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Zhang J, Hao L, Li S, He Y, Zhang Y, Li N, Hu X. mTOR/HIF-1α pathway-mediated glucose reprogramming and macrophage polarization by Sini decoction plus ginseng soup in ALF. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2025; 137:156374. [PMID: 39798342 DOI: 10.1016/j.phymed.2025.156374] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/12/2024] [Revised: 11/22/2024] [Accepted: 01/03/2025] [Indexed: 01/15/2025]
Abstract
BACKGROUND Acute liver failure (ALF) has a high mortality rate, and despite treatment advancements, long-term outcomes remain poor. PURPOSE This study explores the therapeutic targets and pathways of Sini Decoction plus Ginseng Soup (SNRS) in ALF using bioinformatics and network pharmacology, focusing on its impact on macrophage polarization through glucose metabolism reprogramming. The efficacy of SNRS was validated in an LPS/D-GalN-induced ALF model, and its optimal concentration was determined for in vitro macrophage intervention. STUDY DESIGN AND METHODS Differentially expressed genes (DEGs) in HBV-induced and acetaminophen-induced ALF were identified from GEO datasets. The correlation between target gene expression and immune cell infiltration in ALF liver tissue was analyzed. AST, ALT, TNF-α, HMGB1, IL-1β, IL-6, and IL-10 levels were measured, and liver histopathology was assessed. Macrophage polarization was analyzed via immunofluorescence, flow cytometry, and Western blot. Glycolysis-related enzymes and metabolites, including HK2, PFK-1, PKM2, and LDHA, were quantified. Cellular ultrastructure was examined by transmission electron microscopy. RESULTS Five key glycolysis-regulating genes (HK2, CDK1, SOD1, VEGFA, GOT1) were identified, with significant involvement in the HIF-1 signaling pathway. Immune infiltration was markedly higher in ALF liver tissue. SNRS improved survival, reduced ALT/AST levels, alleviated liver injury, and modulated macrophage polarization by decreasing CD86 and increasing CD163 expression. In vitro, SNRS inhibited LPS-induced inflammatory cytokine release, lactate production, p-mTOR/mTOR ratio, and HIF-1α expression. CONCLUSION SNRS modulates macrophage polarization and glucose metabolism reprogramming via the mTOR/HIF-1α pathway, showing promise as a treatment for ALF.
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Affiliation(s)
- Junli Zhang
- Chengdu University of Traditional Chinese Medicine, No. 37 Shi-er-qiao Road, Chengdu 610075, Sichuan Province, PR China; Department of Infectious Diseases, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, 155 Hanzhong Road, Qinghuai District, Nanjing, Jiangsu 210029, PR China
| | - Liyuan Hao
- Chengdu University of Traditional Chinese Medicine, No. 37 Shi-er-qiao Road, Chengdu 610075, Sichuan Province, PR China; Department of Infectious Diseases, Hospital of Chengdu University of Traditional Chinese Medicine, No. 39 Shi-er-qiao Road, Chengdu 610072, Sichuan Province, PR China
| | - Shenghao Li
- Chengdu University of Traditional Chinese Medicine, No. 37 Shi-er-qiao Road, Chengdu 610075, Sichuan Province, PR China; Department of Infectious Diseases, Hospital of Chengdu University of Traditional Chinese Medicine, No. 39 Shi-er-qiao Road, Chengdu 610072, Sichuan Province, PR China
| | - Ying He
- Chengdu University of Traditional Chinese Medicine, No. 37 Shi-er-qiao Road, Chengdu 610075, Sichuan Province, PR China; Department of Infectious Diseases, Hospital of Chengdu University of Traditional Chinese Medicine, No. 39 Shi-er-qiao Road, Chengdu 610072, Sichuan Province, PR China
| | - Yang Zhang
- Department of Infectious Diseases, Hospital of Chengdu University of Traditional Chinese Medicine, No. 39 Shi-er-qiao Road, Chengdu 610072, Sichuan Province, PR China
| | - Na Li
- Chengdu University of Traditional Chinese Medicine, No. 37 Shi-er-qiao Road, Chengdu 610075, Sichuan Province, PR China; Department of Infectious Diseases, Hospital of Chengdu University of Traditional Chinese Medicine, No. 39 Shi-er-qiao Road, Chengdu 610072, Sichuan Province, PR China
| | - Xiaoyu Hu
- Department of Infectious Diseases, Hospital of Chengdu University of Traditional Chinese Medicine, No. 39 Shi-er-qiao Road, Chengdu 610072, Sichuan Province, PR China.
