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Neural Regeneration Research 2021年第4期16卷 635-637页

作者： Francesca Grassivaro Gianvito Martino Cinthia Farina Institute of Experimental Neurology Division of NeuroscienceSan Raffaele Scientific InstituteMilanItaly Vita-Salute San Raffaele University MilanItaly

Microglia,the tissue resident macrophages of the brain,are increasingly recognized as key players for central nervous system development and homeostasis.They are long-lived cells deriving from a transient wave of yolk-sac derived erythro-myeloid progenitors early in development.Their unique ontology has prompted the search for specific markers to be used for their selective investigation and manipulation.The first generation of genomewide expression studies has provided a bundle of transcripts(such as Olfml3,Fcrls,Tmem119,P2ry12,Gpr34,and Siglech)useful to distinguish microglia from peripheral macrophages.However,more recent reports have revealed that microglial phenotype is constantly shaped by the microenvironment in a time-,and context-dependent manner.In this article,we review data that provide additional pieces to this complex scenario and show the existence of unexpected phenotypic convergence between microglia and peripheral macrophages at certain developmental stages and under pathological conditions.These observations suggest that the two cell types act synergically boosting their mutual activities depending on the microenvironment.This novel information about the biology of microglia and peripheral macrophages sheds new light about their therapeutic potential for neuroinflammatory and neurodegenerative diseases.

关键词： cell reprogramming cell therapy macrophages microglia neuroinflammation plasticity

Methyltransferase Dot1l preferentially promotes innate IL-6 and IFN-β production by mediating H3K79me2/3 methylation in macrophages

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Cellular & Molecular Immunology 2020年第1期17卷 76-84页

作者： Xiang Chen Xingguang Liu Yunkai Zhang Wanwan Huai Qingqing Zhou Sheng Xu Xi Chen Nan Li Xuetao Cao National Key Laboratory of Medical Immunology&Institute of Immunology Second Military Medical UniversityShanghai 200433China Institute of Immunology Zhejiang University School of MedicineHangzhou 310058China Department of Immunology&Center for Immunotherapy Institute of Basic Medical SciencesPeking Union Medical CollegeChinese Academy of Medical SciencesBeijing 100005China

Epigenetic modification,including histone modification,precisely controls target gene expression.The posttranscriptional regulation of the innate signaling-triggered production of inflammatory cytokines and type I interferons has been fully elucidated,whereas the roles of histone modification alteration and epigenetic modifiers in regulating inflammatory responses need to be further explored.Di/tri-methylation modifications of histone 3 lysine 79(H3K79me2/3)have been shown to be associated with gene transcriptional activation.Disruptor of telomeric silencing-1-like(Dot1l)is the only known exclusive H3K79 methyltransferase and regulates the proliferation and differentiation of tumor cells.However,the roles of Dot1l and Dot1l-mediated H3K79 methylation in innate immunity and inflammatory responses remain unclear.Here,we found that H3K79me2/3 modification levels at the Il6 and Ifnb1 promoters,as well as H3K79me2 modification at the Tnfαpromoter,were increased in macrophages activated by Toll-like receptor(TLR)ligands or virus infection.The innate signals upregulated Dot1l expression in macrophages and THP1 cells.Dot1l silencing or a Dot1l inhibitor preferentially suppressed the production of IL-6 and interferon(IFN)-βbut not of TNFαin macrophages and THP1 cells triggered by TLR ligands or virus infection.Dot1l was recruited to the proximal promoter of the Il6 and Ifnb1 but not Tnfαgene and then mediated H3K79me2/3 modification at the Il6 and Ifnb1 promoters,consequently facilitating the transcription and expression of Il6 and Ifnb1.Thus,Dot1l-mediated selective H3K79me2/3 modifications at the Il6 and Ifnb1 promoters are required for the full activation of innate immune responses.This finding adds new insights into the epigenetic regulation of inflammatory responses and pathogenesis of autoimmune diseases.

