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macrophages in immunoregulation and therapeutics

Signal Transduction and Targeted Therapy 2023年第6期8卷 I0002-I0002,2821-2854页

作者： Shanze Chen Abdullah F.U.H.Saeed Quan Liu Qiong Jiang Haizhao Xu Gary Guishan Xiao Lang Rao Yanhong Duo Department of Respiratory Diseases and Critic Care Unit Shenzhen Institute of Respiratory DiseaseShenzhen Key Laboratory of Respiratory DiseaseShenzhen People’s Hospital(The Second Clinical Medical CollegeJinan UniversityThe First Affiliated HospitalSouthern University of Science and Technology)Shenzhen518020China Department of Cancer Biology Beckman Research Institute of City of Hope National Medical CenterLos AngelesCA91010USA Department of Laboratory Medicine Huazhong University of Science and Technology Union Shenzhen Hospital(Nanshan Hospital)Shenzhen UniversityShenzhen518052China Department of Respiratory The First Affiliated HospitalSchool of MedicineSouthern University of Science and TechnologyShenzhen518055China State Key Laboratory of Fine Chemicals Department of Pharmaceutical SciencesSchool of Chemical EngineeringDalian University of TechnologyDalianChina Institute of Biomedical Health Technology and Engineering Shenzhen Bay LaboratoryShenzhen518132China Department of Microbiology Tumor and Cell Biology(MTC)Karolinska InstitutetStockholmSweden

macrophages exist in various tissues,several body cavities,and around mucosal surfaces and are a vital part of the innate immune system for host defense against many pathogens and cancers.macrophages possess binary M1/M2 macrophage polarization settings,which perform a central role in an array of immune tasks via intrinsic signal cascades and,therefore,must be precisely regulated.Many crucial questions about macrophage signaling and immune modulation are yet to be uncovered.In addition,the clinical importance of tumor-associated macrophages is becoming more widely recognized as significant progress has been made in understanding their biology.Moreover,they are an integral part of the tumor microenvironment,playing a part in the regulation of a wide variety of processes including angiogenesis,extracellular matrix transformation,cancer cell proliferation,metastasis,immunosuppression,and resistance to chemotherapeutic and checkpoint blockade immunotherapies.Herein,we discuss immune regulation in macrophage polarization and signaling,mechanical stresses and modulation,metabolic signaling pathways,mitochondrial and transcriptional,and epigenetic regulation.Furthermore,we have broadly extended the understanding of macrophages in extracellular traps and the essential roles of autophagy and aging in regulating macrophage functions.Moreover,we discussed recent advances in macrophages-mediated immune regulation of autoimmune diseases and tumorigenesis.Lastly,we discussed targeted macrophage therapy to portray prospective targets for therapeutic strategies in health and diseases.

关键词： becoming polarization macrophages

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Effects of interleukin-10 treated macrophages on bone marrow mesenchymal stem cells via signal transducer and activator of transcription 3 pathway

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World Journal of Stem Cells 2024年第5期16卷 560-574页

作者： Meng-Hao Lyu Ce Bian Yi-Ping Dou Kang Gao Jun-Ji Xu Pan Ma Department of Periodontics School of StomatologyCapital Medical UniversityBeijing 100050China Department of Orthodontics School of StomatologyCapital Medical UniversityBeijing 100050China Department of Dental Implantology School of StomatologyCapital Medical UniversityBeijing 100050China Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction School of StomatologyCapital Medical UniversityBeijing 100050China Beijing Laboratory of Oral Health Capital Medical UniversityBeijing 100050China

BACKGROUND Alveolar bone defects caused by inflammation are an urgent issue in oral implant surgery that must be solved.Regulating the various phenotypes of macrophages to enhance the inflammatory environment can significantly affect the progression of diseases and tissue engineering repair process.AIM To assess the influence of interleukin-10(IL-10)on the osteogenic differentiation of bone marrow mesenchymal stem cells(BMSCs)following their interaction with macrophages in an inflammatory environment.METHODS IL-10 modulates the differentiation of peritoneal macrophages in Wistar rats in an inflammatory environment.In this study,we investigated its impact on the proliferation,migration,and osteogenesis of BMSCs.The expression levels of signal transducer and activator of transcription 3(STAT3)and its activated form,phos-phorylated-STAT3,were examined in IL-10-stimulated macrophages.Subsequently,a specific STAT3 signaling inhibitor was used to impede STAT3 signal activation to further investigate the role of STAT3 signaling.RESULTS IL-10-stimulated macrophages underwent polarization to the M2 type through substitution,and these M2 macrophages actively facilitated the osteogenic differentiation of BMSCs.Mechanistically,STAT3 signaling plays a crucial role in the process by which IL-10 influences macrophages.Specifically,IL-10 stimulated the activation of the STAT3 signaling pathway and reduced the macrophage inflammatory response,as evidenced by its diminished impact on the osteogenic differentiation of BMSCs.CONCLUSION Stimulating macrophages with IL-10 proved effective in improving the inflammatory environment and promoting the osteogenic differentiation of BMSCs.The IL-10/STAT3 signaling pathway has emerged as a key regulator in the macrophage-mediated control of BMSCs’osteogenic differentiation.