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Le Tallec E, Bellamri N, Lelong M, Morzadec C, Frenger Q, Ballerie A, Cazalets C, Lescoat A, Gros F, Lecureur V. Efferocytosis dysfunction in CXCL4-induced M4 macrophages: phenotypic insights in systemic sclerosis in vitro and in vivo. Front Immunol 2024; 15:1468821. [PMID: 39464886 PMCID: PMC11512447 DOI: 10.3389/fimmu.2024.1468821] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2024] [Accepted: 09/27/2024] [Indexed: 10/29/2024] Open
Abstract
Introduction Systemic sclerosis (SSc) is an autoimmune disease characterized by antinuclear antibody production, which has been linked to an excess of apoptotic cells, normally eliminated by macrophages through efferocytosis. Additionally, circulating levels of CXCL4, a novel SSc biomarker, correlate with more severe fibrotic manifestations of the disease. Considering the defective efferocytosis of macrophages in SSc and the CXCL4-related M4 macrophage phenotype, we hypothesized that CXCL4 could be involved in the alteration of phagocytic functions of macrophages in SSc, including LC3-associated phagocytosis (LAP), another phagocytic process requiring autophagy proteins and contributing to immune silencing. Methods In this study, CXCL4 levels were measured by ELISA in vitro in the serum of SSc patients, and also in vivo in the serum and lungs of C57BL/6J SSc mice induced by intradermal injections of hypochloric acid (HOCl) or Bleomycin (BLM), with evaluation of M4 markers. Circulating monocytes from healthy donors were also differentiated in vitro into M4 monocytes-derived macrophages (MDMs) in the presence of recombinant CXCL4. In M4-MDMs, phagocytosis of fluorescent beads and expression level of efferocytic receptors were evaluated by flow cytometry in vitro, while efferocytosis of pHrodo-stained apoptotic Jurkat cells was evaluated by real-time fluorescence microscopy. LAP quantification was made by fluorescence microscopy in M4-MDMs exposed to IgG-coated beads as well as apoptotic Jurkat cells. Results Our results demonstrated that efferocytosis was significantly reduced in M0-MDMs from healthy donors exposed to the CXCL4-rich plasma of SSc patients. In vivo, CXCL4 expression was increased in the lungs of both SSc-mouse models, along with elevated M4 markers, while efferocytosis of BLM-mice alveolar macrophages was decreased. In vitro, M4-MDMs exhibited reduced efferocytosis compared to M0-MDMs, notably attributable to lower CD36 receptor expression and impaired phagocytosis capacities, despite enhanced LAP. Autophagic gene expression was increased both in vitro in SSc MDMs and in vivo in BLM mice, thus acting as a potential compensatory mechanism. Discussion Altogether, our results support the role of CXCL4 on the impaired efferocytosis capacities of human macrophages from SSc patients and in SSc mice.
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Affiliation(s)
- Erwan Le Tallec
- INSERM, EHESP, IRSET (Institut de Recherche en Santé, Environnement et Travail) – UMR_S 1085, Univ Rennes, Rennes, France
- Department of Internal Medicine and Clinical Immunology, Pontchaillou Hospital, Rennes, France
| | - Nessrine Bellamri
- INSERM, EHESP, IRSET (Institut de Recherche en Santé, Environnement et Travail) – UMR_S 1085, Univ Rennes, Rennes, France
| | - Marie Lelong
- INSERM, EHESP, IRSET (Institut de Recherche en Santé, Environnement et Travail) – UMR_S 1085, Univ Rennes, Rennes, France
| | - Claudie Morzadec
- INSERM, EHESP, IRSET (Institut de Recherche en Santé, Environnement et Travail) – UMR_S 1085, Univ Rennes, Rennes, France
| | - Quentin Frenger
- INSERM UMR - S1109, Université de Strasbourg, Strasbourg, France
- Faculty of Life Sciences, Université de Strasbourg, Strasbourg, France
| | - Alice Ballerie
- INSERM, EHESP, IRSET (Institut de Recherche en Santé, Environnement et Travail) – UMR_S 1085, Univ Rennes, Rennes, France
- Department of Internal Medicine and Clinical Immunology, Pontchaillou Hospital, Rennes, France
| | - Claire Cazalets
- Department of Internal Medicine and Clinical Immunology, Pontchaillou Hospital, Rennes, France
| | - Alain Lescoat
- INSERM, EHESP, IRSET (Institut de Recherche en Santé, Environnement et Travail) – UMR_S 1085, Univ Rennes, Rennes, France
- Department of Internal Medicine and Clinical Immunology, Pontchaillou Hospital, Rennes, France
| | - Frédéric Gros
