Journal of Neuroinflammation最新文献

{"title":"Neuron-specific deletion of ADAR1 induces brain malformation and early postnatal lethality.","authors":"Hiroyuki Todo, Jingqi Yang, Tuangtong Vongpipatana, Toshiharu Shibuya, Taisuke Nakahama, Yukio Kawahara","doi":"10.1186/s12974-026-03941-w","DOIUrl":"10.1186/s12974-026-03941-w","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":" ","pages":""},"PeriodicalIF":11.5,"publicationDate":"2026-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13602599/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148382196","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"HSV-1 reactivation as an emergent property of neuronal stress: implications for traumatic brain injury.","authors":"Alyson R Stewart, Amalia Bustillos Saucedo, Lindsey L Beauregard, Christopher D Link, Christy S Niemeyer, Rachel K Rowe","doi":"10.1186/s12974-026-03944-7","DOIUrl":"10.1186/s12974-026-03944-7","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":" ","pages":""},"PeriodicalIF":11.5,"publicationDate":"2026-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13508411/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148368039","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Microglial checkpoint collapse in Alzheimer's disease: a tri-axial framework for biomarker-informed neuroimmune therapy.","authors":"Jiahao Zhang, Ning Yang, Peibin Zou, Xuemei Zong","doi":"10.1186/s12974-026-03924-x","DOIUrl":"10.1186/s12974-026-03924-x","url":null,"abstract":"<p><strong>Background: </strong>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.</p><p><strong>Main body: </strong>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.</p><p><strong>Conclusions: </strong>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.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":" ","pages":""},"PeriodicalIF":11.5,"publicationDate":"2026-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13595677/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148376037","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"SGK1-mediated deficits in microglial phagocytosis drive pathological progression in amyotrophic lateral sclerosis.","authors":"Meijun He, Chaoran Wu, Mengqiu Hu, Xiayi Shi, Ruiqi Liu, Yujie Tong, Heng Wang, Haoran Hu, Hong Liao","doi":"10.1186/s12974-026-03925-w","DOIUrl":"10.1186/s12974-026-03925-w","url":null,"abstract":"<p><p>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^G93A 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^G93A 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^G93A 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^G93A 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.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":" ","pages":""},"PeriodicalIF":11.5,"publicationDate":"2026-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13685294/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148368472","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Neuropsychiatric disorders in pulmonary fibrosis: from brain network alterations to inflammatory mechanisms and therapeutic implications.","authors":"Chengwei Li, Longfei Wang, Fei Wang, Lezhen Wang, Lin Xu, Wenyuan Lyu, Kaiyue Shan, Jianjun Li, Haipeng Zhou, Fei Rong, Xiangyi Kong, Penghui Wei","doi":"10.1186/s12974-026-03921-0","DOIUrl":"10.1186/s12974-026-03921-0","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":" ","pages":""},"PeriodicalIF":11.5,"publicationDate":"2026-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13584596/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148360912","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"N-Acetylcysteine protects the developing brain in neonatal sepsis-like inflammation via a redox-neurovascular pathway.","authors":"Ping Cheng, Shan Zhang, Xiaoli Zhang, Wenhua Li, Mengmeng Du, Mingchao Li, Zengyuan Yu, Jinjin Zhu, Guixiang Zeng, Yiran Xu, Huiqing Sun, Wenqing Kang, Xiaoyang Wang, Changlian Zhu","doi":"10.1186/s12974-026-03942-9","DOIUrl":"10.1186/s12974-026-03942-9","url":null,"abstract":"<p><strong>Background: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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.</p><p><strong>Conclusions: </strong>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.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":"23 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2026-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13317334/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148352190","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hypoxic CA9-high mesenchymal-like glioma stem cells promote ANXA1-FPR1-dependent macrophage polarization in recurrent glioblastoma.","authors":"Hangqi Gao, Guiting You, Jianhuang Huang, Yijing Lin, Jiexin Huang, Risheng Liang, Caihou Lin","doi":"10.1186/s12974-026-03905-0","DOIUrl":"10.1186/s12974-026-03905-0","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;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.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;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.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;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.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusions: &lt;/strong&gt;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 ","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":" ","pages":""},"PeriodicalIF":11.5,"publicationDate":"2026-06-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13579895/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148352264","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Csf1r-mediated depletion of myeloid cells prevents dopaminergic neuron loss during chronic colitis.","authors":"Rebecca Katharina Kutscherauer, Marie Andert, Iris Stolzer, Emely Elisa Neumaier, Mark Dedden, Pavel Kielkowski, Wei Xiang, Alexander Grotemeyer, Marco Prinz, Takahiro Masuda, Klaus-Peter Knobeloch, Veit Rothhammer, Sebastian Zundler, Johannes C M Schlachetzki, Jürgen Winkler, Claudia Günther, Patrick Süß","doi":"10.1186/s12974-026-03926-9","DOIUrl":"10.1186/s12974-026-03926-9","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":"23 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2026-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13309958/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148338927","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hereditary spastic paraplegia (HSP) gene 11 (Spg11) attenuates lipid accumulation in myeloid cells and neuroinflammation in the midbrain without affecting α-synuclein pathology.","authors":"Margaret Hayne, Joanna Lipka, Tawaun A Lucas, Allison L Soung, Max Adrian, Soumitra Ghosh, Han Lin, Sarah Chu, Kimberly Stark, Hai Ngu, Oded Foreman, Joshua Kaminker, Casper C Hoogenraad","doi":"10.1186/s12974-026-03910-3","DOIUrl":"10.1186/s12974-026-03910-3","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":" ","pages":""},"PeriodicalIF":11.5,"publicationDate":"2026-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13576294/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148352222","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Antigen-specific adaptive immunity in Parkinson's disease: peripheral priming, brain-border reactivation and parenchymal injury.","authors":"Kehao Wang, Ke Han, Yanqing Wang","doi":"10.1186/s12974-026-03918-9","DOIUrl":"10.1186/s12974-026-03918-9","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":" ","pages":""},"PeriodicalIF":11.5,"publicationDate":"2026-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13560197/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148330536","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}