关键词： macrophages Interleukin-10 Bone marrow mesenchymal stem cells Signal transducer and activator of transcription 3 Inflammatory response

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Tetrahedral framework nucleic acids-based delivery of microRNA-155 inhibits choroidal neovascularization by regulating the polarization of macrophages

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Bioactive Materials 2022年第8期7卷 134-144页

作者： Xin Qin Lirong Xiao Ni Li Chen Hou Wenman Li Jiajie Li Naihong Yan Yunfeng Lin State Key Laboratory of Oral Diseases National Clinical Research Center for Oral DiseasesWest China Hospital of StomatologySichuan UniversityChengdu610041China Research Laboratory of Ophthalmology West China HospitalSichuan UniversityChengdu610041China College of Biomedical Engineering Sichuan UniversityChengdu610041China

Choroidal neovascularization(CNV)is a common pathological feature of various eye diseases and an important cause of visual impairment in middle-aged and elderly patients.In previous studies,tetrahedral framework nucleic acids(tFNAs)showed good carrier performance.In this experiment,we developed microRNA-155-equipped tFNAs(T-155)and explored its biological effects on CNV.Based on the results of in-vitro experiments,T-155 could regulate macrophages into the antiangiogenic M1 type.Then,we injected T-155 into the vitreous of laser-induced CNV model mice and found that T-155 significantly reduced the size and area of CNV,inhibited blood vessel leakage.In summary,we prove that T-155 could regulate the inflammatory process of CNV by polarizing macrophages,thereby improving the symptoms of CNV.Thus,T-155 might become a new DNA-based drug with great potential for treating CNV.

关键词： Choroidal neovascularization Tetrahedral framework nucleic acid macrophages MicroRNA-155 Immunity therapy

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Sulfated Cyclocarya paliurus polysaccharides exert immunomodulatory potential on macrophages via Toll-like receptor 4 mediated MAPK/NF-κB signaling pathways

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Food Science and Human Wellness 2024年第1期13卷 115-123页

作者： Yue Yu Haibin Zhu Mingyue Shen Qiang Yu Yi Chen Shiru Mo Jianhua Xie State Key Laboratory of Food Science and Technology Nanchang UniversityNanchang 330047China International Institute of Food Innovation Nanchang UniversityNanchang 330200China

The biological activity of plant polysaccharides can be enhanced by sulfated modification.In this study,the immunomodulatory effect of sulfated Cyclocarya paliurus polysaccharides(SCP3)on macrophages RAW264.7 and its potential molecular mechanism were investigated.Results showed that SCP3 at 25-100μg/m L increased viability and improved phagocytosis of RAW264.7 cells.Meanwhile,SCP3 could activate mitogen-activated protein kinase(MAPK)and nuclear factor kappa B(NF-κB)signaling pathways,which increased the phosphorylation of Erk1/2,JNK,p38 and NF-κB p65,promoting secretion of cytokines tumor necrosis factorα(TNF-α),interleukin 6(IL-6)and nitric oxide(NO)as well as the production of reactive oxygen species(ROS).In addition,Toll-like receptor 4(TLR4)receptor inhibitors were able to block the production of NO and TNF-αby SCP3-stimulated macrophages.Based on Western blot analysis and validation using specific inhibitors against MAPK and NF-κB signaling pathways,the results demonstrated that SCP3 induced macrophages activation and enhanced TNF-αand NO production via TLR4-mediated MAPK and NF-κB pathways.In summary,SCP3 has significant immunomodulatory potential.The underlying molecular mechanism was that SCP3 activates macrophages via TLR4 receptors to promote ROS production,which in turn activates the downstream MAPK/NF-κB signaling pathway and then increases the secretion levels of cytokines and NO.

