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Infiltration by monocytes of the central nervous system and its role in multiple sclerosis: reflections on therapeutic strategies

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Neural Regeneration Research 2025年第3期20卷 779-793页

作者： Guangyong Zhang Qing Yao Chubing Long Pengcheng Yi Jiali Song Luojia Wu Wei Wan Xiuqin Rao Yue Lin Gen Wei Jun Ying Fuzhou Hua Department of Anesthesiology the Second Affiliated Hospital of Nanchang UniversityNanchangJiangxi ProvinceChina Key Laboratory of Anesthesiology of Jiangxi Province NanchangJiangxi ProvinceChina

Mononuclear macrophage infiltration in the central nervous system is a prominent feature of neuroinflammation. Recent studies on the pathogenesis and progression of multiple sclerosis have highlighted the multiple roles of mononuclear macrophages in the neuroinflammatory process. Monocytes play a significant role in neuroinflammation, and managing neuroinflammation by manipulating peripheral monocytes stands out as an effective strategy for the treatment of multiple sclerosis, leading to improved patient outcomes. This review outlines the steps involved in the entry of myeloid monocytes into the central nervous system that are targets for effective intervention: the activation of bone marrow hematopoiesis, migration of monocytes in the blood, and penetration of the blood–brain barrier by monocytes. Finally, we summarize the different monocyte subpopulations and their effects on the central nervous system based on phenotypic differences. As activated microglia resemble monocyte-derived macrophages, it is important to accurately identify the role of monocyte-derived macrophages in disease. Depending on the roles played by monocyte-derived macrophages at different stages of the disease, several of these processes can be interrupted to limit neuroinflammation and improve patient prognosis. Here, we discuss possible strategies to target monocytes in neurological diseases, focusing on three key aspects of monocyte infiltration into the central nervous system, to provide new ideas for the treatment of neurodegenerative diseases.

关键词： blood–brain barrier macrophages monocytes multiple sclerosis neuroinflammation review therapy

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multiple sclerosis and sexual dysfunction

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Asian Journal of Andrology 2012年第4期14卷 530-535页

作者： Zhen-Ni Guo Si-Yuan He Hong-Liang Zhang Jiang Wu Yi Yang Department of Neurology the First Norman Bethune Hospital of Jilin UniversityJilin UniversityChangchun 130021China

multiple sclerosis （MS） is a chronic inflammatory demyelinating disorder of the central nervous system characterized by episodic and progressive neurologic dysfunction resulting from inflammatory and autoimmune reactions. The underlying pathogenesis of MS remains largely unclear. However, it is currently accepted as a T cell-mediated autoimmune disease. Among other clinical manifestations, sexual dysfunction （SD） is a painful but still underreported and underdiagnosed symptom of the disorder. SD in MS patients may result from a complex set of conditions and may be associated with multiple anatomic, physiologic, biologic, medical and psychological factors. SD arises primarily from lesions affecting the neural pathways involved in physiologic function. In addition, psychological factors, the side effects of medications and physical symptoms such as fatigue, muscular weakness, menstrual changes, pain and concerns about bladder and bowel incontinence may also be involved. Since MS primarily affects young people, SD secondary to MS may have a great impact on quality of life. Thus, maintaining a healthy sexual life with MS is an important priority. The treatment of SD requires multidisciDlinarv teamwork and coooeration amone specialists,individual patients, partners and the society.

关键词： demyelination endocrine disorder multiple sclerosis sexual dysfunction

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What do we know about the role of lncRNAs in multiple sclerosis?

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Neural Regeneration Research 2021年第9期16卷 1715-1722页

作者： Viviana Nociti Massimo Santoro Institute of Neurology Fondazione Policlinico Universitario‘A.Gemelli’IRCCSUniversitàCattolica del Sacro CuoreRomeItaly IRCCS Fondazione Don Carlo Gnocchi FlorenceItaly