- INSERM UMR - S1109, Université de Strasbourg, Strasbourg, France
- Faculty of Life Sciences, Université de Strasbourg, Strasbourg, France
| | - Valérie Lecureur
- INSERM, EHESP, IRSET (Institut de Recherche en Santé, Environnement et Travail) – UMR_S 1085, Univ Rennes, Rennes, France
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Sotoudeheian M. Galectin-3 and Severity of Liver Fibrosis in Metabolic Dysfunction-Associated Fatty Liver Disease. Protein Pept Lett 2024; 31:290-304. [PMID: 38715329 DOI: 10.2174/0109298665301698240404061300] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2023] [Revised: 03/02/2024] [Accepted: 03/21/2024] [Indexed: 08/13/2024]
Abstract
Metabolic dysfunction-associated Fatty Liver Disease (MAFLD) is a chronic liver disease characterized by the accumulation of fat in the liver and hepatic steatosis, which can progress to critical conditions, including Metabolic dysfunction-associated Steatohepatitis (MASH), liver fibrosis, hepatic cirrhosis, and hepatocellular carcinoma. Galectin-3, a member of the galectin family of proteins, has been involved in cascades that are responsible for the pathogenesis and progression of liver fibrosis in MAFLD. This review summarizes the present understanding of the role of galectin-3 in the severity of MAFLD and its associated liver fibrosis. The article assesses the underlying role of galectin-3-mediated fibrogenesis, including the triggering of hepatic stellate cells, the regulation of extracellular degradation, and the modulation of immune reactions and responses. It also highlights the assessments of the potential diagnostic and therapeutic implications of galectin-3 in liver fibrosis during MAFLD. Overall, this review provides insights into the multifaceted interaction between galectin-3 and liver fibrosis in MAFLD, which could lead to the development of novel strategies for diagnosis and treatment of this prevalent liver disease.
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Zheng Y, Ji S, Li X, Wen L. Qijia rougan formula ameliorates ECM deposition in hepatic fibrosis by regulating the JAK1/STAT6-microRNA-23a feedback loop in macrophage M2 polarization. Biomed Pharmacother 2023; 168:115794. [PMID: 37922651 DOI: 10.1016/j.biopha.2023.115794] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2023] [Revised: 10/15/2023] [Accepted: 10/26/2023] [Indexed: 11/07/2023] Open
Abstract
Hepatic fibrosis is the critical pathological stage in the progression of chronic liver disease to cirrhosis and hepatocellular carcinoma (HCC). However, no approved anti-hepatic fibrosis drugs are available currently. Qijia Rougan Formula (QRF) is a traditional Chinese medicine (TCM) with significant clinical efficacy on hepatic fibrosis. It was derived from Sanjiasan, a famous decoction documented in the Book of Treatise on the Pestilence in the Ming Dynasty of China. However, the underlying regulatory mechanisms remain elusive. This study further confirmed the therapeutic effects of QRF on hepatic fibrosis and dissected its underlying molecular mechanisms from the perspective of macrophage M2 polarization, one of the critical events in hepatic fibrosis. Experimentally, QRF significantly improved extracellular matrix (ECM) deposition and fibrosis in the liver of model rats. QRF diminished the proportion of M2 macrophages, decreased the levels of TGF-β, PDGFB and IL-10, and regulated the expression of p-JAK1, p-STAT6, JAK1 and microRNA-23a both in vitro and in vivo. Collectively, it was confirmed that QRF effectively improves liver function and hepatocyte damage, and reduces ECM deposition. QRF ameliorates hepatic fibrosis by regulating JAK1/STAT6-microRNA-23a negative feedback loop to inhibit macrophage M2 polarization and thus reduce ECM deposition. Our study illustrates the potential of QRF for hepatic fibrosis therapy, suggesting that QRF is a promising anti-hepatic fibrosis drug candidate.
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Affiliation(s)
- Yanfeng Zheng
- Basic Medical College, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
| | - Shaoxiu Ji
- Basic Medical College, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
| | - Xia Li
- Basic Medical College, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
| | - Li Wen
- Basic Medical College, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China.