关键词： H3K79me2/3 Dot1l epigenetic regulation IL-6 IFN-β macrophages inflammation

Jianpi Huazhuo Tiaozhi granules reduce oxidative stress injury in macrophages by inhibiting the nicotinamide adenine dinucleotide phosphate oxidase/reactive oxygen species-nuclear transcription factor kappa B pathway

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Journal of Traditional Chinese Medicine 2020年第6期40卷 922-927页

作者： Liu Yanwei Liu Zhongyong School of Medicine Jiangxi University of Traditional Chinese MedicineNanchang 330004China Department of Cardiology Affiliated Hospital of Jiangxi University of Traditional Chinese MedicineNanchang 330006China

OBJECTIVE:To assess the effect of Jianpi Huazhuo Tiaozhi granules(JHTG)on oxidative stress damage to macrophages and explore the relationship between the levels of this damage and the nicotinamide adenine dinucleotide phosphate oxidase(NOX)/reactive oxygen species(ROS)-nuclear transcription factor kappa B(NF-κB)signaling pathway.METHODS:macrophages cultured in vitro were divided into seven groups:control,model control,inhibitor,positive control,2.5%JHTG,5%JHTG,and10%JHTG.An oxidative stress injury model was established by stimulating macrophages with oxidized low-density lipoprotein.Cell survival and apoptosis were detected by 3-(4,5)-dimethylthiahiazo(-z-y1)-3,5-di-phenytetrazoliumromide and flow cytometry assays,respectively.Malondialdehyde and superoxide dismutase levels were detected by enzyme-linked immunosorbent assays,while ROS levels were detected using a fluorescence probe.Proteins and m RNAs associated with the NOX/ROS-NF-κB pathway,including NOX4,p22 phox,inhibitor of NF-κB kinase-α(IKK-α),inhibitor of NF-κB kinase-β(IKK-β),and NF-κB were detected by Western blot and PCR,respectively.RESULTS:After JHTG treatment,there were fewer damaged and apoptotic macrophages,while superoxide dismutase levels were elevated.The JHTG-treated groups also showed reduced ROS levels.The molecular changes following JHTG treatment included decreased expression of NOX4 and p22 phox at the protein level and decreased IKK-α,IKK-β,and NF-κB expression at the m RNA level.All of these effects were correlated with the JHTG concentration.CONCLUSION:These results demonstrated that the molecular mechanism underlying the antioxidant activity of JHTG in macrophages is through inhibiting the NOX/ROS-NF-κB pathway.

关键词： Atherosclerosis Oxidative stress macrophages NADPH oxidases Reactive oxygen species NF-kappa B Jianpi Huazhuo Tiaozhi granules

Caulerpa okamurae extract attenuates inflammatory interaction,regulates glucose metabolism and increases insulin sensitivity in 3T3-L1 adipocytes and RAW 264.7 macrophages

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Journal of Integrative Medicine 2020年第3期18卷 253-264页

作者： Bikash Manandhar Hyun Jung Kim Dong Young Rhyu Department of Oriental Medicine Resources and Institute of Korean Herbal Medicine Industry Mokpo National UniversityJeonnam 58554South Korea College of Pharmacy Mokpo National UniversityJeonnam 58554South Korea

Objective: To examine whether Caulerpa okamurae ethanolic extract(COE) could inhibit obesitymediated inflammation, improve glucose metabolism and increase insulin sensitivity, using in vitro cell models of RAW 264.7 macrophages and 3 T3-L1 adipocytes.Methods: We cocultured 3 T3-L1 adipocytes in direct contact with lipopolysaccharide-stimulated RAW264.7 macrophages and induced insulin resistance in 3 T3-L1 adipocytes with tumor necrosis factor-a(TNF-a) in the presence or absence of 250 mg/m L of COE. We investigated various markers of inflammation, glucose regulation and insulin sensitivity in these models using Griess reagent to measure nitric oxide(NO) production, 2-[N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl) amino]-2-deoxyglucose to measure glucose uptake, Western blot analysis to quantify protein expression and reverse transcriptasepolymerase chain reaction to evaluate m RNA expression.Results: We found that COE(250 mg/m L) significantly inhibited the lipopolysaccharide-induced inflammatory response in RAW 264.7 macrophages by downregulating NO production, nitric oxide synthase 2 expression and nuclear translocation of nuclear factor-j B. COE also showed similar anti-inflammatory activity in coculture, along with decreased TNF-a, interleukin-6 and monocyte chemoattractant protein m RNA expression. In addition, COE also improved glucose uptake in coculture by upregulating glucose transporter-4(GLUT-4) and adiponectin and reducing serine phosphorylation of insulin receptor substrate-1(IRS1). In the TNF-a-induced insulin resistance model of 3 T3-L1 adipocytes, COE significantly improved both basal and insulin-stimulated glucose uptake, accompanied by phosphorylation of IRS1 at tyrosine 632, phospho-50 adenosine monophosphate-activated protein kinase a and glycogen synthase kinase-3 b(Ser9) as well as upregulation of GLUT-4.Conclusion: Together, these findings suggest that COE has potential to treat or prevent obesity-induced metabolic disorders.

