibited elevated stemness. Recurrent tumors also displayed increased SPP1 + immunosuppressive TAMs. Proteomic, transcriptomic, and cell-cell communication analyses prioritized ANXA1 as a CA9-associated downstream mediator with secreted immunomodulatory potential. Hypoxia induced both CA9 and ANXA1, and mutation of a hypoxia-response element attenuated ANXA1 promoter activation. CA9 depletion reduced ANXA1 expression and secretion, impaired GBM growth phenotypes, and attenuated hypoxia-driven ANXA1 induction. CellChat highlighted enhanced signaling between hypoxic MES-like GSCs and SPP1 + TAMs in recurrent GBM, nominating ANXA1-FPR1 as a leading ligand-receptor axis. Functionally, conditioned medium from CA9-high GBM cells promoted M2-like macrophage polarization, which was weakened by CA9 knockdown, partially restored by recombinant ANXA1, and markedly suppressed by FPR1 antagonism, supporting ANXA1 as a contributory paracrine mediator, and markedly suppressed by FPR1 antagonism. In vivo, CA9 depletion, and in CA9-intact tumors FPR1 blockade, reduced M2-like macrophage-associated signals. CONCLUSIONS: CA9 is enriched in hypoxic MES-like GSCs in rGBM and promotes an ANXA1-dependent paracrine program that supports immunosuppressive macrophage polarization. These findings identify a CA9-ANXA1-FPR1-associated neuroimmune crosstalk axis linking hypoxic stem-like tumor states to myeloid remodeling in recurrent GBM, with ANXA1 functioning as a contributory paracrine mediator rather than a sole effector of CA9-driven immunosuppression.
Csf1r-mediated depletion of myeloid cells prevents dopaminergic neuron loss during chronic colitis.
Kutscherauer RK, Andert M, Stolzer I … +14 more , Neumaier EE, Dedden M, Kielkowski P, Xiang W, Grotemeyer A, Prinz M, Masuda T, Knobeloch KP, Rothhammer V, Zundler S, Schlachetzki JCM, Winkler J, Günther C, Süß P
J Neuroinflammation · 2026 Jun · PMID 42365367 · Full text
Inflammatory bowel disease (IBD) predisposes to neuropsychiatric comorbidity and increases the risk of Parkinson's Disease (PD). Although the gut-immune-brain axis was proposed as a link between IBD and PD and a driver o...
Inflammatory bowel disease (IBD) predisposes to neuropsychiatric comorbidity and increases the risk of Parkinson's Disease (PD). Although the gut-immune-brain axis was proposed as a link between IBD and PD and a driver of PD immunopathogenesis, the regional pattern and single-cell landscape of the brain immune response during colitis and its contribution to PD pathology remain poorly defined. Here, we observe a loss of dopaminergic neurons and synuclein pathology in the substantia nigra pars compacta of adult mice with chronic colitis. By confocal microscopy and integrated multi-omics, we reveal a complex midbrain-specific immune response to chronic colitis. Single-cell mapping of the midbrain immune landscape showed an inflammatory shift of microglial clusters including an expansion of interferon-response microglia, CD8 T cell extravasation, and increased numbers of vessel-associated neutrophils. Selective myeloid cell depletion using a colony stimulating factor 1 receptor (Csf1r) inhibitor after colitis onset reduced midbrain microglia by 67% and led to a complete rescue of dopaminergic neuron loss, without affecting mucosal pathology or T cell and neutrophil migration to the midbrain. Collectively, within the complex midbrain immune response to chronic colitis, we demonstrate a causal role of Csf1r-dependent myeloid cells for dopaminergic neurodegeneration. Thus, Csf1r inhibition in IBD may not locally ameliorate colitis, but provide neuroprotection to dopaminergic neurons.These results reveal a novel cellular link between chronic gut-derived peripheral inflammation and midbrain vulnerability and thereby substantially enhance our understanding of the risk for PD related to the gut-immune-brain axis.
Translational insights into Long-COVID: evaluation of preclinical animal models along the lung-brain-immune axis with focus on Golden Syrian Hamsters.
Kumar N, Khandavalli N, Avedissian SN … +3 more , Chand HS, Acharya A, Byrareddy SN
J Neuroinflammation · 2026 Jun · PMID 42351227 · Full text
Long-COVID, also referred to as post-acute sequelae of COVID-19 (PASC), is a heterogeneous disorder encompassing more than 200 reported symptoms that commonly affect the respiratory and nervous systems. Emerging clinical...