关键词： Cyclocarya paliurus Sulfated polysaccharides macrophages Immunomodulatory Mechanism

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Ccrl2 deficiency deteriorates obesity and insulin resistance through increasing adipose tissue macrophages infiltration

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Genes & Diseases 2022年第2期9卷 429-442页

作者： Min Xu Yu-Meng Wang Wan-Qing Li Cheng-Long Huang Jun Li Wen-Hua Xie Hong-Xiang Zeng Lin-Fen Tao Xi Li Biology Science Institutes Chongqing Medical UniversityChongqing 400016PR China

Obesity-induced inflammation,characterized by augmented infiltration and altered balance of macrophages,is a critical component of systemic insulin resistance.Chemokine-chemokine receptor system plays a vital role in the macrophages accumulation.CC-Chemokine Receptor-like 2(Ccrl2)is one of the receptors of Chemerin,which is a member of atypical chemokine receptors(ACKR)family,reported taking part in host immune responses and inflammation-related conditions.In our study,we found ccrl2 expression significantly elevated in visceral adipose tissue(VAT)of high fat diet(HFD)induced obese mice and ob/ob mice.Systemic deletion of Ccrl2 gene aggravated HFD induced obesity and insulin resistance and ccrl2−/−mice showed aggravated VAT inflammation and increased M1/M2 macrophages ratio,which is due to the increase of macrophages chemotaxis in Ccrl2 deficiency mice.Cumulatively,these results indicate that Ccrl2 has a critical function in obesity and obesity-induced insulin resistance via mediating macrophages chemotaxis.

关键词： Ccrl2 Inflammation Insulin resistance macrophages Obesity

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Elevated DLL3 in stomach cancer by tumor-associated macrophages enhances cancer-cell proliferation and cytokine secretion of macrophages

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Gastroenterology Report 2022年第1期10卷 322-334页

作者： Jian-Bin Ye Jun-Jie Wen Dan-Lin Wu Bing-Xin Hu Mei-Qun Luo Yan-Qing Lin Yun-Shan Ning Yan Li School of Laboratory Medicine and Biotechnology Southern Medical UniversityGuangzhouGuangdongP.R.China Service Union Medicine Southern Medical UniversityZhuhaiGuangdongP.R.China

Background The notch signal pathway is important in the development of both tumor-associated macrophages(TAMs)and stomach cancer,but how Notch signaling affects TAMs in stomach cancer is barely understood.Methods The expressions of Notch1,Notch2,Notch3,Notch4,hes family bHLH transcription factor 1(Hes1),and delta-like canonical Notch ligand 3(DLL3)were detected by Western blot and the expressions of interleukin(IL)-10,IL-12,and IL1-b were detected using enzyme-linked immunosorbent assay after the co-culture of macrophages and stomach-cancer cells.The proliferation and migration of cancer cells were detected using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and scratch assay,respectively,and the cell cycle was detected using Annexin V/propidium iodide assay.The protein interactions with DLL3 were detected using co-immunoprecipitation and mass spectrometry.Results The co-culture of macrophages and stomach-cancer cells MKN45 and BGC823 could enhance cell proliferation accompanied by the activation of Notch1/Notch2 signaling and upregulation of DLL3.Notch signaling gamma-secretase inhibitor(DAPT)blocked this process.The overexpression of DLL3 in stomach-cancer cells could promote the proliferation of cancer cells,enhance the activation of Notch1/Notch2 signaling,induce the expression of IL-33,lead to the degradation of galectin-3–binding protein(LG3BP)and heat shock cognate 71 kDa protein(HSPA8),and result in elevated IL-1b,IL-12,and IL-10 secretion by macrophages.Higher expression of DLL3 or IL-33 could lead to a lower survival rate based on University of California,Santa Cruz Xena Functional Genomics Explorer and The Cancer Genome Atlas data set.Conclusions This is evidence that DLL3 regulates macrophages in stomach cancer,suggesting that DLL3 may be a novel and potential target for stomach-cancer therapy.

关键词： stomach cancer DLL3 macrophages Notch signaling,proliferation cytokines

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LIFU-responsive nanomedicine enables acoustic droplet vaporization-induced apoptosis of macrophages for stabilizing vulnerable atherosclerotic plaques

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Bioactive Materials 2022年第10期7卷 120-133页

作者： Jingxin Hou Jun Zhou Meiqi Chang Guangcheng Bao Jie Xu Man Ye Yixin Zhong Shuling Liu Junrui Wang Wei Zhang Haitao Ran Zhigang Wang Yu Chen Dajing Guo Department of Radiology Second Affiliated Hospital of Chongqing Medical UniversityChongqing400010PR China Materdicine Lab School of Life SciencesShanghai UniversityShanghai200444PR China Chongqing Key Laboratory of Ultrasound Molecular Imaging&Department of Ultrasound Second Affiliated Hospital of Chongqing Medical UniversityChongqing400010PR China State Key Laboratory of High Performance Ceramics and Superfine Microstructure Shanghai Institute of CeramicsChinese Academy of SciencesShanghai200050PR China Department of Radiology Children’s Hospital of Chongqing Medical UniversityChongqing400014PR China

