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Abdominal paracentesis drainage ameliorates severe acute pancreatitis in rats by regulating the polarization of peritoneal macrophages

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World Journal of Gastroenterology 2018年第45期24卷 5131-5143页

作者： Ruo-Hong Liu Yi Wen Hong-Yu Sun Chun-Yu Liu Yu-Fan Zhang Yi Yang Qi-Lin Huang Jia-Jia Tang Can-Chen Huang Li-Jun Tang PLA Center of General Surgery and Pancreatic Injury and Repair Key Laboratory of Sichuan Province Chengdu Military General HospitalChengdu 610083Sichuan ProvinceChina Third Military Medical University(Army Medical University) Chongqing 400037China Jiaotong Hospital Affiliated with the Sichuan Provincial People’s Hospital Chengdu 611730Sichuan ProvinceChina Department of Ultrasound Chinese Academy of Medical Sciences and Peking Union Medical College HospitalBeijing 100032China

AIM To investigate the role of peritoneal macrophage(PM) polarization in the therapeutic effect of abdominal paracentesis drainage(APD) on severe acute pancreatitis(SAP).METHODS SAP was induced by 5% Na-taurocholate retrograde injection in Sprague-Dawley rats. APD was performed by inserting a drainage tube with a vacuum ball into the lower right abdomen of the rats immediately after the induction of SAP. To verify the effect of APD on macrophages, PMs were isolated and cultured in an environment, with the peritoneal inflammatory environment simulated by the addition of peritoneal lavage in complete RPMI 1640 medium. Hematoxylin and eosin staining was performed. The levels of pancreatitis biomarkers amylase and lipase as well as the levels of inflammatory mediators in the blood and peritoneal lavage were determined. The polarization phenotypes of the PMs were identified by detecting the marker expression of M1/M2 macrophages via flow cytometry, qPCR and immunohistochemical staining. The protein expression in macrophages that had infiltrated the pancreas was determined by Western blot.RESULTS APD treatment significantly reduced the histopathological scores and levels of amylase, lipase, tumor necrosis factor-α and interleukin(IL)-1β, indicating that APD ameliorates the severity of SAP. Importantly, we found that APD treatment polarized PMs towards the M2 phenotype, as evidenced by the reduced number of M1 macrophages and the reduced levels of proinflammatory mediators, such as IL-1β and L-selectin, as well as the increased number of M2 macrophages and increased levels of anti-inflammatory mediators, such as IL-4 and IL-10. Furthermore, in an in vitro study wherein peritoneal lavage from the APD group was added to the cultured PMs to simulate the peritoneal inflammatory environment, PMs also exhibited a dominant M2 phenotype, resulting in a significantly lower level of inflammation. Finally, APD treatment increased the proportion of M2 macrophages and upregulated the expression of the anti-inflammatory protein Arg-1

关键词： Abdominal paracentesis drainage Peritoneal macrophages Polarization Severe acute pancreatitis

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Co-delivery of Andrographolide and Notch1-targeted siRNA to macrophages with Polymer-based Nanocarrier for Enhanced Anti-inflammation

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Chinese Journal of Polymer Science 2018年第12期36卷 1312-1320页

作者： Teng Wu Min Tan Heng-Ye Gong Yong Wang Xin-Tao shuai PCFM Lab of Ministry of Education School of Materials Science and Engineering Sun Yat-Sen University Guangzhou 510275 China Center of Biomedical Engineering Zhongshan School of Medicine Sun Yat-sen University Guangzhou 510080 China

Chronic inflammatory responses induced by macrophages play a pivotal role in the progression of atherosclerosis. In the present study, a multifunctional nanocarrier based on poly（ethylene glycol）-block-poly（L-aspartic acid） grafted with diethylenetriamine, lysine and cholic acid （PEG-PAsp（DETA）-Lys-CA2） polymer was synthesized for co-delivery of andrographolide and siRNA targeting Notchl gene to alleviate the inflammatory response in macrophages. The nanocarrier exerted low cytotoxicity as well as high performance in drug/siRNA co-delivery. In vitro studies demonstrated the co-delivery of andrographolide and Notchl siRNA not only significantly inhibited lipopolysaccharide （LPS）-activated interleukin-6 （IL-6） and monocytes chemotactic protein 1 （MCP-1） expression as well as blocked nuclear factor-rd3 （NF-rd3） signal activation, but also interfered the Notchl gene expression and increased anti-inflammatory cytokines such as interleukin-10 （IL-10） and arginase-1 expression obviously in macrophages. These results suggested that the combination therapy based on Notchl siRNA and andrographolide co-delivered nanocarrier, i.e. suppressing the expression of proinflammatory cytokines while simultaneously increasing anti-inflammatory factors expression, be a feasible strategy for atherosclerosis treatment.