Long-COVID, also referred to as post-acute sequelae of COVID-19 (PASC), is a heterogeneous disorder encompassing more than 200 reported symptoms that commonly affect the respiratory and nervous systems. Emerging clinical evidence indicates that unresolved lung inflammation, vascular injury, and immune dysregulation drive sustained neuroinflammation and impaired neurocognitive function in Long-COVID patients. Given the ethical and logistical constraints of human studies, biologically relevant animal models are essential for understanding the mechanisms and for evaluating therapeutic strategies against Long-COVID. In this review, we synthesize current evidence from preclinical animal models of Long-COVID, with a particular emphasis on the Golden Syrian Hamsters. Golden Syrian Hamsters are naturally susceptible to SARS-CoV-2 infection without the need for genetic modification and recapitulate key features of human disease, including robust viral replication, pulmonary pathology, and inflammatory response during acute infection. Importantly, accumulating evidence demonstrates that Golden Syrian Hamsters develop persistent post-acute abnormalities along the lung-brain-immune axis, including impaired alveolar repair, fibrotic lung remodeling, neuroinflammation, viral or antigen persistence, and behavioral alterations that parallel core features of Long-COVID. We compare the strengths and limitations of Golden Syrian Hamsters with other commonly used pre-clinical animal models including mice, and non-human primates, highlighting differences in translational relevance, feasibility, and ability to model chronic lung-brain-immune axis dysfunction. While there are limitations, particularly regarding limited availability of immunological reagents and validated cognitive and behavioral assays, the Golden Syrian Hamsters offers a balanced and accessible platform for mechanistic studies of PASC. Overall, this review positions Golden Syrian Hamster as a robust translational model for investigating lung-brain-immune axis pathology in Long-COVID and for advancing the development of targeted therapeutic interventions.
An irradiation-free platform for localized skull bone marrow manipulation to dissect the skull-brain axis.
Lv Y, Yi J, You D … +4 more , Yan Y, Tang B, Qiu Y, Wu Y
J Neuroinflammation · 2026 Jun · PMID 42351188 · Full text
The skull bone marrow (SBM) has recently emerged as a crucial regulator of brain physiology and pathology. However, its direct impact on the brain remains elusive, as existing methods cannot isolate local SBM functions f...
The skull bone marrow (SBM) has recently emerged as a crucial regulator of brain physiology and pathology. However, its direct impact on the brain remains elusive, as existing methods cannot isolate local SBM functions from systemic confounds. Here, we developed an irradiation-free cranial bone flap transplantation platform that enables localized SBM replacement and niche-preserving engraftment. Our method establishes exclusive chimerism within CNS compartments, achieving a "peripherally clean" profile that cleanly separates SBM-brain communication from systemic variables. Comprehensive characterization of this model revealed age- and sex-dependent chimerism patterns specifically within central nervous system (CNS) niches. In contrast to conventional long bone marrow (LBM) transplantation, our model achieved robust CNS-targeted engraftment with minimal peripheral involvement. Proof-of-concept functional studies further demonstrated its functional utility by attenuating brain aging and neuroinflammation through young SBM transplantation into old recipients. Our model provides a targeted approach to dissect the skull-brain axis in health and disease, opening avenues to decipher its role in neurological disorders and to identify niche-specific therapeutic targets.
Antigen-specific adaptive immunity in Parkinson's disease: peripheral priming, brain-border reactivation and parenchymal injury.
Wang K, Han K, Wang Y
J Neuroinflammation · 2026 Jun · PMID 42351163 · Full text
Adaptive immune signals in Parkinson's disease (PD) now extend beyond descriptive neuroinflammation. Human genetic studies have implicated HLA variation, peripheral assays have detected α-synuclein- and PINK1-reactive T...
Adaptive immune signals in Parkinson's disease (PD) now extend beyond descriptive neuroinflammation. Human genetic studies have implicated HLA variation, peripheral assays have detected α-synuclein- and PINK1-reactive T cells, neuropathology has identified early nigral CD8 + T-cell accumulation, and PD-relevant models have linked α-synuclein or mitochondrial antigen presentation to defined T-cell programs. This Review first places these findings in the modifying context of aging and then examines two antigen-specific routes across peripheral T-cell priming, central nervous system (CNS)-border reactivation or retention, and parenchymal effector injury. The α-synuclein/HLA-II/CD4 + T-cell route has the clearest support from human T-cell reactivity and border-associated macrophage (BAM)-dependent antigen presentation. The mitochondrial antigen/MHC-I/CD8 + T-cell route is strongest in PINK1-Parkin dysfunction and inflammatory settings, including CD8 + T-cell-mediated killing of Pink1 - / - dopaminergic neurons after mitochondrial antigen presentation. Trafficking mechanisms drawn from experimental autoimmune encephalomyelitis (EAE), multiple sclerosis (MS), viral encephalitis and cerebral malaria provide useful candidate pathways for PD studies, especially for post-vascular retention and glia-limitans passage. We also consider viral antigens as potential contributors to resident-memory-like CD8 + T-cell pools in the brain and discuss why PD models should be selected according to antigen axis, T-cell subset and immune context.