关键词： Caulerpa okamurae RAW 264.7 macrophages 3T3-L1 adipocytes Coculture Metabolic disorder

Metformin improved oxidized low-density lipoprotein-impaired mitochondrial function and increased glucose uptake involving Akt-AS160 pathway in raw264.7 macrophages

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Chinese Medical Journal 2019年第14期132卷 1713-1722页

作者： Xuan He Lei Wang Xiu-Fang Chen Qiao Liang Wen-Qing Wang An-Qi Lin Long Yi Yong Wang Qian Gao Medical School of Nanjing University NanjingJiangsu 210093China Department of Biochemistry School of Basic Medical SciencesWenzhou Medical UniversityWenzhouZhejiang 325035China

Background:Macrophage accumulation in the vascular wall is a hallmark of atherosclerosis.Studies showed that shifting of oxidized lipids-induced inflammatory macrophages towards an anti-inflammatory phenotype by promoting oxidative metabolism attenuated atherosclerosis progression.Therefore,this study aimed to investigate whether metformin,which has ameliorated atherosclerosis in animal models and clinical trials,modulated oxidized low-density lipoprotein (Ox-LDL) induced inflammatory status in macrophages by regulating cellular oxidative metabolism.Methods:Murine raw264.7 macrophages were incubated with Ox-LDL (50 μg/mL) in the presence or absence of metformin (15 μmol/L) for 24 h.Real-time polymerase chain reaction was used to quantify the transcription of classically activated (M1) proinflammatory and alternatively activated (M2) anti-inflammatory markers and mitochondrial DNA copy numbers.Cellular reactive oxygen species (ROS) production and mitochondrial membrane potential were detected by immunofluorescence.Cellular adenosine triphosphate (ATP) synthesis,glucose uptake,and lactic acid production were measured by commercial kit and normalized to cellular lysates.Western blotting analysis was performed to detect the expression of mitochondrial fusion/fission related proteins,enzymes mediating lipid metabolism and signaling pathway of glucose transport.Differences between groups were analyzed using one-way analysis of variance.Results:Metformin improved Ox-LDL-impaired anti-inflammatory phenotype in raw264.7 macrophages as shown by up-regulated transcription of anti-inflammatory markers including interleukin 10 (0.76 ± 0.04 vs.0.94 ± 0.01,P =0.003) and Resistin-like molecule alpha (0.67 ± 0.08 vs.1.78 ± 0.34,P =0.030).Conversely,Ox-LDL-diminished phosphorylation of Akt was up regulated by metformin treatment (0.47 ± 0.05 vs.1.02 ± 0.08,P =0.040),associated with an improvement of mitochondrial function,characterized by decreased ROS generation (2.50 ± 0.07 vs.2.15 ± 0.04,P =0.040),increased lipid oxidation,and

关键词： Atherosclerosis macrophages Oxidized low-density lipoprotein Mitochondria Metabolism

macrophages and microglia in inflammation and neuroinflammation underlying different pain states

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Medical Review

Medical Review 2023年第5期3卷 381-407页

作者： Ouyang Chen Xin Luo Ru-Rong Ji Department of Anesthesiology Center for Translational Pain MedicineDuke University Medical CenterDurhamNCUSA Department of Cell Biology Duke University Medical CenterDurhamNCUSA Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence Southern Medical UniversityGuangzhouGuangdong ProvinceChina Department of Anesthesiology Center for Translational Pain MedicineDuke University Medical CenterDurhamNC 27710USA Department of Cell Biology Duke University Medical CenterDurhamNC 27710USA