关键词： macrophages Anti-inflamatory Andrographolide Notchl siRNA

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Neutrophil peptide 1 accelerates the clearance of degenerative axons during Wallerian degeneration by activating macrophages after peripheral nerve crush injury

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Neural Regeneration Research 2024年第8期19卷 1822-1827页

作者： Yuhui Kou Yusong Yuan Qicheng Li Wenyong Xie Hailin Xu Na Han Department of Trauma and Orthopedics Peking University People’s HospitalBeijingChina National Center for Trauma Medicine BeijingChina Key Laboratory of Trauma and Neural Regeneration(Peking University) Ministry of EducationBeijingChina Department of Orthopedics China-Japan Friendship HospitalBeijingChina Department of Central Laboratory and Institute of Clinical Molecular Biology Peking University People’s HospitalBeijingChina

macrophages play an important role in peripheral nerve regeneration,but the specific mechanism of regeneration is still unclear.Our preliminary findings indicated that neutrophil peptide 1 is an innate immune peptide closely involved in peripheral nerve regeneration.However,the mechanism by which neutrophil peptide 1 enhances nerve regeneration remains unclear.This study was designed to investigate the relationship between neutrophil peptide 1 and macrophages in vivo and in vitro in peripheral nerve crush injury.The functions of RAW 264.7 cells we re elucidated by Cell Counting Kit-8 assay,flow cytometry,migration assays,phagocytosis assays,immunohistochemistry and enzyme-linked immunosorbent assay.Axonal debris phagocytosis was observed using the CUBIC(Clear,Unobstructed Brain/Body Imaging Cocktails and Computational analysis)optical clearing technique during Wallerian degeneration.Macrophage inflammatory factor expression in different polarization states was detected using a protein chip.The results showed that neutrophil peptide 1 promoted the prolife ration,migration and phagocytosis of macrophages,and CD206 expression on the surfa ce of macrophages,indicating M2 polarization.The axonal debris clearance rate during Wallerian degeneration was enhanced after neutrophil peptide 1 intervention.Neutrophil peptide 1 also downregulated inflammatory factors interleukin-1α,-6,-12,and tumor necrosis factor-αin invo and in vitro.Thus,the results suggest that neutrophil peptide 1 activates macrophages and accelerates Wallerian degeneration,which may be one mechanism by which neutrophil peptide 1 enhances peripheral nerve regeneration.

关键词： axonal debris inflammatory factors macrophages neutrophil peptide 1 peripheral nerve injury peripheral nerve regeneration RAW 264.7 cells sciatic nerve Wallerian degeneration

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Tumor-associated macrophages,dendritic cells,and neutrophils:biological roles,crosstalk,and therapeutic relevance

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Medical Review 2021年第2期1卷 222-243页

作者： Mingyi Shen Yanhua Du Youqiong Ye Department of Immunology and Microbiology Shanghai Institute of ImmunologyShanghai Jiao Tong University School of MedicineShanghai 200025China

Tumor-associated myeloid cells constitute a series of plastic and heterogeneous cell populations within the tumor microenvironment(TME),and exhibit different phenotypes and functions in response to various microenvironmental signals.In light of promising preclinical data indicating that myeloid-based therapy can effectively suppress tumor growth,a series of novel immune-based therapies and approaches are currently undergoing clinical evaluation.A better understanding of the diversity and functional roles of different myeloid cell subtypes and of how they are associated with TME remodeling may help to improve cancer therapy.Herein,we focus on myeloid cells and discuss how tumor cells can simultaneously reprogram these cells through tumor-derived factors and metabolites.In addition,we discuss the interactions between myeloid cells and other cells in the TME that have the potential to directly or indirectly regulate tumor initiation,invasion,or angiogenesis.We further discuss the current and future potential applications of myeloid cells in the development of focused therapeutic strategies in cancer treatment.