Due to the high risk of tearing and rupture,vulnerable atherosclerotic plaques would induce serious cardiovascular and cerebrovascular diseases.Despite the available clinical methods can evaluate the vulnerability of plaques and specifically treat vulnerable plaques before a cardiovascular event,but the efficiency is still low and undesirable.Herein,we rationally design and engineer the low-intensity focused ultrasound(LIFU)-responsive FPD@CD nanomedicine for the highly efficient treatment of vulnerable plaques by facilely loading phase transition agent perfluorohexane(PFH)into biocompatible PLGA-PEG-PLGA nanoparticles(PPP NPs)and then attaching dextran sulphate(DS)onto the surface of PPP NPs for targeting delivery.DS,as a typical macrophages-targeted molecule,can achieve the precise vaporization of NPs and subsequently controllable apoptosis of RAW 264.7 macrophages as induced by acoustic droplet vaporization(ADV)effect.In addition,the introduction of DiR and Fe3O4 endows nanomedicine with near-infrared fluorescence(NIRF)and magnetic resonance(MR)imaging capabilities.The engineered FPD@CD nanomedicine that uses macrophages as therapeutic targets achieve the conspicuous therapeutic effect of shrinking vulnerable plaques based on in vivo and in vitro evaluation outcomes.A reduction of 49.4%of vascular stenosis degree in gross pathology specimens were achieved throughout the treatment period.This specific,efficient and biosafe treatment modality potentiates the biomedical application in patients with cardiovascular and cerebrovascular diseases based on the relief of the plaque rupture concerns.

关键词： Vulnerable plaques Acoustic droplet vaporization macrophages Apoptosis Nanomedicine

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Effect of dual targeting procyanidins nanoparticles on metabolomics of lipopolysaccharide-stimulated inflammatory macrophages

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Food Science and Human Wellness 2023年第6期12卷 2252-2262页

作者： Shanshan Tie Lijuan Zhang Bin Li Shanghua Xing Haitao Wang Yannan Chen Weina Cui Shaobin Gu Mingqian Tan Academy of Food Interdisciplinary Science School of Food Science and TechnologyDalian Polytechnic UniversityDalian 116034China College of Food and Bioengineering Henan University of Science and TechnologyLuoyang 471023China College of Food Science Shenyang Agricultural UniversityNational R&D Professional Center for Berry ProcessingShenyang 110866China

Inflammation plays an important role in the occurrence and development of many inflammatory diseases.The purpose of this study was to evaluate the anti-inflammatory effect and metabolic behavior of the dual targeting procyanidins(PC)nanoparticles on lipopolysaccharide(LPS)-stimulated inflammatory macrophages by metabolomics method.The double-targeting PC nanoparticles could specifi cally target both the CD44 receptor and mitochondria,while the single targeting PC-loaded nanoparticles that could target the CD44 receptor on the surface of macrophages.The double-targeting PC nanoparticles had better inhibitory effect than single-targeting PC nanoparticles on the leakage of lactate dehydrogenase and reactive oxygen species overexpression induced by LPS.Amino acid metabolism,energy metabolism and purine metabolism were disordered in LPS-treated group,and metabolic pathway analysis indicated that the double-targeting PC nanoparticles reversed some of LPS impacts.The changes of these potential biomarkers and their corresponding pathways are helpful to further understand the mechanism of PC nanoparticles in alleviating inflammation,and promote their application in nutrition intervention.

关键词： Procyanidins nanoparticles Metabolomics Inflammation macrophages Lipopolysaccharide

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The combination of ciprofloxacin and indomethacin suppresses the level of inflammatory cytokines secreted by macrophages in vitro

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Chinese Journal of Traumatology 2022年第6期25卷 379-388页

作者： Ke Liu Jing Yu Yu Xia Lei-Ting Zhang Sui-Yan Li Jun Yan School of Life Science and Engineering Southwest Jiaotong UniversityChengdu 610031China State Key Laboratory of Trauma Burns and Combined InjuryResearch Institute of SurgeryDaping HospitalArmy Medical University(Third Military Medical University)Chongqing 400042China