Complement C5a/C5aR1 pathway facilitates glioblastoma progression via fostering glioma stem cell-macrophage symbiosis.
Zhu H, Cheng L, Liu D … +13 more , Ma Y, Fan H, He S, Liang W, Mei D, Ma X, Li R, Mi H, Wang J, Li J, Yu X, Zhang S, Shu K
J Neuroinflammation · 2026 Jun · PMID 42343442 · Full text
Tumor-associated macrophages (TAMs) symbiotically interact with glioma stem cells (GSCs) to facilitate GSCs stemness maintenance and glioblastoma (GBM) progression. Here we identified the complement 5a (C5a) as a key med...
Tumor-associated macrophages (TAMs) symbiotically interact with glioma stem cells (GSCs) to facilitate GSCs stemness maintenance and glioblastoma (GBM) progression. Here we identified the complement 5a (C5a) as a key mediator of GSCs-TAMs symbiosis through integrative screening. C5a is preferentially expressed and secreted by GSCs. C5a activates the p-STAT3-cMyc-PD-L1 axis to promote GSCs proliferation, self-renewal and resistance against cytotoxic T cells through its receptor C5aR1. Moreover, GSCs-derived C5a trigger the infiltration and immunosuppressive polarization of TAMs through C5aR1-p-AKT T308 axis in tumor microenvironment. Importantly, silencing or pharmacological inhibition of C5a/C5aR1 disrupts both GSCs and TAMs and suppresses GBM tumor growth. In human GBM, the C5a/C5aR1 axis is activated and positively correlates with stemness, immunosuppressive TAMs and predicts poor prognosis. Collectively, these results demonstrate the key role of C5a/C5aR1 pathway in GSCs-TAMs symbiosis and indicate the therapeutic potential of targeting this pathway for GBM treatment.
Immune checkpoint LAG-3 governs stage-dependent and disease-associated microglial modules in ALS model mice.
Morisaki Y, Nomura N, Ohshima M … +5 more , Matsuda M, Komine O, Okuda T, Yamanaka K, Misawa H
J Neuroinflammation · 2026 Jun · PMID 42343420 · Full text
Immune checkpoint molecules, inhibitory receptors originally characterized in T cell biology, have recently emerged as regulators of microglial function in neurodegeneration, yet their roles in amyotrophic lateral sclero...
Immune checkpoint molecules, inhibitory receptors originally characterized in T cell biology, have recently emerged as regulators of microglial function in neurodegeneration, yet their roles in amyotrophic lateral sclerosis (ALS) remain unexplored. Here, we investigated LAG-3, an inhibitory immune checkpoint receptor, in microglial regulation during ALS pathogenesis using SOD1 mice. LAG-3 expression was progressively upregulated in spinal cord microglia during disease progression, and LAG-3-high microglia exhibited a disease-associated microglia (DAM) transcriptional signature. Genetic deletion of LAG-3 produced a biphasic phenotype, with accelerated disease onset but significantly prolonged disease duration. LAG-3 deficiency enhanced inflammatory microglial responses at the early disease stage, whereas at the late stage it suppressed inflammatory signaling while selectively preserving phagocytic effector gene expression, demonstrating that LAG-3 dissociates the inflammatory and phagocytic modules within the DAM program in a stage-dependent manner. These transcriptional changes translated into enhanced phagocytic capacity in primary microglia and amelioration of the spinal cord environment through suppression of inflammatory pathways and restoration of oxidative phosphorylation. Our findings identify LAG-3 as a stage-dependent regulator of microglial functional states in ALS and support the concept that immune checkpoint molecules constitute a class of module-level regulators of microglial function in neurodegeneration.
IRF7 deficiency in myeloid cells results in increased disease severity and death during alphavirus encephalomyelitis despite intact expression of type I interferons.
Nguyen BH, Stanley E, Dai W … +2 more , Troisi EM, Griffin DE
J Neuroinflammation · 2026 Jun · PMID 42343382 · Full text
Alphaviruses are arthropod-borne pathogens that cause immune-mediated encephalomyelitis. The prototypic alphavirus, Sindbis virus (SINV), primarily infects neurons in mice, resulting in neurologic disease involving both...