关键词： cell-interaction dendritic cells macrophages neutrophils therapy tumor microenvironment.

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Flavonoids from Scutellaria barbata inhibit activation of tumor-associated macrophages by blocking the Toll-like receptor 4/myeloid differentiation factor 88/nuclear factor-κB signaling pathway

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Journal of Traditional Chinese Medicine 2019年第2期39卷 160-165页

作者： Bao Xiaoxia Li Liuye Xue Xiaoou Department of Gynecology Dongzhimen Hospital Beijing University of Chinese Medicine

OBJECTIVE: To determine the efficacy of Scutellaria barbata flavonoids and polysaccharides on Ishikawa endometrial carcinoma cells co-cultured with U937 macrophages.METHODS: The presence of CD163 and CD206 was determined by flow cytometry. Thiazolyl Blue Tetrazolium Bromide assays were used to assess the proliferation effect of tumor-associated macrophages(TAMs) on Ishikawa cells. The secretion of interleukin(IL)-10 in the co-culture conditioned media was examined using an enzyme-linked immunosorbent assay. The protein expression levels of Toll-like receptor 4(TLR4), myeloid differentiation factor 88(MyD88) and nuclear factor(NF)-κB p65 were detected by Western blot. The mRNA expression levels of TLR4 and MyD88 were analyzed by real-time polymerase chain reaction(PCR). The expression levels of IL-12, IL-1β and tumor necrosis factor-α(TNF-α) were evaluated with real-time PCR.RESULTS: Compared with the U937 control group,the expression levels of CD163 and CD206 in the TAM group were higher(P < 0.05). TAMs co-cultured with Ishikawa cells for 24 or 48 h showed higher proliferation rates(P < 0.05). The expression levels of IL-12 decreased than compared with those in the U937 untreated group(P <0.05) and those of the Scutellaria barbata flavonoids group(P < 0.05). The expression levels of CD206, CD163, IL-10, IL-1β and TNF-α, NF-κB p65 and TLR4/MyD88 in the TAMs control group were greater than those in the U937 untreated group(P < 0.05) and those of the Scutellaria barbata flavonoids group(P < 0.05).CONCLUSION: Scutellaria barbata flavonoids may inhibit TAM activation by blocking the TLR4/MyD88/NF-κB signaling pathway.

关键词： Endometrial neoplasms Scutellaria baicalensis Flavonoids Toll-like receptor 4 Myeloid differentiation factor 88 macrophages

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Young Yum pill inhibits inflammatory mediators and nuclear factor-kappa B signaling in lipopolysaccharide-stimulated RAW 264.7 macrophages

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Journal of Traditional Chinese Medicine 2019年第5期39卷 624-631页

作者： Yin Chengle Muhammad Jahangir Hossen Anfernee Kai-Wing Tse Su Tao Fu Xiuqiong Li Ting Guo Hui Zhu Peili Li Junkui Chou Jiyao Wang Yaping Yu Zhiling Centre for Cancer and Inflammation Research School of Chinese Medicine Hong Kong Baptist UniversityHong KongChina Research and Development Centre for Natural Health Products Hong Kong Baptist University Shenzhen Research Institute and Continuing EducationShenzhen 518057China Centre for Cancer and Inflammation Research School of Chinese MedicineHong Kong Baptist University Hong KongChina