multiple sclerosis is a chronic, inflammatory and degenerative disease of the central nervous system of unknown aetiology although well-defined evidence supports an autoimmune pathogenesis. So far, the exact mechanisms leading to autoimmune diseases are still only partially understood. We know that genetic, epigenetic, molecular, and cellular factors resulting in pathogenic inflammatory responses are certainly involved. Long non-coding RNAs(lncRNAs) are non-protein coding transcripts longer than 200 nucleotides that play an important role in both innate and acquired immunity, so there is great interest in lncRNAs involved in autoimmune diseases. The research on multiple sclerosis has been enriched with many studies on the molecular role of lncRNAs in the pathogenesis of the disease and their potential application as diagnostic and prognostic biomarkers. In particular, many multiple sclerosis fields of research are based on the identification of lncRNAs as possible biomarkers able to predict the onset of the disease, its activity degree, its progression phase and the response to disease-modifying drugs. Last but not least, studies on lncRNAs can provide a new molecular target for new therapies, missing, so far, a cure for multiple sclerosis. While our knowledge on the role of lncRNA in multiple sclerosis has recently improved, further studies are required to better understand the specific role of lncRNAs in this neurological disease. In this review, we present the most recent studies on molecular characterization of lncRNAs in multiple sclerosis disorder discussing their clinical relevance as biomarkers for diagnosis and treatments.

关键词： antisense lncRNAs enhancer lncRNAs epigenetics immune system intergenic lncRNA intronic lncRNA multiple sclerosis sense lncRNAs single nucleotide polymorphisms

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CDP-choline to promote remyelination in multiple sclerosis:the need for a clinical trial

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Neural Regeneration Research 2023年第12期18卷 2599-2605页

作者： Viktoria Gudi PawełGrieb Ralf ALinker Thomas Skripuletz Department of Neurology Hannover Medical SchoolHannoverGermany Department of Experimental Pharmacology Mossakowski Medical Research InstitutePolish Academy of SciencesWarsawPoland Department of Neurology University Hospital RegensburgRegensburgGermany

multiple sclerosis is a multifactorial chronic inflammatory disease of the central nervous system that leads to demyelination and neuronal cell death,resulting in functional *** is the natural repair process of demyelination,but it is often incomplete or fails in multiple *** therapies reduce the inflammatory state and prevent clinical ***,therapeutic approaches to increase myelin repair in humans are not yet *** substance cytidine-5′-diphosphocholine,CDP-choline,is ubiquitously present in eukaryotic cells and plays a crucial role in the synthesis of cellular *** properties have been shown in various animal models of diseases of the central nervous *** have already shown that the compound CDPcholine improves myelin regeneration in two animal models of multiple ***,the results from the animal models have not yet been studied in patients with multiple *** this review,we summarise the beneficial effects of CDP-choline on biolipid metabolism and turnover with regard to inflammatory and regenerative *** also explain changes in phospholipid and sphingolipid homeostasis in multiple sclerosis and suggest a possible therapeutic link to CDP-choline.

关键词： astrocytes CDP-choline cuprizone microglia multiple sclerosis oligodendrocytes

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Automatic and Robust Segmentation of multiple sclerosis Lesions with Convolutional Neural Networks

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Computers, Materials & Continua 2021年第1期66卷 977-991页

作者： H.M.Rehan Afzal Suhuai Luo Saadallah Ramadan Jeannette Lechner-Scott Mohammad Ruhul Amin Jiaming Li M.Kamran Afzal M.Kamran Afzal School of Electrical Engineering and Computing University of NewcastleCallaghanNSW 2308Australia Hunter Medical Research Institute New Lambton HeightsNSW 2305Australia Department of Neurology John Hunter HospitalNew Lambton HeightsNSW 2305Australia CSIRO Data61 MarsfieldNSW 2122Australia School of Computer Science and Technology Xiamen UniversityXiamen361005China

The diagnosis of multiple sclerosis(MS)is based on accurate detection of lesions on magnetic resonance imaging(MRI)which also provides ongoing essential information about the progression and status of the *** detection of lesions is very time consuming and lacks *** of the lesions are difficult to detect manually,especially within the grey *** paper proposes a novel and fully automated convolution neural network(CNN)approach to segment *** proposed system consists of two 2D patchwise CNNs which can segment lesions more accurately and *** first CNN network is implemented to segment lesions accurately,and the second network aims to reduce the false positives to increase *** system consists of two parallel convolutional pathways,where one pathway is concatenated to the second and at the end,the fully connected layer is replaced with *** routine MRI sequences T1-w,T2-w and FLAIR are used as input to the CNN,where FLAIR is used for segmentation because most lesions on MRI appear as bright regions and T1-w&T2-w are used to reduce MRI *** evaluated the proposed system on two challenge datasets that are publicly available from MICCAI and *** and qualitative evaluation has been performed with various metrics like false positive rate(FPR),true positive rate(TPR)and dice similarities,and were compared to current state-of-the-art *** proposed method shows consistent higher precision and sensitivity than other *** proposed method can accurately and robustly segment MS lesions from images produced by different MRI scanners,with a precision up to 90%.