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Luo L, Wang S, Hu Y, Wang L, Jiang X, Zhang J, Liu X, Guo X, Luo Z, Zhu C, Xie M, Li Y, You J, Yang F. Precisely Regulating M2 Subtype Macrophages for Renal Fibrosis Resolution. ACS NANO 2023; 17:22508-22526. [PMID: 37948096 DOI: 10.1021/acsnano.3c05998] [Citation(s) in RCA: 31] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/12/2023]
Abstract
Macrophages are central to the pathogenesis of kidney disease and serve as an effective therapeutic target for kidney injury and fibrosis. Among them, M2-type macrophages have double-edged effects regarding anti-inflammatory effects and tissue repair. Depending on the polarization of the M2 subtypes (M2a or M2c) in the diseased microenvironment, they can either mediate normal tissue repair or drive tissue fibrosis. In renal fibrosis, M2a promotes disease progression through macrophage-to-myofibroblast transition (MMT) cells, while M2c possesses potent anti-inflammatory functions and promotes tissue repair, and is inhibited. The mechanisms underlying this differentiation are complex and are currently not well understood. Therefore, in this study, we first confirmed that M2a-derived MMT cells are responsible for the development of renal fibrosis and demonstrated that the intensity of TGF-β signaling is a major factor determining the differential polarization of M2a and M2c. Under excessive TGF-β stimulation, M2a undergoes a process known as MMT cells, whereas moderate TGF-β stimulation favors the polarization of M2c phenotype macrophages. Based on these findings, we employed targeted nanotechnology to codeliver endoplasmic reticulum stress (ERS) inhibitor (Ceapin 7, Cea or C) and conventional glucocorticoids (Dexamethasone, Dex or D), precisely modulating the ATF6/TGF-β/Smad3 signaling axis within macrophages. This approach calibrated the level of TGF-β stimulation on macrophages, promoting their polarization toward the M2c phenotype and suppressing excessive MMT polarization. The study indicates that the combination of ERS inhibitor and a first-line anti-inflammatory drug holds promise as an effective therapeutic approach for renal fibrosis resolution.
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Affiliation(s)
- Lihua Luo
- College of Pharmaceutical Sciences, Zhejiang University, 886 Yuhangtang Road, Hangzhou 310058, Zhejiang, China
- National Key Laboratory of Advanced Drug Delivery and Release Systems, Hangzhou 310058, Zhejiang, China
| | - Sijie Wang
- College of Pharmaceutical Sciences, Zhejiang University, 886 Yuhangtang Road, Hangzhou 310058, Zhejiang, China
| | - Yilong Hu
- College of Pharmaceutical Sciences, Zhejiang University, 886 Yuhangtang Road, Hangzhou 310058, Zhejiang, China
| | - Litong Wang
- College of Pharmaceutical Sciences, Zhejiang University, 886 Yuhangtang Road, Hangzhou 310058, Zhejiang, China
| | - Xindong Jiang
- College of Pharmaceutical Sciences, Zhejiang University, 886 Yuhangtang Road, Hangzhou 310058, Zhejiang, China
| | - Junlei Zhang
- College of Pharmaceutical Sciences, Zhejiang University, 886 Yuhangtang Road, Hangzhou 310058, Zhejiang, China
| | - Xu Liu
- College of Pharmaceutical Sciences, Zhejiang University, 886 Yuhangtang Road, Hangzhou 310058, Zhejiang, China
| | - Xuemeng Guo
- College of Pharmaceutical Sciences, Zhejiang University, 886 Yuhangtang Road, Hangzhou 310058, Zhejiang, China
| | - Zhenyu Luo
- College of Pharmaceutical Sciences, Zhejiang University, 886 Yuhangtang Road, Hangzhou 310058, Zhejiang, China
| | - Chunqi Zhu
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei, China
| | - Miaomiao Xie
- The Second Affiliated Hospital of Shenzhen University, 118 Longjinger Road, Baoan District, Shenzhen 518101, Guangdong, China
| | - Yeqing Li
- The People's Hospital of Baoan Shenzhen, 118 Longjinger Road, Baoan District, Shenzhen 518101, Guangdong, China
| | - Jian You
- College of Pharmaceutical Sciences, Zhejiang University, 886 Yuhangtang Road, Hangzhou 310058, Zhejiang, China
| | - Fuchun Yang
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, Zhejiang, China
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Xie D, Ouyang S. The role and mechanisms of macrophage polarization and hepatocyte pyroptosis in acute liver failure. Front Immunol 2023; 14:1279264. [PMID: 37954583 PMCID: PMC10639160 DOI: 10.3389/fimmu.2023.1279264] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2023] [Accepted: 10/16/2023] [Indexed: 11/14/2023] Open
Abstract
Acute liver failure (ALF) is a severe liver disease caused by disruptions in the body's immune microenvironment. In the early stages of ALF, Kupffer cells (KCs) become depleted and recruit monocytes derived from the bone marrow or abdomen to replace the depleted macrophages entering the liver. These monocytes differentiate into mature macrophages, which are activated in the immune microenvironment of the liver and polarized to perform various functions. Macrophage polarization can occur in two directions: pro-inflammatory M1 macrophages and anti-inflammatory M2 macrophages. Controlling the ratio and direction of M1 and M2 in ALF can help reduce liver injury. However, the liver damage caused by pyroptosis should not be underestimated, as it is a caspase-dependent form of cell death. Inhibiting pyroptosis has been shown to effectively reduce liver damage induced by ALF. Furthermore, macrophage polarization and pyroptosis share common binding sites, signaling pathways, and outcomes. In the review, we describe the role of macrophage polarization and pyroptosis in the pathogenesis of ALF. Additionally, we preliminarily explore the relationship between macrophage polarization and pyroptosis, as well as their effects on ALF.
