Journal of Neuroinflammation最新文献

{"title":"Glyphosate exposure exacerbates neuroinflammation and Alzheimer's disease-like pathology despite a 6-month recovery period in mice.","authors":"Samantha K Bartholomew, Wendy Winslow, Ritin Sharma, Khyatiben V Pathak, Savannah Tallino, Jessica M Judd, Hector Leon, Julie Turk, Patrick Pirrotte, Ramon Velazquez","doi":"10.1186/s12974-024-03290-6","DOIUrl":"10.1186/s12974-024-03290-6","url":null,"abstract":"<p><strong>Background: </strong>Glyphosate use in the United States (US) has increased each year since the introduction of glyphosate-tolerant crops in 1996, yet little is known about its effects on the brain. We recently found that C57BL/6J mice dosed with glyphosate for 14 days showed glyphosate and its major metabolite aminomethylphosphonic acid present in brain tissue, with corresponding increases in pro-inflammatory cytokine tumor necrosis factor-⍺ (TNF-⍺) in the brain and peripheral blood plasma. Since TNF-⍺ is elevated in neurodegenerative disorders such as Alzheimer's Disease (AD), in this study, we asked whether glyphosate exposure serves as an accelerant of AD pathogenesis. Additionally, whether glyphosate and aminomethylphosphonic acid remain in the brain after a recovery period has yet to be examined.</p><p><strong>Methods: </strong>We hypothesized that glyphosate exposure would induce neuroinflammation in control mice, while exacerbating neuroinflammation in AD mice, causing elevated Amyloid-β and tau pathology and worsening spatial cognition after recovery. We dosed 4.5-month-old 3xTg-AD and non-transgenic (NonTg) control mice with either 0, 50 or 500 mg/kg of glyphosate daily for 13 weeks followed by a 6-month recovery period.</p><p><strong>Results: </strong>We found that aminomethylphosphonic acid was detectable in the brains of 3xTg-AD and NonTg glyphosate-dosed mice despite the 6-month recovery. Glyphosate-dosed 3xTg-AD mice showed reduced survival, increased thigmotaxia in the Morris water maze, significant increases in the beta secretase enzyme (BACE-1) of amyloidogenic processing, amyloid-β (Aβ) 42 insoluble fractions, Aβ 42 plaque load and plaque size, and phosphorylated tau (pTau) at epitopes Threonine 181, Serine 396, and AT8 (Serine 202, Threonine 205). Notably, we found increased pro- and anti-inflammatory cytokines and chemokines persisting in both 3xTg-AD and NonTg brain tissue and in 3xTg-AD peripheral blood plasma.</p><p><strong>Conclusion: </strong>Taken together, our results are the first to demonstrate that despite an extended recovery period, exposure to glyphosate elicits long-lasting pathological consequences. As glyphosate use continues to rise, more research is needed to elucidate the impact of this herbicide and its metabolites on the human brain, and their potential to contribute to dysfunctions observed in neurodegenerative diseases.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":"21 1","pages":"316"},"PeriodicalIF":9.3,"publicationDate":"2024-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11619132/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142780330","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":"Autoantibody profiles in Alzheimer´s, Parkinson´s, and dementia with Lewy bodies: altered IgG affinity and IgG/IgM/IgA responses to alpha-synuclein, amyloid-beta, and tau in disease-specific pathological patterns.","authors":"Luisa Knecht, Katrine Dalsbøl, Anja Hviid Simonsen, Falk Pilchner, Jean Alexander Ross, Kristian Winge, Lisette Salvesen, Sara Bech, Anne-Mette Hejl, Annemette Løkkegaard, Steen G Hasselbalch, Richard Dodel, Susana Aznar, Gunhild Waldemar, Tomasz Brudek, Jonas Folke","doi":"10.1186/s12974-024-03293-3","DOIUrl":"10.1186/s12974-024-03293-3","url":null,"abstract":"<p><strong>Background: </strong>Alzheimer's disease (AD) and Parkinson's disease (PD) are leading neurodegenerative disorders marked by protein aggregation, with AD featuring amyloid-beta (Aβ) and tau proteins, and PD alpha-synuclein (αSyn). Dementia with Lewy bodies (DLB) often presents with a mix of these pathologies. This study explores naturally occurring autoantibodies (nAbs), including Immunoglobulin (Ig)G, IgM, and IgA, which target αSyn, Aβ and tau to maintain homeostasis and were previously found altered in AD and PD patients, among others.