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macrophages-regulating nanomedicines for sepsis therapy

Chinese Chemical Letters 2023年第3期34卷 100-112页

作者： Jiali Deng Rui Wang Shu Huang Jinsong Ding Wenhu Zhou Xiangya School of Pharmaceutical Sciences Central South UniversityChangsha 410013China Department of Orthopedics Hunan Provincial People’s HospitalThe First-Affiliated Hospital of Hunan Normal UniversityChangsha 410005China

Sepsis is the leading cause of death in intensive care unit(ICU), which is caused by deregulated immune responses to pathogens infection. Clinically, sepsis treatment is limited to antibiotics and supportive care, while there still lacks of specific molecular therapy. As a type of immune dysfunction disease,macrophages have been recognized as the key immune cells precipitating in the whole process of sepsis,which is activated into M1-like to trigger various inflammatory responses at early stage whereas polarized into M2-like to cause immunosuppression in later stage. Therefore, great attention has been paid on the design of nanomedicines to regulate the functions of macrophages for etiological treatment of sepsis, by virtue of the unique advantages of nano-drug delivery systems, such as enhanced drug bioavailability, targetability, reduced side-effects. This critical review aims to summarize the recent progress of macrophages-regulating nanoparticles for sepsis therapy. First, the essential roles of macrophages in the development and progression of sepsis have been introduced, including the positive roles of macrophages to combat infections and dysfunction of macrophages to cause body damages. We then focus our main attention to discuss the nanomedicines with different therapeutic mechanisms corresponding to each stage of sepsis, such as infection blockage, inflammation inhibition, immune functions recovery, as well as multifunctional nanomedicines. Finally, a few limitations of current nanomedicines are highlighted,and future perspective are speculated for potential clinical translation, which might pave the way for the development of macrophages-centered nanomedicines for more effective sepsis therapy.

关键词： Nanomedicine Sepsis macrophages Infections Inflammation Immunity

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macrophages and the maintenance of homeostasis

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Cellular & Molecular Immunology 2021年第3期18卷 579-587页

作者： David M.Mosser Kajal Hamidzadeh Ricardo Goncalves The Department of Cell Biology and Molecular Genetics The University of MarylandCollege ParkMD 20742USA The Department of General Pathology Federal University of Minas GeraisBelo HorizonteMGBrazil

There have been many chapters written about macrophage polarization.These chapters generally focus on the role of macrophages in orchestrating immune responses by highlighting the T-cell-derived cytokines that shape these polarizing responses.This bias toward immunity is understandable,given the importance of macrophages to host defense.However,macrophages are ubiquitous and are involved in many different cellular processes,and describing them as immune cells is undoubtedly an oversimplification.It disregards their important roles in development,tissue remodeling,wound healing,angiogenesis,and metabolism,to name just a few processes.In this chapter,we propose that macrophages function as transducers in the body.According to Wikipedia,WA transducer is a device that converts energy from one form to another.^The word transducer is a term used to describe both the"sensor,which can interpret a wide range of energy forms,and the"actuator,which can switch voltages or currents to affect the environment.macrophages are able to sense a seemingly endless variety of inputs from their environment and transduce these inputs into a variety of different response outcomes.Thus,rather than functioning as immune cells,they should be considered more broadly as cellular transducers that interpret microenvironmental changes and actuate vital tissue responses.In this chapter,we will describe some of the sensory stimuli that macrophages perceive and the responses they make to these stimuli to achieve their prime directive,which is the maintenance of homeostasis.

