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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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Decreased human leukocyte antigen-D-related expression on CD14^(+)Monocytes in patients with out-of-hospital cardiac arrest provided target temperature management therapy:a prospective observational study

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Emergency and Critical Care Medicine 2024年第1期4卷 16-21页

作者： Huan Shao Wei Yuan Ziren Tang Zhijiang Qi Le An Qiang Zhang Chunsheng Li Department of Emergency Medicine Beijing Chao-Yang HospitalCapital Medical UniversityBeijingChina Beijing Key Laboratory of Cardiopulmonary Cerebral Resuscitation Beijing Chao-Yang HospitalCapital Medical UniversityBeijingChina.

Background:Post–cardiac arrest syndrome involves systemic inflammation,which causes subsequent neurological impairments.We investigated the influence of targeted temperature management(TTM)therapy in patients with out-of-hospital cardiac arrest(OHCA)after return of spontaneous circulation(ROSC)by observing the changes in circulating CD14^(+)Monocytes and the expression of human leukocyte antigen D–related(HLA-DR)and programmed cell death ligand 1(PD-L1)in CD14^(+)Monocytes.Methods:Adult patients admitted to the emergency department of Beijing Chao-Yang Hospital after OHCA between January 2017 and March 2018 were included in this study.Thirty control subjects,10 patients with OHCA,and 37 patients with OHCA who received 72 hours of TTM therapy were enrolled.Peripheral blood samples of patients in the OHCA and TTM groups were collected on Days 1 and 3(D1 and D3)after ROSC and evaluated for HLA-DR and PD-L1 expression on CD14^(+)Monocytes using flow cytometry.Results:Compared with control subjects,the percentage of circulating CD14^(+)Monocytes,HLA-DR+/CD14^(+)monocyte ratios,and mean fluorescence intensity were significantly decreased in patients with OHCA.After ROSC,HLA-DR expression in CD14^(+)Monocytes in the TTM group was lower than that in patients with OHCA.However,there were no significant differences in the percentage of PD-L1+/CD14^(+)Monocytes or the mean fluorescence intensity between patients with OHCA and healthy volunteers.Conclusion:After ROSC,circulating CD14^(+)Monocytes and HLA-DR+/CD14^(+)monocyte ratios decreased significantly in patients with OHCA.Human leukocyte antigen D–related expression in CD14^(+)Monocytes was lower in patients treated with TTM.

关键词： Human leukocyte antigen D-related Monocytes Out-of-hospital cardiac arrest Target temperature management

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JAK inhibition ameliorated experimental autoimmune encephalomyelitis by blocking GM-CSF-driven inflammatory signature of Monocytes

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Acta Pharmaceutica Sinica B 2023年第10期13卷 4185-4201页

作者： Shuai Shao Chengjuan Chen Gaona Shi Yu Zhou Yazi Wei Lei Wu Lan Sun Tiantai Zhang State Key Laboratory of Bioactive Substance and Function of Natural Medicines Institute of Materia MedicaChinese Academy of Medical Sciences&Peking Union Medical CollegeBeijing 100050China

Monocytes are key effectors in autoimmunity-related diseases in the central nervous system(CNS)due to the critical roles of these cells in the production of proinflammatory cytokines,differentiation of T-helper(Th)cells,and antigen presentation.The JAK-STAT signaling is crucial for initiating Monocytes induced immune responses by relaying cytokines signaling.However,the role of this pathway in modulating the communication between Monocytes and Th cells in the pathogenesis of multiple sclerosis(MS)is unclear.Here,we show that the JAK1/2/3 and STAT1/3/5/6 subtypes involved in the demyelination mediated by the differentiation of pathological Th1 and Th17 and the CNS-infiltrating inflammatory Monocytes in experimental autoimmune encephalomyelitis(EAE),a model for MS.JAK inhibition prevented the CNS-infiltrating CCR2-dependent Ly6^(Chi)Monocytes and monocyte-derived dendritic cells in EAE mice.In parallel,the proportion of GM-CSF^(+)CD4^(+)T cells and GM-CSF secretion were decreased in pathological Th17 cells by JAK inhibition,which in turns converted CNS-invading Monocytes into antigen-presenting cells to mediate tissue damage.Together,our data highlight the therapeutic potential of JAK inhibition in treating EAE by blocking the GM-CSF-driven inflammatory signature of Monocytes.