</p><p><strong>Main text: </strong>We extended this investigation across AD, PD and DLB patients investigating both the affinities of IgGs and levels of IgGs, IgMs and IgAs towards αSyn, Aβ and tau utilizing chemiluminescence assays. We confirmed that AD and PD patients exhibited lower levels of high-affinity anti-Aβ and anti-αSyn IgGs, respectively, than healthy controls. AD patients also showed diminished levels of high-affinity anti-αSyn IgGs, while anti-tau IgG affinities did not differ significantly across groups. However, DLB patients exhibited increased anti-αSyn IgG but decreased anti-αSyn IgM levels compared to controls and PD patients, with AD patients showing a similar pattern. Interestingly, AD patients had higher anti-Aβ IgG but lower anti-Aβ IgA levels than DLB patients. DLB patients had reduced anti-Aβ IgM levels compared to controls, and anti-tau IgG levels were lower in AD than PD patients, who had reduced anti-tau IgM levels compared to controls. AD patients uniquely showed higher anti-tau IgA levels. Significant correlations were observed between clinical measures and nAbs, with negative correlations between anti-αSyn IgG affinity and levels in DLB patients and a positive correlation with anti-αSyn IgA levels in PD patients. Disease-specific changes in nAb levels and affinity correlations were identified, highlighting altered immune responses.</p><p><strong>Conclusion: </strong>This study reveals distinctive nAb profiles in AD, DLB, and PD, pinpointing specific immune deficiencies against pathological proteins. These insights into the autoreactive immune system's role in neurodegeneration suggest nAbs as potential markers for vulnerability to protein aggregation, offering new avenues for understanding and possibly diagnosing these conditions.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":"21 1","pages":"317"},"PeriodicalIF":9.3,"publicationDate":"2024-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11613470/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142769854","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":"Ketogenic diet modulates immune cell transcriptional landscape and ameliorates experimental autoimmune uveitis in mice.","authors":"Runping Duan, Tianfu Wang, Zhaohuai Li, Loujing Jiang, Xiaoyang Yu, Daquan He, Tianyu Tao, Xiuxing Liu, Zhaohao Huang, Lei Feng, Wenru Su","doi":"10.1186/s12974-024-03308-z","DOIUrl":"10.1186/s12974-024-03308-z","url":null,"abstract":"<p><strong>Background: </strong>Uveitis manifests as immune-mediated inflammatory disorders within the eye, posing a serious threat to vision. The ketogenic diet (KD) has emerged as a promising dietary intervention, yet its impact on the immune microenvironments and role in uveitis remains unclear.</p><p><strong>Methods: </strong>Utilizing single-cell RNA sequencing (scRNA-seq) data from lymph node and retina of mice, we conduct a comprehensive investigation into the effects of KD on immune microenvironments. Flow cytometry is conducted to verify the potential mechanisms.</p><p><strong>Results: </strong>This study demonstrates that KD alters the composition and function of immune profiles. Specifically, KD promotes the differentiation of Treg cells and elevates its proportion in heathy mice. In response to experimental autoimmune uveitis challenges, KD alleviates the inflammatory symptoms, lowers CD4⁺ T cell pathogenicity, and corrects the Th17/Treg imbalance. Additionally, KD decreases the proportion of Th17 cell and increases Treg cells in the retina. Analysis of combined retinal and CDLN immune cells reveals that retinal immune cells, particularly CD4⁺ T cells, exhibit heightened inflammatory responses, which KD partially reverses.</p><p><strong>Conclusions: </strong>The KD induces inhibitory structural and functional alterations in immune cells from lymph nodes to retina, suggesting its potential as a therapy for uveitis.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":"21 1","pages":"319"},"PeriodicalIF":9.3,"publicationDate":"2024-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11613848/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142769856","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":"Metformin attenuates central sensitization by regulating neuroinflammation through the TREM2-SYK signaling pathway in a mouse model of chronic migraine.","authors":"Zhenzhen Fan, Dandan Su, Zi Chao Li, Songtang Sun, Zhaoming Ge","doi":"10.1186/s12974-024-03313-2","DOIUrl":"10.1186/s12974-024-03313-2","url":null,"abstract":"<p><strong>Background: </strong>Chronic migraine (CM) is a serious neurological disorder. Central sensitization is one of the important pathophysiological mechanisms underlying CM, and microglia-induced neuroinflammation conduces to central sensitization. Triggering receptor expressed on myeloid cells 2 (TREM2) is presented solely in microglia residing within the central nervous system and plays a key role in neuroinflammation. Metformin has been shown to regulate inflammatory responses and exert analgesic effects, but its relationship with CM remains unclear. In the study, we investigated whether metformin modulates TREM2 to improve central sensitization of CM and clarified the potential molecular mechanisms.