OBJECTIVE: To investigate the effect of Young Yum pill (YYP) on inflammatory mediators in cultured RAW 264.7 cells and elucidate the nuclear factor- kappa B (NF-κB)-related mechanism behind the action. METHODS: YYP was extracted with 95% ethanol Lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages were used to evaluate the effect of YYP on inflammatory mediators. Production of nitric oxide (NO) and prostaglandin E2 (PGE2) were measured by Griess test and enzyme-linked immunosorbent assay, respectively. The levels of genes and proteins involved in the generation of inflammatory mediators were examined using real-time polymerase chain reaction and Western blotting, respectively. RESULTS: YYP dose-dependently suppressed LPS-induced production of NO, PGE2 and tumor necrosis factor-α(TNF-α), and elevation of mRNA and protein levels of inducible NO synthase and cyclooxygenase- 2 in RAW 264.7 macrophages. These observations were associated with decreased NF-κB p65 phosphorylation and nuclear localization, enhanced Akt (protein kinase B) phosphorylation, as well as reduced inhibitor of κB (IκB)α degradation and IκB kinase α/β phosphorylation. CONCLUSION: The present study demonstrated an inhibitory effect of YYP on the NF-κB-regulated inflammatory mediators NO, PGE2 and TNF-α in LPS-stimulated RAW 264.7 macrophages, providing a pharmacological basis for the use of YYP in treating inflammatory disorders.

关键词： Inflammation NF-kappa B Lipopolysaccharides RAW 264.7 cells macrophages Young Yum pill

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Roles of macrophages in tumor development: a spatiotemporalperspective

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Cellular & Molecular Immunology 2023年第9期20卷 983-992页

作者： Mathilde Bied William W.Ho Florent Ginhoux Camille Blériot Institut Gustave Roussy INSERM U1015VillejuifFrance Singapore Immunology Network(SIgN) Agency for ScienceTechnology and Research(A∗STAR)SingaporeSingapore Shanghai Institute of Immunology Shanghai JiaoTong University School of MedicineShanghaiChina Translational Immunology Institute SingHealth Duke-NUSSingaporeSingapore Institut Necker des Enfants Malades INSERMCNRSUniversitéParis CitéParisFrance

macrophages are critical regulators of tissue homeostasis but are also abundant in the tumor microenvironment (TME). In bothprimary tumors and metastases, such tumor-associated macrophages (TAMs) seem to support tumor development. While we knowthat TAMs are the dominant immune cells in the TME, their vast heterogeneity and associated functions are only just beingunraveled. In this review, we outline the various known TAM populations found thus far and delineate their specialized rolesassociated with the main stages of cancer progression. We discuss how macrophages may prime the premetastatic niche to enablethe growth of a metastasis and then how subsequent metastasis-associated macrophages can support secondary tumor growth.Finally, we speculate on the challenges that remain to be overcome in TAM research.

关键词： macrophages Tumor associated macrophages Tumor microenvironment Metastasis

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A MyD88-JAK1-STAT1 complex directly induces SOCS-1 expression in macrophages infected with Group A Streptococcus

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Cellular & Molecular Immunology 2015年第3期12卷 373-383页

作者： Jinghua Wu Cuiqing Ma Haixin Wang Shuhui Wu Gao Xue Xinli Shi Zhang Song Lin Wei Hebei Medical University Shijiazhuang China Hebei United University Affiliated Hospital Tangshan China Tangshan City Hospital of TraditionalChinese Medicine Tangshan China

Some pathogens can use host suppressor of cytokine signaling I （SOCS-1）, an important negative-feedback molecule, as the main mode of immune evasion. Here we found that group A Streptococcus （GAS） is capable of inducing SOCS-1 expression in RAW264.7 and BMDM macrophages. IFN-p plays a role in GAS-induced SOCS-1 expression in macrophages following the induction of cytokine expression by GAS, representing the classical pathway of SOCS-1 expression. However, GAS also induced STAT1 activation and SOCS-1 expression when GAS-infected cells were incubated with anti-IFN-p monoclonal antibody in this study. Moreover, upon comparing TLR4-/- BMDM macrophages with wild-type （WT） cells, we found that TLR4 also plays an essential role in the induction of SOCS-1. MyD88, which is an adaptor protein for TLR4, contributes to STAT1 activation and phosphorylation by forming a complex with Janus kinase 1 （JAK1） and signal transducer and activator of transcription 1 （STAT1） in macrophages. GAS-stimulated expression of STAT1 was severely impaired in MyD88-/- macrophages, whereas expression of JAK1 was unaffected, suggesting that MyD88 was involved in STAT1 expression and phosphorylation. Together, these data demonstrated that in addition to IFN-p signaling and MyD88 complex formation, JAK1 and STAT1 act in a novel pathway to directly induce SOCS-1 expression in GAS-infected macrophages, which may be more conducive to rapid bacterial infection.