关键词： multiple sclerosis lesion segmentation automatic segmentation CNN automated tool lesion detection

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The contribution of oligodendrocytes and oligodendrocyte progenitor cells to central nervous system repair in multiple sclerosis： perspectives for remyelination therapeutic strategies

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Neural Regeneration Research 2017年第12期12卷 1939-1944页

作者： Adriana Octaviana Dulamea Department of Neurology Fundeni Clinical Institute University of Medicine and Pharmacy "Carol Davila" Bucharest Romania

Oligodencrocytes（OLs） are the main glial cells of the central nervous system involved in myelination of axons. In multiple sclerosis（MS）, there is an imbalance between demyelination and remyelination processes, the last one performed by oligodendrocyte progenitor cells（OPCs） and OLs, resulting into a permanent demyelination, axonal damage and neuronal loss. In MS lesions, astrocytes and microglias play an important part in permeabilization of blood-brain barrier and initiation of OPCs proliferation. Migration and differentiation of OPCs are influenced by various factors and the process is finalized by insufficient acummulation of OLs into the MS lesion. In relation to all these processes, the author will discuss the potential targets for remyelination strategies.

关键词： multiple sclerosis oligodencrocytes oligodendrocyte progenitor cells demyelination remyelination semaphorin basic helix-loop-helix transcription factor oligodendrocyte transcription factor 2 leucin-rich repeatand immunoglobulin-like-domain-containing nogo receptor-interacting protein I canonical Notch signaling endocrine receptors

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Detecting white matter alterations in multiple sclerosis using advanced diffusion magnetic resonance imaging

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Neural Regeneration Research 2019年第1期14卷 114-123页

作者： Sourajit M.Mustafi Jaroslaw Harezlak Chandana Kodiweera Jennifer S.Randolph James C.Ford Heather A.Wishart Yu-Chien Wu Department of Radiology and Imaging Sciences Indiana University School of Medicine Department of Epidemiology and Biostatistics School of Public Health Indiana University Department of Psychological and Brain Sciences and Dartmouth Brain Imaging Center Dartmouth College Department of Psychiatry Geisel School of Medicine at Dartmouth

multiple sclerosis is a neurodegenerative and inflammatory disease, a hallmark of which is demyelinating lesions in the white matter. We hypothesized that alterations in white matter microstructures can be non-invasively characterized by advanced diffusion magnetic resonance imaging. Seven diffusion metrics were extracted from hybrid diffusion imaging acquisitions via classic diffusion tensor imaging, neurite orientation dispersion and density imaging, and q-space imaging. We investigated the sensitivity of the diffusion metrics in 36 sets of regions of interest in the brain white matter of six female patients(age 52.8 ± 4.3 years) with multiple sclerosis. Each region of interest set included a conventional T2-defined lesion, a matched perilesion area, and normal-appearing white matter. Six patients with multiple sclerosis(n = 5) or clinically isolated syndrome(n = 1) at a mild to moderate disability level were recruited. The patients exhibited microstructural alterations from normal-appearing white matter transitioning to perilesion areas and lesions, consistent with decreased tissue restriction, decreased axonal density, and increased classic diffusion tensor imaging diffusivity. The findings suggest that diffusion compartment modeling and q-spa ce analysis appeared to be sensitive for detecting subtle microstructural alterations between perilesion areas and normal-appearing white matter.