</p><p><strong>Methods: </strong>A CM mouse model was induced by administration of nitroglycerin (NTG). Behavioral evaluations were conducted using von Frey filaments and hot plate experiments. Western blot and immunofluorescence techniques were employed to investigate the molecular mechanisms. Metformin and the SYK inhibitor R406 were administered to mice to assess their regulatory effects on neuroinflammation and central sensitization. To explore the role of TREM2-SYK in regulating neuroinflammation with metformin, a lentivirus encoding TREM2 was injected into the trigeminal nucleus caudalis (TNC). In vitro experiments were conducted to evaluate the regulation of TREM2-SYK by metformin, involving interventions with LPS, metformin, R406, siTREM2, and TREM2 plasmids.</p><p><strong>Results: </strong>Metformin and R406 pretreatment can effectively improve hyperalgesia in CM mice. Both metformin and R406 significantly inhibit c-fos and CGRP expression in CM mice, effectively suppressing the activation of microglia and NLRP3 inflammasome induced by NTG. With the administration of NTG, TREM2 expression gradually increased in TNC microglia. Additionally, we observed that metformin significantly inhibits TREM2 and SYK expression in CM mice. Lv-TREM2 attenuated metformin-mediated anti-inflammatory responses. In vitro experiments, knockdown of TREM2 inhibited LPS-induced SYK pathway activation and alleviated inflammatory responses. After the sole overexpression of TREM2, the SYK signaling pathway is activated, resulting in the activation of the NLRP3 inflammasome and an increased expression of pro-inflammatory cytokines; nevertheless, this consequence can be reversed by R406. The overexpression of TREM2 attenuates the inhibition of SYK activity mediated by metformin, and this effect can be reversed by R406.</p><p><strong>Conclusions: </strong>Our findings suggest that metformin attenuates central sensitization in CM by regulating the activation of microglia and NLRP3 inflammasome through the TREM2-SYK pathway.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":"21 1","pages":"318"},"PeriodicalIF":9.3,"publicationDate":"2024-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11613737/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142769857","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":"TRPM7 contributes to pyroptosis and its involvement in status epilepticus.","authors":"Xin Tong, Yu Tong, Jiahe Zheng, Ruixue Shi, Hongyue Liang, Meixuan Li, Yulu Meng, Jian Shi, Dongyi Zhao, Corey Ray Seehus, Jialu Wang, Xiaoxue Xu, Tomasz Boczek, Sayuri Suzuki, Andrea Fleig, Reinhold Penner, Naining Zhang, Jianjun Xu, Jingjing Duan, Zhiyi Yu, Wuyang Wang, Weidong Zhao, Feng Guo","doi":"10.1186/s12974-024-03292-4","DOIUrl":"https://doi.org/10.1186/s12974-024-03292-4","url":null,"abstract":"<p><strong>Background: </strong>Pyroptosis, a novel form of programmed cell death, has been implicated in neurodegeneration diseases. However, its role in status epilepticus (SE)-a condition characterized by prolonged or repeated seizures-remains inadequately understood.</p><p><strong>Methods: </strong>SE were induced by intraperitoneal injection of pilocarpine (PILO). Neuronal excitability was assessed through electroencephalogram (EEG) recordings and patch clamp. Chromatin immunoprecipitation (ChIP) assay was applied to verify the interaction of phosphorylated signal transducer and activator of transcription 3 (p-STAT3) protein with the promoters of Nlrp3 (the gene encoding NOD-like receptor family pyrin domain containing 3) and Trpm7 (transient receptor potential melastatin 7). To further investigate the role of TRPM7 in SE, AAV-sh-TRPM7-EGFP transfected mice and TRPM7 conditional knockout (TRPM7-CKO) mice were utilized.</p><p><strong>Results: </strong>Our findings revealed elevated levels of IL-18 and IL-1β levels in primary epilepsy patients, along with increased expression level of the TRPM7 in SE models. Knockdown of TRPM7 alleviated neuronal damage and pyroptosis, reversing PILO-treated neuronal hyperexcitability. We demonstrated that p-STAT3 binds to the promoters of both Trpm7 and Nlrp3, modulating their transcriptions in SE. Importantly, inhibition of TRPM7 with NS8593, and inflammasome inhibition with MCC950, alleviated neuronal hyperexcitability and pyroptosis in SE. A new compound, SDUY-225, formulated based on the structure of NS8593 mitigated neuronal damage, pyroptosis, and hyperexcitability.</p><p><strong>Conclusions: </strong>TRPM7 contributes to pyroptosis in SE, establishing a positive feedback loop involving the p-STAT3/TRPM7/Zn²⁺/p-STAT3 signaling pathway. Findings in this study raise the possibility that targeting TRPM7 and NLRP3 represents a promising therapeutic approach for SE.