关键词： Monocytes T-helper cells Monocyte-derived dendritic cells GM-CSF JAK-STAT signaling JAK inhibitor Experimental autoimmune encephalomyelitis Multiple sclerosis

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Identification of Monocytes Associated with Severe COVID-19 in the PBMCs of Severely Infected Patients Through Single-Cell Transcriptome Sequencing

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Engineering 2022年第10期17卷 161-169页

作者： Yan Zhang Shuting Wang He Xia Jing Guo Kangxin He Chenjie Huang Rui Luo Yanfei Chen Kaijin Xu Hainv Gao Jifang Sheng Lanjuan Li State Key Laboratory for Diagnosis and Treatment of Infectious Disease National Clinical Research Center for Infectious DiseasesCollaborative Innovation Center for Diagnosis and Treatment of Infectious DiseasesDepartment of Infectious DiseaseThe First Affiliated HospitalCollege of MedicineZhejiang UniversityHangzhou 310003China Shulan(Hangzhou)Hospital Affiliated to Zhejiang Shuren University Shulan International Medical College Hangzhou 310022China

Understanding the immunological characteristics of Monocytes-including the characteristics associated with fibrosis-in severe coronavirus disease 2019(COVID-19)is crucial for understanding the pathogenic mechanism of the disease and preventing disease severity.In this study,we performed single-cell transcriptomic sequencing of peripheral blood samples collected from six healthy controls and 14 COVID-19samples including severe,moderate,and convalescent samples from three severely/critically ill and four moderately ill patients.We found that the Monocytes were strongly remodeled in the severely/critically ill patients with COVID-19,with an increased proportion of Monocytes and seriously reduced diversity.In addition,we discovered two novel severe-disease-specific monocyte subsets:Mono 0 and Mono 5.These subsets expressed amphiregulin(AREG),epiregulin(EREG),and cytokine interleukin-18(IL-18)gene,exhibited an enriched erythroblastic leukemia viral oncogene homolog(ErbB)signaling pathway,and appeared to exhibit pro-fibrogenic and pro-inflammation characteristics.We also found metabolic changes in Mono 0 and Mono 5,including increased glycolysis/gluconeogenesis and an increased hypoxia inducible factor-1(HIF-1)signaling pathway.Notably,one pre-severe sample displayed a monocyte atlas similar to that of the severe/critical samples.In conclusion,our study discovered two novel severedisease-specific monocyte subsets as potential predictors and therapeutic targets for severe COVID-19.Overall,this study provides potential predictors for severe disease and therapeutic targets for COVID-19 and thus provides a resource for further studies on COVID-19.

关键词： COVID-19 Severe infection Critically ill Monocytes Fibrosis

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Soluble CD163 and CD163 Expression on Monocytes Associated with Chronic Hepatitis B Inflammation and HBsAg Loss

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Journal of Clinical and Translational Hepatology 2022年第6期10卷 1059-1067页

作者： Peilin Xie Bilian Yao Dao Huang Yongyan Chen Qiming Gong Xinxin Zhang Department of Infectious Diseases Research Laboratory of Clinical VirologyRuijin HospitalShanghai Jiao Tong Univer-sity School of MedicineShanghaiChina Department of General Practice Ruijin HospitalShanghai Jiao Tong University School of MedicineShanghaiChina Department of Geriatrics Ruijin HospitalShanghai Jiao Tong University School of MedicineShanghaiChina Department of Infectious Diseases Ruijin HospitalShanghai Jiao Tong University School of MedicineShanghaiChina