Alphaviruses are arthropod-borne pathogens that cause immune-mediated encephalomyelitis. The prototypic alphavirus, Sindbis virus (SINV), primarily infects neurons in mice, resulting in neurologic disease involving both the brain and spinal cord. Interferon (IFN) regulatory factor (IRF) 7-deficient mice (Irf7) rapidly succumb to SINV infection with extensive immunopathology while wildtype mice experience only mild disease and recover. IRF7 is widely recognized to be the main transcription factor required for the amplification of type I IFN, specifically IFNα, as Irf7 mice do not produce IFNα but do express IFNβ. However, based on the current experimental evidence, it is not clear if the severe outcome of SINV infection in Irf7 mice is due to the absence of IFNα or heretofore unappreciated noncanonical actions of IRF7. In this study, we demonstrate that the administration of IFNα to Irf7 mice early in infection restricted SINV replication and largely rescued the animals from severe disease and mortality but did not alter the nature of CNS inflammation. Further, Cre-Lox-mediated deletion of Irf7 in myeloid cells (Irf7Lyz2-cre mice) resulted in severe disease and lethality despite significantly higher peak levels of IFNα than WT animals, suggesting that the lethal phenotype of Irf7 mice was attributed to the myeloid cell-specific loss of IRF7 and not to the loss of IFNα production. Both Irf7 and Irf7Lyz2-cre mice had increased levels of monocytes infiltrating into the brain compared to WT, indicating a potential role for IRF7 in the trafficking and activation of myeloid cells. Therefore, while IFNα supplementation may contribute to reducing disease severity by restricting virus replication, disease was ultimately exacerbated by the increased infiltration of inflammatory myeloid cells in Irf7 mice.
Extracellular vesicles from plasma of patients with minimal hepatic encephalopathy induce neuroinflammation and cognitive impairment in rats, which are prevented by treating the patients with rifaximin.
Lopez-Gramaje A, Arenas YM, Gallego JJ … +7 more , Izquierdo-Altarejos P, Urios A, Escudero-García D, Benlloch S, Kosenko E, Felipo V, Montoliu C
J Neuroinflammation · 2026 Jun · PMID 42343379 · Full text
Minimal hepatic encephalopathy (MHE) appearance is associated with a pro-inflammatory shift in peripheral inflammation. Treatment of MHE patients with rifaximin reverses this shift in and improves MHE. How peripheral alt...
Minimal hepatic encephalopathy (MHE) appearance is associated with a pro-inflammatory shift in peripheral inflammation. Treatment of MHE patients with rifaximin reverses this shift in and improves MHE. How peripheral alterations are transmitted to brain to induce MHE remains unclear. In rats with MHE, plasma extracellular vesicles (EV) induce cognitive impairment. We hypothesized that in cirrhotic patients, the shift in peripheral inflammation is associated with alterations in plasma EV which contribute to induce MHE in cirrhotic patients. We also hypothesized that rifaximin treatment reverses MHE by reversing changes in EV. The aims were: 1) assess if injecting rats with plasma EV from MHE patients (MHE-EV) induce cognitive impairment, 2) identify the underlying mechanisms, 3) assess if treating MHE patients with rifaximin reverses the pathological effects of their EV and, 4) if this is associated with reversal of changes in EV protein cargo. We isolated plasma EV from cirrhotic patients without and with MHE, treated or not with rifaximin, and controls and injected them to rats. We analysed cognitive function, neuroinflammation and glutamate receptors membrane expression in hippocampus. MHE-EV, but not EV from patients without MHE show increased TNFα content and trigger a strong cognitive impairment in rats. This is mediated by altered membrane expression of AMPA and NMDA glutamate receptors in hippocampus, due to increased neuroinflammation, with glial activation and enhanced activation of the TNFα-TNFR1-S1PR2-IL-1β-IL-1R pathway. The EV from MHE patients treated with rifaximin did not show increased TNFα levels and did not induce the above pathological effects. Rifaximin treatment reverses the changes in the cargo of the EV from plasma of MHE patients, including the increase in TNFα and eliminates the pathological effects of the EV. The data show that in cirrhotic patients the presence of MHE is associated with changes in their blood EV which transmit pathological effects to the brain, inducing neuroinflammation and altered glutamatergic neurotransmission in hippocampus which leads to cognitive impairment. Rifaximin treatment reduces TNFα and other altered proteins in the EV and reverses their pathological effects. EV could be a therapeutic target to improve MHE by modifying EV content or blocking the TNFα effects.
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