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":"21 1","pages":"315"},"PeriodicalIF":9.3,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11608501/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142769871","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":"Sitagliptin eye drops prevent the impairment of retinal neurovascular unit in the new Trpv2^+/- rat model.","authors":"Hugo Ramos, Josy Augustine, Burak M Karan, Cristina Hernández, Alan W Stitt, Tim M Curtis, Rafael Simó","doi":"10.1186/s12974-024-03283-5","DOIUrl":"https://doi.org/10.1186/s12974-024-03283-5","url":null,"abstract":"<p><p>Impaired function of the retinal neurovascular unit (NVU) is an early event in diabetic retinopathy (DR). It has been previously shown that topical delivery of the dipeptidyl peptidase-4 (DPP-4) inhibitor sitagliptin can protect against diabetes-mediated dysfunction of the retinal NVU in the db/db mouse. The aim of the present study was to examine whether sitagliptin could prevent the DR-like lesions within the NVU of the new non-diabetic model of DR, the Trpv2 knockout rat (Trpv2^+/-). For that purpose, at 3 months of age, Trpv2^+/- rats were topically treated twice daily for two weeks with sitagliptin or PBS-vehicle eyedrops. Trpv2^+/+ rats treated with vehicle served as the control group. Body weight and glycemia were monitored. Optical coherence tomography recordings, fundus images and retinal samples were obtained to evaluate sitagliptin effects. The results revealed that sitagliptin eye drops had no effect on body weight or glycemia. Vehicle-treated Trpv2^+/- rats exhibited retinal thinning and larger diameters of major retinal blood vessels, upregulation of inflammatory factors and oxidative markers, glial activation and formation of acellular capillaries. However, topical administration of sitagliptin significantly prevented all these abnormalities. In conclusion, sitagliptin eye drops exert a protective effect against DR-like lesions in Trpv2^+/- rats. Our results suggest that sitagliptin eye drops carry significant potential to treat not only early-stages of DR but also other diseases with impairment of the NVU unrelated to diabetes.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":"21 1","pages":"312"},"PeriodicalIF":9.3,"publicationDate":"2024-11-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11607821/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142769858","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":"Synergistic effects of repeated transcranial magnetic stimulation and mesenchymal stem cells transplantation on alleviating neuroinflammation and PANoptosis in cerebral ischemia.","authors":"Shimei Cheng, Qiying Lu, Qiuli Liu, Yuanchen Ma, Jinshuo Chen, Di Lu, Mudan Huang, Yinong Huang, Erming Zhao, Jing Luo, Haiqing Zheng","doi":"10.1186/s12974-024-03302-5","DOIUrl":"https://doi.org/10.1186/s12974-024-03302-5","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;Neuronal death is the primary cause of poor outcomes in cerebral ischemia. The inflammatory infiltration in the early phase of ischemic stroke plays a vital role in triggering neuronal death. Either transplantation of mesenchymal stem cells (MSCs) derived from humans or repetitive transcranial magnetic stimulation (rTMS) have respectively proved to be neuroprotective and anti-inflammatory in cerebral ischemia. However, either treatment above has its limitations. Whether these two therapies have synergistic effects on improving neurological function and the underlying mechanisms remains unclear. This investigation aims to elucidate the synergistic effects and underlying mechanisms of MSCs combined with rTMS treatment on the neurological function recovery post-ischemia.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;A Sprague-Dawley rat model of cerebral infarction was induced via transient middle cerebral artery occlusion (tMCAO). The rats were divided into five groups (n = 50): sham, tMCAO, rTMS, MSCs, and MSCs + rTMS groups. Transplantation of human umbilical cord MSCs and rTMS intervention were performed 24 h post-stroke. Neurological function was further assessed via several behavioral tests and the 2,3,5-triphenyltetrazolium chloride (TTC) staining companied with Nissl staining were used to assess neuronal survival. TUNEL staining, western blotting, immunofluorescence, immunohistochemistry, ELISA, and flow cytometry were employed to measure the levels of neuroinflammation and PANoptosis. The molecular mechanisms underlying the special role of rTMS in the combined therapy were distinguished with transcriptome sequencing via PC12 cells in oxygen-glucose deprivation/reoxygenation (OGD/R) conditions.