Background and Aims:Monocyte/macrophage-associat-ed CD163 is an indicator of the severity of liver inflam-mation and cirrhosis,but the difference of soluble CD163(sCD163)levels in chronic hepatitis B(CHB)patients and hepatitis B surface antigen(HBsAg)-loss patients is un-clear.Herein,we aimed to compare the sCD163 levels in CHB patients and HBsAg-loss patients with or without an-tiviral treatment.Methods:sCD163 and CD163 expres-sion on Monocytes were compared among four groups,healthy subjects,treatment-naïve CHB patients,sponta-neous HBsAg-loss patients,and treatment-related HBsAg-loss patients.The correlation between sCD163 levels and clinical parameters in CHB patients was analyzed.A group of 80 patients with hepatitis B virus(HBV)infection and liver biopsy were recruited.Results:sCD163 levels were higher in the CHB group than in the other three groups.sCD163 levels were higher in treatment-related HBsAg-loss patients than in spontaneous HBsAg-loss patients.sCD163 levels were negatively correlated with hepatitis B e-antigen(HBeAg)and HBsAg levels in HBeAg-positive patients.Liv-er biopsy results further demonstrated that sCD163 levels were elevated in CHB patients with substantial inflamma-tion(A≥2)or fibrosis(F≥2).The sCD163 model was more sensitive in predicting inflammation than other noninvasive models.Its levels were higher in patients with normal ala-nine aminotransferase levels and significant inflammation(A≥2)than in patients with no or mild inflammation.Con-clusions:sCD163 and CD163 expression on Monocytes were associated with CHB inflammation and HBsAg loss,and may be used as markers to predict HBV-specific im-mune activation.

关键词： CD163 Hepatitis B virus HBsAg loss Monocytes Immune activa-tion

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Machine learning identified genetic features associated with HIV sequences in the Monocytes

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Chinese Medical Journal 2023年第24期136卷 3002-3004页

作者： Xiaorong Peng Biao Zhu State Key Laboratory for Diagnosis and Treatment of Infectious Diseases National Clinical Research Center for Infectious DiseasesCollaborative Innovation Center for Diagnosis and Treatment of Infectious DiseasesThe First Affiliated HospitalSchool of MedicineZhejiang UniversityHangzhouZhejiang 310003China

To the Editor:Human immunodeficiency virus(HIV)DNA has been detected in circulating Monocytes isolated from HIV-infected individuals with or without antiretroviral therapy(ART).[1]Infrequent and low levels of HIV DNA were detected in circulating Monocytes.[2]Monocytes harbor replication-competent,non-latent HIV-1 in patients on ART.Earlier studies on circulating Monocytes have revealed distinct viral populations and genetic characteristics compared to T cells.[3,4]However,there is currently no easy way to clearly distinguish virus in monocyte from virus in T-cell.

关键词： Monocytes latent harbor

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Single-cell transcriptome profiling of sepsis identifies HLA-DR^(low)S100A^(high)Monocytes with immunosuppressive function

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Military Medical Research 2023年第6期10卷 778-797页

作者： Ren-Qi Yao Peng-Yue Zhao Zhi-Xuan Li Yu-Yang Liu Li-Yu Zheng Yu Duan Lu Wang Rong-Li Yang Hong-Jun Kang Ji-Wei Hao Jing-Yan Li Ning Dong Yao Wu Xiao-Hui Du Feng Zhu Chao Ren Guo-Sheng Wu Zhao-Fan Xia Yong-Ming Yao Translational Medicine Research Center Medical Innovation Research Division and the Fourth Medical Center of Chinese PLA General HospitalBei‑jing 100853China Department of Burn Surgery the First Affiliated Hospital of Naval Medical UniversityShanghai 200433China Research Unit of Key Techniques for Treatment of Burns and Combined Burns and Trauma Injury Chinese Academy of Medical SciencesBeijing 100730China Department of General Surgery the First Medical Center of Chinese PLA General HospitalBeijing 100853China Department of Neurosurgery the First Medical Center of Chinese PLA General HospitalBeijing 100853China Department of Critical Care Medicine the First Medical Center of Chinese PLA General HospitalBeijing 100853China Intensive Care Unit Dalian Municipal Central Hospital Affiliated Dalian University of TechnologyDalian 116033LiaoningChina Department of Emergency the Second Hospital of Hebei Medical UniversityShijiazhuang 050000China Department of Pulmonary and Criti‑cal Care Medicine Beijing Chaoyang HospitalCapital Medical UniversityBeijing 100020China.