Purpose:The combined use of antibiotics and anti-inflammatory medicine to manage bacterial endotoxin-induced inflammation following injuries or diseases is increasing.The cytokine level produced by macrophages plays an important role in this treatment course.Ciprofloxacin and indomethacin,two typical representatives of antibiotics and anti-inflammatory medicine,are cost-effective and has been reported to show satisfactory effect.The current study aims to investigate the effect of ciprofloxacin along with indomethacin on the secretion of inflammatory cytokines by macrophagesin vitro.Methods:Primary murine peritoneal macrophages and RAW 264.7 cells were administrated with lipopolysaccharide(LPS)for 24 h.The related optimal dose and time point of ciprofloxacin or indomethacin in response to macrophage inflammatory response inflammation were determined via macrophage secretion induced by LPS.Then,the effects of ciprofloxacin and indomethacin on the secretory functions and viability of various macrophages were determined by enzyme-linked immunosorbent assay and flow cytometry analysis,especially for the levels of interleukin(IL)-1β,IL-6,IL-10,and tumor necrosis factor(TNF)-α.The optimal dose and time course of ciprofloxacin affecting macrophage inflammatory response were determined by testing the maximum inhibitory effect of the drugs on pro-inflammatory factors at each concentration or time point.Results:According to the levels of cytokines secreted by various macrophages(1.2×10^(6) cells/well)after administration of 1μg/mL LPS,the optimal dose and usage timing for ciprofloxacin alone were 80μg/mL and 24 h,respectively,and the optimal dose for indomethacin alone was 10μg/mL.Compared with the LPS-stimulated group,the combination of ciprofloxacin and indomethacin reduced the levels of IL-1β(p<0.05),IL-6(p<0.05),IL-10(p<0.01),and TNF-α(p<0.01).Furthermore,there was greater stability in the reduction of inflammatory factor levels in the combination group compared with those in which only ciprofloxacin or indomethacin was

关键词： Ciprofloxacin Indomethacin Inflammatory cytokines In vitro macrophages

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Huoxue Jiedu Huayu recipe(活血解毒化瘀方)alleviates contralateral renal fibrosis in unilateral ureteral obstruction rats by inhibiting the transformation of macrophages to myofibroblast

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Journal of Traditional Chinese Medicine 2023年第1期43卷 105-112页

作者： XIONG Yunzhao LIU Lingjin LIU Ziqian CHEN Gege HAO Juan GAO Xiaomeng QIANG Panpan WANG Zheng XU Qingyou Graduate School Hebei University of Chinese MedicineHebei Key Laboratory of Integrative Medicine on Liver-Kidney PatternsHebei University of Chinese MedicineHebei University of Chinese MedicineShijiazhuang 050091China Graduate School Hebei University of Chinese Medicine Hebei Key Laboratory of Integrative Medicine on Liver-Kidney PatternsHebei University of Chinese MedicineShijiazhuang 050091China Graduate School Hebei University of Chinese MedicineHebei Key Laboratory of Integrative Medicine on Liver-Kidney PatternsHebei University of Chinese MedicineDepartment of Internal MedicineHebei University of Chinese MedicineShijiazhuang 050091China

OBJECTIVE:To investigate the action and underlying mechanisms of Huoxue Jiedu Huayu recipe(活血解毒化瘀方,HJHR)against unilateral ureteral obstruction(UUO)-induced injury in the contralateral kidney.METHODS:Forty-eight male Sprague-Dawley rats weighing(200±10)g were used in this study and randomly assigned to 4 groups:a sham group,a UUO group,a UUO+eplerenone(EPL)group,and a UUO+HJHR group.The contralateral kidneys were harvested for further study 180 d after surgery.Histological analysis,immunohistochemistry and immunofluorescence were used to study the fibrosis of the contralateral kidneys obtained from UUO rats.Contralateral kidney damagerelated pathway proteins were detected by real-time polymerase chain reaction and Western blot analysis.RESULTS:HJHR significantly inhibited fibrosis of the contralateral kidney in UUO rats by attenuating the UUOinduced macrophage-to-myofibroblast transition(MMT)in the contralateral kidney.Moreover,HJHR attenuated fibrosis in the contralateral kidney of UUO rats by preventing MMT through the aldosterone/mineralocorticoid receptor/serum/glucocorticoid regulated kinase 1 pathway.CONCLUSIONS:Our findings suggest that HJHR may be a potential treatment for renal interstitial fibrosis of obstructive nephropathy.

关键词： ureteral obstruction renal fibrosis aldosterone receptors,mineralocorticoid macrophages myofibroblast Huoxue Jiedu Huayu recipe

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