关键词： macrophages polarization cytokines development inflammation

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The disbalance of LRP1 and SIRPα by psychological stress dampens the clearance of tumor cells by macrophages

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Acta Pharmaceutica Sinica B 2022年第1期12卷 197-209页

作者： Yanping Wu Xiang Luo Qingqing Zhou Haibiao Gong Huaying Gao Tongzheng Liu Jiaxu Chen Lei Liang Hiroshi Kurihara Yi-Fang Li Rong-Rong He Guangdong Engineering Research Center of Chinese Medicine&Disease Susceptibility Jinan UniversityGuangzhou 510632China International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Chinese Ministry of Education College of PharmacyJinan UniversityGuangzhou 510632China Guangdong Province Key Laboratory of Pharmacodynamic Constituents of Traditional Chinese Medicine and New Drugs Research College of PharmacyJinan UniversityGuangzhou 510632China Formula-pattern Research Center School of Traditional Chinese MedicineJinan UniversityGuangzhou 510632China Integrated Chinese and Western Medicine Postdoctoral Research Station Jinan UniversityGuangzhou 510632China Institute of Tumor Pharmacology College of PharmacyJinan UniversityGuangzhou 510632China

The relationship between chronic psychological stress and tumorigenesis has been well defined in epidemiological studies;however, the underlying mechanism remains underexplored. In this study, we discovered that impaired macrophage phagocytosis contributed to the psychological stressevoked tumor susceptibility, and the stress hormone glucocorticoid(GC) was identified as a principal detrimental factor. Mechanistically, GC disturbed the balance of the "eat me" signal receptor(low-density lipoprotein receptor-related protein-1, LRP1) and the "don’t eat me" signal receptor(signal regulatory protein alpha, SIRPa). Further analysis revealed that GC led to a direct, glucocorticoid receptor(GR)-dependent trans-repression of LRP1 expression, and the repressed LRP1, in turn, resulted in the elevatedgene level of SIRPa by down-regulating mi RNA-4695-3 p. These data collectively demonstrate that stress induces the imbalance of the LRP1/SIRPa axis and entails the disturbance of tumor cell clearance by macrophages. Our findings provide the mechanistic insight into psychological stress-evoked tumor susceptibility and indicate that the balance of LRP1/SIRPa axis may serve as a potential therapeutic strategy for tumor treatment.

关键词： Psychological stress Tumorigenesis macrophages Phagocytosis LRP1 SIRPa Therapeutic target

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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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Oral nanoparticles containing naringenin suppress atherosclerotic progression by targeting delivery to plaque macrophages

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Nano Research 2023年第1期16卷 925-937页

作者： Mengran Guo Zhongshan He Zhaohui Jin Lingjing Huang Jingmei Yuan Shugang Qin Xinchun Wang Lili Cao Xiangrong Song Department of Critical Care Medicine Department of Anesthesiology and Translational Neuroscience CenterDepartment of Clinical PharmacyFrontiers Science Center for Disease-related Molecular NetworkState Key Laboratory of Biotherapy and Cancer CenterWest China HospitalSichuan UniversityChengdu 610000China First Affiliated Hospital of the Medical College Shihezi UniversityShihezi 832008China College of Medicine Chengdu UniversityChengdu 610000China

Atherosclerosis is the main cause of ischemic stroke and myocardial infarction diseases.Nanoparticles have shown unique benefits for atherosclerosis treatment by targeting the lesional macrophages of plaques.However,most of the nanocarriers are administered intravenously,which is inconvenient and may cause complications.Herein,we developed an oral lipid-polymer based nanoparticles(FA-LNPs)decorated with folic acid,which can not only effectively overcome intestinal mucosal-epithelial barrier by increasing the transmembrane transport through intestinal epithelial and the accumulation in Peyer’s patches but also actively target to the aortic plaque sites and accumulate in lesional macrophages.Subsequently,naringenin(Nrg),one of the antiinflammation drugs,was designed to be the oral nanomedicine(FA-LNPs/Nrg)for the first time via the encapsulation of FALNPs.FA-LNPs/Nrg presented highly anti-atherosclerotic efficacy.After the atherosclerotic ApoE−/−mice were treated by FALNPs/Nrg via oral administration for three months,the aortic lesion area,plaque area,and necrotic core area of the aortic root were significantly decreased.Meanwhile,the lipid-related blood parameters recovered to normal levels.Our study provides a promising approach to atherosclerosis treatment based on the novel oral targeting delivery system.

关键词： atherosclerosis macrophages Peyer’s patches oral delivery folic acid naringenin

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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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macrophages in immunoregulation and therapeutics

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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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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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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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