Background Sustained yet intractable immunosuppression is commonly observed in septic patients,resulting in aggravated clinical outcomes.However,due to the substantial heterogeneity within septic patients,precise indicators in deciphering clinical trajectories and immunological alterations for septic patients remain largely lacking.Methods We adopted cross-species,single-cell RNA sequencing(scRNA-seq)analysis based on two published datasets containing circulating immune cell profile of septic patients as well as immune cell atlas of murine model of sepsis.Flow cytometry,laser scanning confocal microscopy(LSCM)imaging and Western blotting were applied to identify the presence of S100A9^(+)Monocytes at protein level.To interrogate the immunosuppressive function of this subset,splenic Monocytes isolated from septic wild-type or S100a9^(–/–)mice were co-cultured with naive CD4^(+)T cells,followed by proliferative assay.Pharmacological inhibition of S100A9 was implemented using Paquinimod via oral gavage.Results scRNA-seq analysis of human sepsis revealed substantial heterogeneity in monocyte compartments following the onset of sepsis,for which distinct monocyte subsets were enriched in disparate subclusters of septic patients.We identified a unique monocyte subset characterized by high expression of S100A family genes and low expression of human leukocyte antigen DR(HLA-DR),which were prominently enriched in septic patients and might exert immunosuppressive function.By combining single-cell transcriptomics of murine model of sepsis with in vivo experiments,we uncovered a similar subtype of monocyte significantly associated with late sepsis and immunocompromised status of septic mice,corresponding to HLA-DR^(low)S100A^(high)Monocytes in human sepsis.Moreover,we found that S100A9^(+)Monocytes exhibited profound immunosuppressive function on CD4^(+)T cell immune response and blockade of S100A9 using Paquinimod could partially reverse sepsis-induced immunosuppression.Conclusions This study identifies HLA-DR^(low)S100A^(h

关键词： Single-cell analysis Sepsis Immunosuppression S100A Human leukocyte antigen DR(HLA-DR) Monocytes Myeloid-derived suppressor cells(MDSCs) Paquinimod

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SARS-CoV-2 infection of Monocytes:balancing acts of antibodies and inflammasomes

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Signal Transduction and Targeted Therapy 2022年第8期7卷 2668-2669页

作者： R.Camille Brewer William H.Robinson Tobias V.Lanz Division of Immunology and Rheumatology Department of MedicineStanford University School of Medicine269 Campus DriveStanfordCA 94305USA Geriatric Research Educationand Clinical Centers(GRECC)VA Palo Alto Health Care System3801 Miranda AvePalo AltoCA 94304USA

In a recent study in Nature,Junqueira et al.provided evidence that severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)infects human Monocytes and lung macrophages.1 The infection is antibody-mediated via Fc-receptors(FcγRs),and activates NLRP3 and AIM2 inflammasomes,which in turn induce pyroptosis and halt viral replication.Infected Monocytes secrete the proinflammatory cytokines interleukin-1β(IL-1β)and IL-18,which contribute to systemic inflammation and severe coronavirus disease 19(COVID-19)(Fig.1).