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Affiliation(s)
| | - Shi Ouyang
- Key Laboratory of Biological Targeting Diagnosis, Therapy and Rehabilitation of Guangdong Higher Education Institutes, Department of Infectious Diseases, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
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7
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Magnetic liposome as a dual-targeting delivery system for idiopathic pulmonary fibrosis treatment. J Colloid Interface Sci 2023; 636:388-400. [PMID: 36640550 DOI: 10.1016/j.jcis.2023.01.007] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2022] [Revised: 12/13/2022] [Accepted: 01/02/2023] [Indexed: 01/08/2023]
Abstract
Idiopathic pulmonary fibrosis (IPF) is the most common form of idiopathic interstitial pneumonia, where M2 macrophages play an irreplaceable role in the anti-inflammatory progress. Targeting M2 macrophages and regulating their polarization may be a potential treatment strategy for IPF. Herein, we designed a magnetic liposome based dual-targeting delivery system for the IPF treatment, constructed by mannose-modified magnetic nanoparticles (MAN-MNPs) loaded on the surface of the liposome (MAN-MNPs@LP). The delivery system is capable of responding to a static magnetic field (SMF) and then recognizing in situ of M2 macrophages through the mannose receptor-dependent internalization. Firstly, a series of physical and chemical assays were used to characterize these nanoparticles. Subsequently, magnetic liposomes accumulation in the damaged lung with/without mannose modification and SMF were compared by in vivo imaging system. Finally, the reduction of M2 macrophages and inhibition of their polarization confirmed that the development of IPF was retarded due to the in situ release of encapsulated dexamethasone (Dex) in lungs under the SMF. Further investigation demonstrated that the expression of α-SMA and collagen deposition was reduced. Altogether, this dual-targeting delivery system can effectively deliver Dex into M2 macrophages in the lung, making it a novel and promising therapeutic system for the IPF treatment.
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8
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Kong X, Xu M, Cui X, Ma L, Cheng H, Hou J, Sun X, Ma L, Jiang L. Potential Role of Macrophage Phenotypes and CCL2 in the Pathogenesis of Takayasu Arteritis. Front Immunol 2021; 12:646516. [PMID: 34079541 PMCID: PMC8165246 DOI: 10.3389/fimmu.2021.646516] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2020] [Accepted: 04/30/2021] [Indexed: 12/28/2022] Open
Abstract
Objectives To investigate vascular macrophage phenotype as well as vascular and peripheral chemokine (C-C motif) ligand 2 (CCL2) expression during different stages of disease progression in patients with Takayasu Arteritis (TA). Methods In this study, 74 patients with TA and 50 controls were recruited. TA disease activity was evaluated with Kerr scores. Macrophage phenotype and CCL2 expression were examined by immunohistochemistry in vascular specimens from 8 untreated and 7 treated TA patients, along with 4 healthy controls. Serum CCL2 were quantified by enzyme-linked immune-absorbent assay from TA patients at baseline (n=59), at 6-months (n=38), and from 46 healthy volunteers. Vascular macrophage phenotype, vascular CCL2 expression and serum CCL2 levels during different stages, as well as the relationship between serum CCL2 and disease activity or other inflammatory parameters (erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and interleukin 6 (IL-6)) were investigated. Results In untreated patients, vascular M1 macrophages and CCL2 showed increased expression, mainly in the adventitia. In contrast, in treated patients, vascular adventitial M1 and CCL2 expression were decreased, while vascular medial M2 macrophages and CCL2 levels were increased. Distribution of macrophages and CCL2 was consistent within the TA vascular lesions regardless of the disease stage. Furthermore, peripheral CCL2 was elevated in patients with TA (TA: 160.30 ± 120.05 vs. Control: 65.58 ± 54.56 pg/ml, P < 0.001). CCL2 levels were found to correlate with ESR, CRP, and IL-6 (all R values between 0.55 and 0.6, all P < 0.001). Receiver operating curve analysis demonstrated that CCL2 (at the cut-off value of 100.36 pg/ml) was able to predict disease activity (area under the curve = 0.74, P = 0.03). Decrease in CCL2 level was observed in patients with clinical remission (CR), but not in patients without CR, after 6 months of treatment (CR patients: baseline 220.18 ± 222.69 vs. post-treatment 88.71 ± 55.89 pg/ml, P = 0.04; non-CR patients: baseline 142.45 ± 104.76 vs. post-treatment 279.49 ± 229.46 pg/ml, P = 0.02). Conclusions Macrophages contribute to vascular pathological changes in TA by undergoing phenotype transformation. CCL2 is an important factor for recruiting macrophages and a potential biomarker for disease activity.