关键词： Group A Streptococcus macrophages SOCS-1 TLR4/MyD88 signaling

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Effect of micro/nano-sheet array structures on the osteo-immunomodulation of macrophages

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Regenerative Biomaterials 2022年第1期9卷 888-899页

作者： Xinhui Zheng Lan Chen Ji Tan Jianhua Miao Xuanyong Liu Tieyi Yang Zhihong Ding Department of Orthopedics Gongli Hospital of Shanghai Pudong New AreaShanghai 200135China Department of Orthopedics Zhengzhou Central Hospital Affiliated Zhengzhou UniversityZhengzhou 450007China State Key Laboratory of High-Performance Ceramics and Superfine Microstructure Shanghai Institute of CeramicsChinese Academy of SciencesShanghai 200050China School of Materials Science and Engineering&Henan Key Laboratory of Advanced Magnesium Alloy&Key Laboratory of Materials Processing and Mold Technology(Ministry of Education) Zhengzhou UniversityZhengzhou 450001China

The immune response induced by surface topography crucially determines the implant success.However,how the immune response is mediated by the size of surface topography remains unclear.Hence,various biocompatible Mg-Al layered double hydroxides sheet-array films with different sizes(nano,micro and nano/micro mixture)were constructed on the biomedical titanium,and their osteo-immunomodulation effects on the macrophages were explored.The nano-sheet array structures significantly promoted the polarization of M2 macrophages by activating the PI3K-AKT-mTOR signaling pathway with high gene expressions of integrin b2 and FAK.While the micro-sheet array structures enhanced osteogenic differentiation of mouse bone marrow mesenchymal stem cells(mBMSCs)via ROCK-YAP/TAZ-mediated mechanotransduction.Moreover,the nano-sheet array structures promoted the osteogenic differentiation of mBMSCs with a high proportion of M2 macrophages through a shared medium.This study gave further information concerning integrin-induced focal adhesions in cells of different sheet array structures and their role in macrophage polarization and osteogenic differentiation of mBMSCs,which might help to design biomaterial surfaces with optimal geometry for a desired immunemodulation.

关键词： micro-nano topography immunomodulation macrophages osteogenesis

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FAM19A4 is a novel cytokine ligand of formyl peptide receptor I （FPR 1） and is able to promote the migration and phagocytosis of macrophages

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Cellular & Molecular Immunology 2015年第5期12卷 615-624页

作者： Wenyan Wang Ting Li Xiaolin Wang Wanxiong Yuan Yingying Cheng Heyu Zhang Enquan Xu Yingmei Zhang Shuang Shi Dalong Ma Wenling Han Department of Immunology School of Basic Medical Sciences Peking University Health Science Center Peking University Center for Human Disease Genomics Key Laboratory of Medical Immunology Ministry of Health Beijing China Department of Microbiologyand Infectious Disease Center School of Basic Medical Sciences Peking University Health Science Center Beijing China

FAM 19A4 is an abbreviation for family with sequence similarity 19 （chemokine （C-C motif）-Iike） member A4, which is a secretory protein expressed in low levels in normal tissues. The biological functions of FAM19A4 remain to be determined, and its potential receptor（s） is unclarified. In this study, we demonstrated that FAM 19A4 was a classical secretory protein and we verified for the first time that its mature protein is composed of 95 amino acids. We found that the expression of this novel cytokine was upregulated in lipopolysaccharide （LPS）-stimulated monocytes and macrophages and was typically in polarized M 1. FAM 19A4 shows chemotactic activities on macrophages and enhances the macrophage phagocytosis of zymosan both in vitro and in vivo with noticeable increases of the phosphorylation of protein kinase B （Akt）. FAM 19A4 can also increase the release of reactive oxygen species （ROS） upon zymosan stimulation. Furthermore, based on receptor internalization, radio ligand binding assays and receptor blockage, we demonstrated for the first time that FAM19A4 is a novel ligand of formyl peptide receptor 1 （FPR1）. The above data indicate that upon inflammatory stimulation, monocyte/macrophage-derived FAM 19A4 may play a crucial role in the migration and activation of macrophages during pathogenic infections.

关键词： cytokine FAM 19A4 FPR 1 macrophages phagocytosis

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