关键词： NLRP3 Monocytes infection

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Single-cell RNA sequencing reveals classical Monocytes are the major precursors of rat osteoclasts

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BIOCELL 2022年第3期46卷 655-665页

作者： JIRUI WEN WENCHAO WU MIN TANG MINGYUE BAO XUELING HE XINGHONG YAO LIANG LI Institute of Biomedical Engineering West China School of Basic Medical Science and Forensic MedicineSichuan UniversityChengdu610041China Laboratory of Cardiovascular Diseases Regenerative Medicine Research CenterWest China HospitalSichuan UniversityChengdu610041China Laboratory Animal Center Sichuan UniversityChengdu610041China

To dissect which subset of bone marrow monocyte is the major precursor of osteoclast,3-month-old rat bone marrow was obtained for single-cell RNA sequencing.A total of 6091 cells were acquired for detailed analysis,with a median number of 1206 genes detected per cell and 17,959 genes detected in total.A total of 19 cell clusters were recognized,with the main lineages identified as B cells,Granulocytes,Monocytes,T cells,Erythrocytes and Macrophages.Monocytes were further divided into classical Monocytes and non-classical Monocytes.Compared with non-classical Monocytes,classical Monocytes highly expressed osteoclast differentiation related genes Mitf,Spi1,Fos and Csf1r.Additionally,biological processes of classical Monocytes were related to osteoclast differentiation.qPCR revealed differentially expressed genes of classical Monocytes played a role in osteoclast differentiation.In conclusion,classical Monocytes were identified as the main precursors of osteoclasts in rats,and may contribute to osteoclast differentiation by regulating S100a4,S100a6,S100a10,Fn1,Vcan and Bcl2a1.The results of this study contribute to the understanding of the origin of osteoclasts and may provide potential biomarkers for early diagnosis of bone metabolic diseases,as well as molecular and cellular targets for clinical intervention in bone metabolic diseases.

关键词： Single-cell RNA sequencing Monocytes Subsets Osteoclast differentiation

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An unbalanced PD-L1/CD86 ratio in CD14^＋＋CD16^＋ Monocytes is correlated with HCV viremia during chronic HCV infection

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Cellular & Molecular Immunology 2014年第3期11卷 294-304页

作者： Jiajia Zheng Hua Liang Chunhui Xu Qiang Xu Ting Zhang Tao Shen Fengmin LU Department of Microbiology Peking University Health Science Center Beijing China Department of Laboratory Medicine Peking University Third Hospital Beijing China State Key Laboratory for infectious Disease Prevention and Control National Center for AIDS/STD Control and Prevention China CDC Beijing China Center of Infectious Diseases Peking University Beijing China These authors contributed equally to this work

Circulating monocyte subsets with distinct functions play important roles in hepatitis C virus （HCV） infection. However, the mechanisms have not been well studied. In this study, we analyzed the distributions and phenotypic characteristics of three circulating monocyte subsets--CD14^＋＋CD16^-, CD14^＋＋CD16^＋ and CD14^＋＋mCD16^——in chronic HCV-infected patients, HCV spontaneous resolvers and healthy controls, and we evaluated the possible link between HCV viremia and disease progression. Our results indicated that the frequency of the CD 14^＋＋CD 16^＋ monocyte subset was decreased, and negatively correlated with HCV RNA and core antigen levels during chronic HCV infection. PD-L1 expression and the PD-L1/CD86 ratio in CD14^＋＋CD16^＋ Monocytes were higher during chronic HCV infection than in spontaneous HCV resolvers and healthy controls. The PD-L1/CD86 ratio positively correlated with HCV viral load and core antigen levels. Finally, PD-L1 was significantly increased, while cytokine secretions were dramatically decreased upon Toll-like receptor （TLR） ligand binding and HCV JFH-lstimulation. These findings indicates the compromised immune status of the CD14^＋＋CD16^＋ Monocytes during chronic HCV infection and provides new insights into the specific role of the CD14^＋＋CD16^＋ Monocytes and their significance in chronic HCV infection.

关键词： core antigen hepatitis C virus Monocytes PD-L1/CD86 viral load

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