关键词： multiple sclerosis hybrid diffusion imaging NODDI diffusion tensor imaging q-space imaging

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Genomic and functional evaluation of TNFSF14 in multiple sclerosis susceptibility

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Journal of Genetics and Genomics 2021年第6期48卷 497-507页

作者： Miriam Zuccala Nadia Barizzone Elena Boggio Luca Gigliotti Melissa Sorosina Chiara Basagni Roberta Bordoni Ferdinando Clarelli Santosh Anand Eleonora Mangano Domizia Vecchio Elena Corsetti Serena Martire Simona Perga Daniela Ferrante Alberto Gajofatto Andrei Ivashynka Claudio Solaro Roberto Cantello Vittorio Martinelli Giancarlo Comi Massimo Filippi Federica Esposito Maurizio Leone Gianluca De Beilis Umberto Dianzani Filippo Martinelli-Boneschi Sandra D’Alfonso Department of Health Sciences Center on Autoimmune and Allergic Diseases(CAAD)UPOUniversity of Eastern PiedmontA.AvogadroNovara 28100Italy Consorzio Interuniversitario di Biotecnologie(CIB) Trieste 34149Italy Laboratory of Human Genetics of Neurological Disorders Institute of Experimental NeurologyDivision of NeurosciencesIRCCS San Raffaele Scientific InstituteMilan 20132Italy National Research Council of Italy Institute for Biomedical TechnologiesSegrateMilan 20090Italy Department of Genetic Medicine and Development(GEDEV) Faculty of MedicineUniversity of Geneva Medical SchoolGeneva 1211Switzerland Department of Informatics Systems and Communications(DISCo)University of Milano-BicoccaMilan 20126Italy MS Centre SCDU NeurologyAOU Maggiore della CaritàNovara 28100Italy Department of Translational Medicine Interdisciplinary Research Center of Autoimmune Diseases(IRCAD)University of Eastern PiedmontNovaraAvogadro UniversityNovara 28100Italy Neuroscience Institute Cavalieri Ottolenghi OrbassanoTurin 10043Italy Neurobiology Unit Neurology-CReSM(Regional Referring Center of Multiple Sclerosis)AOU San Luigi GonzagaOrbassanoTurin 10043Italy Department of Neuroscience‘Rita Levi Montalcini’ University of TurinTurin 10126Italy Department of Neuroscience Biomedicine and Movement SciencesUniversity of VeronaVerona 37134Italy UO Neurologia Fondazione IRCCS Casa Sollievo della Sofferenza San Giovanni RotondoFoggia 71013Italy Centro Recupero e Rieducazione Funzionale“Mons L Novarese” Moncrivello(VC)13040Italy Department of Neurology IRCCS San Raffaele Scientific InstituteMilan 20132Italy Neuroimaging Research Unit Institute of Experimental NeurologyDivision of NeuroscienceIRCCS San Raffaele Scientific InstituteMilan 20132Italy Vita-Salute San Raffaele University Milan 20138Italy Neurophysiology Unit IRCCS San Raffaele Scientific InstituteMilan 20138Italy Dino Ferrari Centre Neuroscience SectionDepartment of Pathophysiology and Transplantation(DEPT)University of MilanMilan 20122

Among multiple sclerosis(MS)susceptibility genes,the strongest non-human leukocyte antigen(HLA)signal in the Italian population maps to the TNFSF14 gene encoding LIGHT,a glycoprotein involved in dendritic cell(DC)*** fine-mapping in a large Italian dataset(4,198 patients with MS and3,903 controls),we show that the TNFSF14 intronic SNP rs1077667 is the primarily MS-associated variant in the *** quantitative trait locus(e QTL)analysis indicates that the MS risk allele is significantly associated with reduced TNFSF14 messenger RNA levels in blood cells,which is consistent with the allelic imbalance in RNA-Seq reads(P<0.0001).The MS risk allele is associated with reduced levels of TNFSF14 gene expression(P<0.01)in blood cells from 84 Italian patients with MS and 80 healthy controls(HCs).Interestingly,patients with MS are lower expressors of TNFSF14 compared to HC(P<0.007).Individuals homozygous for the MS risk allele display an increased percentage of LIGHT-positive peripheral blood myeloid DCs(CD11 c+,P=0.035)in 37 HCs,as well as in in vitro monocyte-derived DCs from 22 HCs(P=0.04).Our findings suggest that the intronic variant rs1077667 alters the expression of TNFSF14 in immune cells,which may play a role in MS pathogenesis.