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;The combined therapy efficiently reduced lesion volume and improved neuronal survival (P &lt; 0.05), subsequently improving functional recovery after ischemic stroke. MSCs + rTMS treatment ameliorated the PANoptosis in neurons (P &lt; 0.05), accompanied by decreased levels of inflammatory factors in the cerebral tissue and serum during the subacute phase of cerebral infarction. To further explore the roles of either therapy on synergistic effect, we found that the transplanted MSCs primarily localized in the spleen and reduced cerebral inflammatory infiltration after ischemia via suppressed splenic inflammation. Meanwhile, rTMS significantly protects neurons from PANoptosis in MSCs-inhibited inflammatory conditions by downregulating REST unveiled by transcriptome sequencing.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusions: &lt;/strong&gt;Our study elucidates an unidentified mechanism by which the combination of MSCs and rTMS could synergistically promote neuronal survival and suppress neuroinflammation during the subacute phase of cerebral infarction, thus improving neurological outcomes. The downregulating REST induced by rTMS may potentially contribute to the neuroprotective effect against PANoptosis in MSCs-inhibited inflammatory co","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":"21 1","pages":"311"},"PeriodicalIF":9.3,"publicationDate":"2024-11-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11607903/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142769869","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":"CD22 blockade exacerbates neuroinflammation in Neuromyelitis optica spectrum disorder.","authors":"Wenjun Zhang, Yali Han, Huachen Huang, Yue Su, Honglei Ren, Caiyun Qi, Jinyi Li, Huaijin Yang, Jing Xu, Guoqiang Chang, Wenjin Qiu, Qiang Liu, Ting Chang","doi":"10.1186/s12974-024-03305-2","DOIUrl":"https://doi.org/10.1186/s12974-024-03305-2","url":null,"abstract":"<p><strong>Background: </strong>Neuromyelitis optica spectrum disorder (NMOSD) is an autoantibody-triggered central nervous system (CNS) demyelinating disease that primarily affects the spinal cord, optic nerves and brainstem. Among the first responders to CNS injury, microglia are prominent players that drive NMOSD lesion formation. However, the key molecular switches controlling the detrimental activity of microglia in NMOSD are poorly understood. CD22 governs the activity of innate and adaptive immunity. In this study, we investigated to what extent and by what mechanisms CD22 may modulate microglial activity, neuroinflammation and CNS lesion formation.</p><p><strong>Methods: </strong>To determine the expression profile of CD22 in NMOSD, we performed single-cell sequencing and flow cytometry analysis of immune cells from human peripheral blood. We investigated the potential effects and mechanisms of CD22 blockade on microglial activity, leukocyte infiltration and CNS demyelination in a mouse model of NMOSD induced by injection of NMOSD patient serum-derived AQP4-IgG and human complement.</p><p><strong>Results: </strong>Single-cell sequencing and flow cytometry analysis revealed that CD22 was expressed in B cells, neutrophils, monocytes and microglia-derived exosomes in human peripheral blood from NMOSD patients and controls (n = 5 per group). In a mouse model of NMOSD, CD22 was expressed in B cells, neutrophils, monocytes and microglia (n = 8 per group). In NMOSD mice, CD22 blockade significantly increased the number of CNS lesions, astrocyte loss and demyelination, accompanied by increased inflammatory activity and phagocytosis in microglia. Furthermore, the detrimental effects of CD22 blockade were significantly alleviated in NMOSD mice subjected to depletion of microglia or Gr-1⁺ myeloid cells, suggesting the involvement of microglia and peripheral Gr-1⁺ myeloid cells. Additionally, CD22 blockade also led to significantly reduced phosphorylation of SYK and GSK3β in NMOSD. Notably, the detrimental effects of CD22 blockade were greatly diminished in NMOSD mice receiving the phosphorylated SYK inhibitor R406.</p><p><strong>Conclusions: </strong>Our findings revealed a previously unrecognized role of CD22 as a key molecular switch that governs the detrimental effects of microglia and Gr-1⁺ myeloid cells in NMOSD, which paves the way for the future design of immune therapies for NMOSD.