Pain is a main symptom in inflammation,and inflammation induces pain via inflammatory mediators acting on nociceptive neurons.macrophages and microglia are distinct cell types,representing immune cells and glial cells,respectively,but they share similar roles in pain regulation.macrophages are key regulators of inflammation and pain.Macrophage polarization plays different roles in inducing and resolving pain.Notably,macrophage polarization and phagocytosis can be induced by specialized pro-resolution mediators(SPMs).SPMs also potently inhibit inflammatory and neuropathic pain via immunomodulation and neuromodulation.In this review,we discuss macrophage signaling involved in pain induction and resolution,as well as in maintaining physiological pain.Microglia are macrophage-like cells in the central nervous system(CNS)and drive neuroinflammation and pathological pain in various inflammatory and neurological disorders.Microglia-produced inflammatory cytokines can potently regulate excitatory and inhibitory synaptic transmission as neuromodulators.We also highlight sex differences in macrophage and microglial signaling in inflammatory and neuropathic pain.Thus,targeting macrophage and microglial signaling in distinct locations via pharmacological approaches,including immunotherapies,and non-pharmacological approaches will help to control chronic inflammation and chronic pain.

关键词： inflammation macrophages microglia neuroinflammation pain

The prognostic impact of traditional Chinese medicine monomers on tumor-associated macrophages in non-small cell lung cancer

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Chinese Journal of Natural Medicines 2019年第10期17卷 729-737页

作者： WAN Liang-Qin TAN Yan JIANG Miao HUA Qian School of Acupuncture-Moxibustion and Tuina Beijing University of Chinese MedicineBeijing 100029China Dongzhimen Hospital Beijing University of Chinese MedicineBeijing 100029China

Non-small cell lung cancer(NSCLC) accounts for 80%-85% of all lung malignancies and good diagnosis and prognosis of NSCLC are critical to the increase of its survival rate. Tumor-associated macrophages(TAM) abundantly present in numerous cancer types, and the role of TAMs in tumor biology and their prognostic value in cancer become major topics of interest. After various stimulations in the tumor microenvironment, TAMs develop into a M1(tumor-inhibitory) phenotype or M2(tumor-promoting) phenotype. Recent studies show that traditional Chinese medicine(TCM) monomers have markedly inhibitory actions for NSCLC through M1/M2 modulation. Due to the TCM monomers mainly covered five categories, i.e. terpenoids, flavonoids, polysaccharides, natural polyphenols, and alkaloids. Thus, we will discuss the regulation of TCM monomers on TAM involve in these five parts in this review. In addition, the potential role of TAMs as therapeutic targets will be discussed.

关键词： Lung cancer Tumor microenvironment Tumor-associated macrophages Traditional Chinese medicine (TCM) monomer Immunotherapy

Induced migration of endothelial cells into 3D scaffolds by chemoattractants secreted by pro-inflammatory macrophages in situ

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Regenerative Biomaterials 2017年第3期4卷 139-148页

作者： Xuguang Li Yuankun Dai Tao Shen Changyou Gao MOE Key Laboratory of Macromolecular Synthesis and Functionalization Department of Polymer Science and EngineeringZhejiang UniversityHangzhou 310027China

Cell migration in scaffolds plays a crucial role in tissue regeneration,which can better mimic cell behaviors in vivo.In this study,a novel model has been proposed on controlling 3D cell migration in porous collagen-chitosan scaffolds with various pore structures under the stimulation of inflammatory cells to mimic the angiogenesis process.Endothelial cells(ECs)cultured atop the scaffolds in the Transwell molds which were placed into a well of a 24-well culture plate were promoted to migrate into the scaffolds by chemoattractants such as vascular endothelial growth factor(VEGF)and tumor necrosis factor-alpha(TNF-α)secreted by the pro-inflammatory macrophages incubated in the well culture plate.The phenotype of macrophages was mediated by 50 ng/ml interferongamma(IFN-c)and different concentrations of lipopolysaccharide(LPS,150–300 ng/ml).The cell migration depth had a positive correlation with LPS concentration,and thereby the TNF-a concentration.The ECs migrated easier to a deeper zone of the scaffolds prepared at10C(187 lm in pore diameter)than that at20C(108 lm in pore diameter)as well.The method provides a useful strategy to study the 3D cell migration,and is helpful to reveal the vascularization process during wound healing in the long run.