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Affiliation(s)
- Xiufang Kong
- Department of Rheumatology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Ming Xu
- Department of Urology, Zhongshan Hospital, Fudan University, Shanghai, China.,Shanghai Key Laboratory of Organ Transplantation, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Xiaomeng Cui
- Department of Rheumatology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Lingying Ma
- Department of Rheumatology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Huiyong Cheng
- Department of Rheumatology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Jun Hou
- Department of Cardiac Surgery, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Xiaoning Sun
- Department of Cardiac Surgery, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Lili Ma
- Department of Rheumatology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Lindi Jiang
- Department of Rheumatology, Zhongshan Hospital, Fudan University, Shanghai, China.,Center of Clinical Epidemiology and Evidence-based Medicine, Fudan University, Shanghai, China
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9
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Du Y, Rong L, Cong Y, Shen L, Zhang N, Wang B. Macrophage polarization: an effective approach to targeted therapy of inflammatory bowel disease. Expert Opin Ther Targets 2021; 25:191-209. [PMID: 33682588 DOI: 10.1080/14728222.2021.1901079] [Citation(s) in RCA: 51] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Introduction: Inflammatory bowel disease (IBD) is a systemic disease with immune abnormalities that can affect the entire digestive tract. A high percentage of patients with IBD are unresponsive to current pharmacological agents, hence the need exists for novel therapeutic approaches. There is compelling evidence that macrophage polarization plays a key role in the remission of IBD patients and that it could open up future treatment options for patients.Areas covered: This paper highlights the crucial role of macrophage polarization in IBD. The authors shed light on the phenotype and function of macrophages and potential drug targets for polarization regulation. Existing approaches for regulating macrophage polarization are discussed and potential solutions for safety concerns are considered. We performed a literature search on the IBD and macrophage polarization mainly published in PubMed January 2010-July 2020.Expert opinion: Evidence indicates that there are fewer M2 macrophages and a high proportion of M1 macrophages in the intestinal tissues of individuals who are non- responsive to treatment. Regulating macrophage polarization is a potential novel targeted option for IBD treatment. Improved mechanistic insights are required to uncover more precise and effective targets for skewing macrophages into a proper phenotype.