关键词： multiple sclerosis TNFSF14 LIGHT Fine-mapping analysis SNV

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Microglia depletion as a therapeutic strategy:friend or foe in multiple sclerosis models?

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Neural Regeneration Research 2023年第2期18卷 267-272页

作者： Victoria Sofia Berenice Wies Mancini Anabella Ayelen Di Pietro Laura Andrea Pasquini Universidad de Buenos Aires Facultad de Farmacia y BioquímicaDepartamento de Química BiológicaCátedra de Química Biológica PatológicaBuenos AiresArgentina Universidad de Buenos Aires Consejo Nacional de Investigaciones Científicas y TécnicasInstituto de Química y Fisicoquímica Biológicas Prof.Dr.Alejandro C.PaladiniFacultad de Farmacia y BioquímicaBuenos AiresArgentina

M ultiple sclerosis is a chro nic central nervous system demyelinating disease whose onset and progression are driven by a combination of immune dysregulation,genetic predisposition,and environmental fa *** activation of microglia and astrocytes is a key player in multiple sclerosis immunopathology,playing specific roles associated with anatomical location and phase of the disease and controlling demyelination and *** though reactive mic roglia can damage tissue and heighten deleterious effects and neurodegeneration,activated microglia also perform neuroprotective functions such as debris phagocytosis and growth fa ctor *** can be activated into pro-inflammato ry phenotype A1 through a mechanism mediated by activated neuroinflammatory microglia,which could also mediate *** A1 phenotype inhibits oligodendrocyte prolife ration and differe ntiation and is toxic to both oligodendrocytes and *** r,astroglial activation into phenotype A2 may also take place in response to neurodegeneration and as a protective mechanism.A variety of animal models mimicking specific multiple sclerosis features and the associated pathophysiological processes have helped establish the cascades of events that lead to the initiation,progression,and resolution of the *** colonystimulating facto r-1 receptor is expressed by myeloid lineage cells such as peripheral monocytes and macrophages and central nervous system ***,as microglia development and survival critically rely on colony-stimulating factor-1 receptor signaling,colony-stimulating factor-1 receptor inhibition can almost completely eliminate microglia from the *** this context,the present review discusses the impact of microglial depletion through colo ny-stimulating factor-1 receptor inhibition on demyelination,neurodegeneration,astroglial activation,and behavior in different multiple sclerosis models,highlighting the diversity of micr

关键词： astrocytes colony-stimulating factor-1 receptor inhibition cuprizone demyelnation microglia multiple sclerosis neurodegeneration

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Phloroglucinol derivative compound 21 attenuates cuprizoneinduced multiple sclerosis mice through promoting remyelination and inhibiting neuroinflammation

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Science China(Life Sciences) 2020年第6期63卷 905-914页

作者： Zhe Zhao Xiu-qi Bao Zihong Zhang Hui Liu Dan Zhang State Key Laboratory of Bioactive Substrate and Function of Natural Medicine Institute of Materia MedicaChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100050China

multiple sclerosis(MS) is a chronic autoimmune demyelinating disease in the central nervous system. The myelin loss is mainly caused by dysfunction of oligodendrocytes and inflammatory responses of microglia and astrocytes further aggravate the demyelination. Current therapies for MS focus on suppressing the overactivated immune response but cannot halt the disease progress, so effective drugs are urgently needed. Compound 21 is a phloroglucinol derivative that has been proved to have an outstanding anti-inflammatory effect. The purpose of the present study is to investigate whether this novel compound is effective in MS. The cuprizone-induced model was used in this study to mimic the pathological progress of MS. The results showed that Compound 21 significantly improved the neurological dysfunction and motor coordination impairment. Luxol Fast Blue staining and myelin basic protein immunostaining demonstrated that Compound 21 remarkably promoted remyelination. In addition,Compound 21 significantly promoted oligodendrocytes differentiation. Furthermore, we found that Compound 21 decreased microglia and astrocytes activities and the subsequent neuroinflammatory response, indicating that the anti-inflammatory effect of Compound 21 was also involved in its neuro-protection. All the data prove that Compound 21 exerts protective effect on MS through promoting remyelination and suppressing neuroinflammation, indicating that Compound 21 might be a potential drug candidate for MS treatment.

关键词： multiple sclerosis oligodendrocytes demyelination microglia astrocytes

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