关键词： cell migration chemoattractants endothelial cells macrophages scaffolds

BMP4 facilitates beige fat biogenesis via regulating adipose tissue macrophages

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Journal of Molecular Cell Biology 2019年第1期11卷 14-25页

作者： Shu-Wen Qian Meng-Yuan Wu Yi-Na Wang Ya-Xin Zhao Ying Zou Jia-Bao Pan Yan Tang Yang Liu Liang Guo Qi-Qun Tang Key Laboratory of Metabolism and Molecular Medicine The Ministry of EducationDepartment of Biochemistry and Molecular BiologyFudan University Shanghai Medical CollegeShanghai 200032China

Thermogenic beige fat improves metabolism and prevents obesity.Emerging evidence shows that the activation of M2 macrophages stimulates beige adipogenesis,whereas the activation of Ml macrophages,which play a major role in inflammation,impedes beige adipogenesis.Thus,the identification of factors that regulate adipose tissue macrophages(ATMs)will help clarify the mechanism involved in beiging.Here,we found that one of the secreted proteins in adipose tissue,namely,BMP4,alters the ATM profile in subcutaneous adipose tissue by activating M2 and inhibiting Ml macrophages.Mechanistically,the BMP4-stimutated p38/MAPK/STAT6/PI3K-AKT signalling pathway is involved.Meanwhile,BMP4 improved the potency of M2 macrophages to induce beige fat biogenesis.Considering that the overexpression of BMP4 in adipose tissue promotes the beiging of subcutaneous adipose tissue and improves insulin sensitivity,these findings provide evidence that BMP4 acts as an activator of beige fat by targeting immuno-metabolic pathways.

关键词： BMP4 fat browning adipose tissue macrophages

Kinsenoside attenuates osteoarthritis by repolarizing macrophages through inactivating NF-κB/MAPK signaling and protecting chondrocytes

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Acta Pharmaceutica Sinica B 2019年第5期9卷 973-985页

作者： Feng Zhou Jingtian Mei Xiuguo Han Hanjun Li Shengbing Yang Minqi Wang Linyang Chu Han Qiao Tingting Tang Shanghai Key Laboratory of Orthopaedic Implants Department of Orthopaedic Surgery Shanghai Ninth People’s Hospital Shanghai Jiao Tong University School of Medicine

The objective was to investigate the effect of kinsenoside(Kin) treatments on macrophage polarity and evaluate the resulting protection of chondrocytes to attenuate osteoarthritis(OA) progression.RAW264.7 macrophages were polarized to M1/M2 subtypes then administered with different concentrations of Kin. The polarization transitions were evaluated with quantitative real-time polymerase chain reaction(q RT-PCR), confocal observation and flow cytometry analysis. The mechanism of Kin repolarizing M1 macrophages was evaluated by Western blot. Further, macrophage conditioned medium(CM) and IL-1β were administered to chondrocytes. Micro-CT scanning and histological observations were conducted in vivo on anterior cruciate ligament transection(ACLT) mice with or without Kin treatment. We found that Kin repolarized M1 macrophages to the M2 phenotype. Mechanistically, Kin inhibited the phosphorylation of IκBα, which further reduced the downstream phosphorylation of P65 in nuclear factor-κB(NF-κB) signaling. Moreover, Kin inhibited mitogen-activated protein kinases(MAPK) signaling molecules p-JNK, p-ERK and p-P38. Additionally, Kin attenuated macrophage CM and IL-1β-induced chondrocyte damage. In vivo, Kin reduced the infiltration of M1 macrophages,promoted M2 macrophages in the synovium, inhibited subchondral bone destruction and reduced articular cartilage damage induced by ACLT. All the results indicated that Kin is an effective therapeutic candidate for OA treatment.

关键词： Kinsenoside Osteoarthritis macrophages Polarization Chondrocytes