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Affiliation(s)
- Yaoyao Du
- Experiment Center for Science and Technology, Shanghai University of Traditional Chinese Medicine, Shanghai, China.,School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Lan Rong
- Department of Digestive Diseases, Huashan Hospital Affiliated to Fudan University, Shanghai, China
| | - Yuanhua Cong
- Center for Pharmaceutics Research, Shanghai Institute of Materia Medica Chinese Academy of Sciences, Shanghai, China
| | - Lan Shen
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Ning Zhang
- Experiment Center for Science and Technology, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Bing Wang
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, China.,Center for Pharmaceutics Research, Shanghai Institute of Materia Medica Chinese Academy of Sciences, Shanghai, China
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10
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Sang X, Wang Y, Xue Z, Qi D, Fan G, Tian F, Zhu Y, Yang J. Macrophage-Targeted Lung Delivery of Dexamethasone Improves Pulmonary Fibrosis Therapy via Regulating the Immune Microenvironment. Front Immunol 2021; 12:613907. [PMID: 33679754 PMCID: PMC7935565 DOI: 10.3389/fimmu.2021.613907] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2020] [Accepted: 02/01/2021] [Indexed: 12/18/2022] Open
Abstract
Idiopathic pulmonary fibrosis (IPF) is serious chronic lung disease with limited therapeutic approaches. Inflammation and immune disorders are considered as the main factors in the initiation and development of pulmonary fibrosis. Inspired by the key roles of macrophages during the processes of inflammation and immune disorders, here, we report a new method for direct drug delivery into the in-situ fibrotic tissue sites in vitro and in vivo. First, liposomes containing dexamethasone (Dex-L) are prepared and designed to entry into the macrophages in the early hours, forming the macrophages loaded Dex-L delivery system (Dex-L-MV). Chemokine and cytokine factors such as IL-6, IL-10, Arg-1 are measured to show the effect of Dex-L to the various subtypes of macrophages. Next, we mimic the inflammatory and anti-inflammatory microenvironment by co-culture of polarized/inactive macrophage and fibroblast cells to show the acute inflammation response of Dex-L-MV. Further, we confirm the targeted delivery of Dex-L-MV into the inflammatory sites in vivo, and surprisingly found that injected macrophage containing Dex can reduce the level of macrophage infiltration and expression of the markers of collagen deposition during the fibrotic stage, while causing little systematic toxicity. These data demonstrated the suitability and immune regulation effect of Dex-L-MV for the anti-pulmonary process. It is envisaged that these findings are a step forward toward endogenous immune targeting systems as a tool for clinical drug delivery.
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Affiliation(s)
- Xiaoqing Sang
- Tianjin Key Laboratory of Chinese Medicine Pharmacology, Tianjin University of Traditional Chinese Medicine, Tianjin, China.,State Key Laboratory of Component-Based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Yuanyuan Wang
- Tianjin Key Laboratory of Chinese Medicine Pharmacology, Tianjin University of Traditional Chinese Medicine, Tianjin, China.,State Key Laboratory of Component-Based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Zhifeng Xue
- Tianjin Key Laboratory of Chinese Medicine Pharmacology, Tianjin University of Traditional Chinese Medicine, Tianjin, China.,State Key Laboratory of Component-Based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Dawei Qi
- Medcity Research Laboratory, University of Turku, Turku, Finland
| | - Guanwei Fan
- Medical Experiment Center, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China.,Tianjin Key Laboratory of Translational Research of Traditional Chinese Medicine Prescription and Syndrome, Tianjin, China
| | - Fei Tian
- State Key Laboratory of Component-Based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China.,Tianjin Key Laboratory of Traditional Chinese Medicine Chemistry and Analysis, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Yan Zhu
- Tianjin Key Laboratory of Chinese Medicine Pharmacology, Tianjin University of Traditional Chinese Medicine, Tianjin, China.,State Key Laboratory of Component-Based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Jian Yang
- Tianjin Key Laboratory of Chinese Medicine Pharmacology, Tianjin University of Traditional Chinese Medicine, Tianjin, China.,State Key Laboratory of Component-Based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
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11
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Wang J, Xing H, Qin X, Ren Q, Yang J, Li L. Pharmacological effects and mechanisms of muscone. JOURNAL OF ETHNOPHARMACOLOGY 2020; 262:113120. [PMID: 32668321 DOI: 10.1016/j.jep.2020.113120] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/03/2019] [Revised: 05/27/2020] [Accepted: 06/17/2020] [Indexed: 06/11/2023]
Abstract
Musk, the dried secretion from the preputial follicles of the male musk deer (genus Moschus), possesses various pharmacological activities and has been used extensively in traditional Chinese medicine for thousands of years. Muscone is the main active ingredient of musk and exerts pharmacological effects similar to those of musk. Although muscone was notably used to treat various disorders and diseases, such as neurological disorders, chronic inflammation and ischemia-reperfusion injury, most of the mechanisms of the pharmacological action of muscone remain unclear because of slow progress in research before the 21st century. In recent years, the pharmacological activities and mechanisms of muscone have been clarified. The present article summarizes the pharmacological and biological studies on cerebrovascular disease, cardiovascular disease, neurological effects, cancer and others and the associated mechanisms of the action of muscone to date.