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":"21 1","pages":"313"},"PeriodicalIF":9.3,"publicationDate":"2024-11-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11607829/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142769855","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":"A transient blood IL-17 increase triggers neuroinflammation in cerebellum and motor incoordination in hyperammonemic rats.","authors":"Yaiza M Arenas, Carmina Montoliu, Marta Llansola, Vicente Felipo","doi":"10.1186/s12974-024-03310-5","DOIUrl":"https://doi.org/10.1186/s12974-024-03310-5","url":null,"abstract":"<p><p>Patients with liver cirrhosis may show minimal hepatic encephalopathy (MHE) with motor incoordination which is reproduced in hyperammonemic rats. Hyperammonemia induces peripheral inflammation which triggers neuroinflammation and enhanced GABAergic neurotransmission in cerebellum and motor incoordination. The mechanisms involved remain unknown. The aims were to assess if the early increase of peripheral IL-17 triggers motor incoordination in hyperammonemic rats and to identify some underlying mechanisms. We assessed if blocking peripheral IL-17 with anti-IL-17 at 2-4 days of hyperammonemia prevents motor incoordination and analyzed underlying mechanisms. Hyperammonemia induces a transient blood IL-17 increase at days 3-4. This is associated with increased IL-17 receptor membrane expression and activation in cerebellum, leading to NADPH oxidase activation, increased superoxide production and MLCK that induce blood-brain barrier (BBB) permeabilization by reducing occludin and ZO-1. BBB permeabilization facilitates the entry of IL-17, which increases in cerebellum and activates microglia. This increases TNFα and the TNFR1-S1PR2-CCL2-BDNF-TrkB pathway. This enhances GABAergic neurotransmission which impairs motor coordination. Blocking peripheral IL-17 with anti-IL-17 prevents all the above process and prevents motor incoordination. Early treatment to reduce blood IL-17 may be a useful treatment to reverse motor incoordination in patients with MHE.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":"21 1","pages":"314"},"PeriodicalIF":9.3,"publicationDate":"2024-11-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11608494/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142769853","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":"Impact of perinatal factors on T cells and transcriptomic changes in preterm infant brain injury.","authors":"Xiaoli Zhang, Yu Yang, Yiran Xu, Liuji Chen, Ming Niu, Jinjin Zhu, Shan Zhang, Yanan Wu, Bingbing Li, Lingling Zhang, Juan Song, Falin Xu, Dan Bi, Xin Zhao, Changlian Zhu, Xiaoyang Wang","doi":"10.1186/s12974-024-03311-4","DOIUrl":"10.1186/s12974-024-03311-4","url":null,"abstract":"<p><strong>Background: </strong>T cells have been implicated in various neurological conditions, yet their role in neonatal brain injuries remains unclear. This study aimed to investigate the impact of perinatal factors on frequencies of T cell subsets in preterm infants and to explore the differences in blood genome expression profiles between preterm infants with and without brain injury.</p><p><strong>Materials and methods: </strong>Three cohorts of preterm infants were used. Blood samples were collected soon after birth for the first cohort and late timepoint for the second and third cohorts. In the first cohort (88 infants), flow cytometry measured the proportions of αβT and γδT cell subsets in peripheral blood, analyzing associations with gestational age, birth weight, sex, delivery type, and maternal conditions. The second cohort focused on the relationship between T cell subsets and brain injury. In the third cohort, transcriptome sequencing identified differentially expressed genes and pathways in infants with brain injury, highlighting immune-related changes.</p><p><strong>Results: </strong>Infants born at 29-30 weeks or with a birth weight of 1000-1500 g had significantly higher proportions of Vδ2⁺ T cells compared to those born at 30-32 weeks or with a birth weight > 1500 g, while no significant difference was found between infants born at < 29 weeks or with a birth weight < 1000 g. A negative correlation was observed between gestational age and Vδ2⁺ T cell frequency. No significant associations were found between Vδ2⁺ T cell proportions and perinatal factors other than gestational age or brain injury. Blood transcriptome analysis revealed 173 differentially expressed genes, characterized by downregulated interferon signaling and upregulated antimicrobial and neutrophil pathways in infants with brain injury.</p><p><strong>Conclusions: </strong>Gestational age and birth weight influence Vδ2⁺ T cell proportions in preterm infants, likely reflecting immune maturation. While no direct link to brain injury was found, altered immune pathways suggest potential biomarkers for prognosis, warranting further research into their roles and therapeutic implications in neonatal brain injuries.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":"21 1","pages":"310"},"PeriodicalIF":9.3,"publicationDate":"2024-11-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11607874/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142755247","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}