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Affiliation(s)
- Jun Wang
- Health Management Center, Xiangyang Central Hospital, Affiliated Hospital of Hubei University of Arts and Science, Xiangyang, People's Republic of China
| | - Hui Xing
- Department of Obstetrics and Gynaecology, Xiangyang Central Hospital, Affiliated Hospital of Hubei University of Arts and Science, Xiangyang, People's Republic of China
| | - Xiaomin Qin
- Department of Obstetrics and Gynaecology, Xiangyang Central Hospital, Affiliated Hospital of Hubei University of Arts and Science, Xiangyang, People's Republic of China
| | - Qun Ren
- Health Management Center, Xiangyang Central Hospital, Affiliated Hospital of Hubei University of Arts and Science, Xiangyang, People's Republic of China
| | - Jiang Yang
- Department of Obstetrics and Gynaecology, Xiangyang Central Hospital, Affiliated Hospital of Hubei University of Arts and Science, Xiangyang, People's Republic of China; Department of Obstetrics and Gynaecology, Renmin Hospital of Wuhan University, Wuhan, People's Republic of China.
| | - Lin Li
- Department of Obstetrics and Gynaecology, Xiangyang Central Hospital, Affiliated Hospital of Hubei University of Arts and Science, Xiangyang, People's Republic of China.
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12
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Li H, Zhou Y, Wang H, Zhang M, Qiu P, Zhang M, Zhang R, Zhao Q, Liu J. Crosstalk Between Liver Macrophages and Surrounding Cells in Nonalcoholic Steatohepatitis. Front Immunol 2020; 11:1169. [PMID: 32670278 PMCID: PMC7326822 DOI: 10.3389/fimmu.2020.01169] [Citation(s) in RCA: 75] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2020] [Accepted: 05/12/2020] [Indexed: 12/12/2022] Open
Abstract
Nonalcoholic steatohepatitis (NASH), the advanced stage of nonalcoholic fatty liver disease (NAFLD), is emerging as a leading cause of progressive liver fibrosis and end-stage liver disease. Liver macrophages, mainly composed of Kupffer cells (KCs) and monocyte-derived macrophages (MoMFs), play a vital role in NASH progression and regression. Recent advances suggest that cell–cell communication is a fundamental feature of hepatic microenvironment. The reprogramming of cell–cell signaling between macrophages and surrounding cells contributes to the pathogenesis of NASH. In this review, we summarize the current knowledge of NASH regarding the composition of liver macrophages and their communication with surrounding cells, which are composed of hepatocytes, hepatic stellate cells (HSCs), liver sinusoidal endothelial cells (LSECs) and other immune cells. We also discuss the potential therapeutic strategies based on the level of macrophages.
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Affiliation(s)
- Haiou Li
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, China.,Hubei Clinical Center, Key Lab of Intestinal and Colorectal Diseases, Wuhan, China
| | - Yunjiao Zhou
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, China.,Hubei Clinical Center, Key Lab of Intestinal and Colorectal Diseases, Wuhan, China
| | - Haizhou Wang
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, China.,Hubei Clinical Center, Key Lab of Intestinal and Colorectal Diseases, Wuhan, China
| | - Meng Zhang
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, China.,Hubei Clinical Center, Key Lab of Intestinal and Colorectal Diseases, Wuhan, China
| | - Peishan Qiu
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, China.,Hubei Clinical Center, Key Lab of Intestinal and Colorectal Diseases, Wuhan, China
| | - Mengna Zhang
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, China.,Hubei Clinical Center, Key Lab of Intestinal and Colorectal Diseases, Wuhan, China
| | - Ruike Zhang
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, China.,Hubei Clinical Center, Key Lab of Intestinal and Colorectal Diseases, Wuhan, China
| | - Qiu Zhao
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, China.,Hubei Clinical Center, Key Lab of Intestinal and Colorectal Diseases, Wuhan, China
| | - Jing Liu
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, China.,Hubei Clinical Center, Key Lab of Intestinal and Colorectal Diseases, Wuhan, China
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13
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Wang Y, Kuai Q, Gao F, Wang Y, He M, Zhou H, Han G, Jiang X, Ren S, Yu Q. Overexpression of TIM-3 in Macrophages Aggravates Pathogenesis of Pulmonary Fibrosis in Mice. Am J Respir Cell Mol Biol 2020; 61:727-736. [PMID: 31162951 DOI: 10.1165/rcmb.2019-0070oc] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive lung disorder and lacks effective treatments because of unclear mechanisms. Aberrant function of alveolar macrophages is directly linked to pulmonary fibrosis. Here, we show TIM-3 (T-cell immunoglobulin domain and mucin domain-3), a key regulator of macrophage function, aggravates pulmonary fibrosis. TIM-3 mRNA of patients with IPF was analyzed based on the Gene Expression Omnibus and Array Express databases. Lung pathology and profibrotic molecules were assessed in a bleomycin (BLM)-induced pulmonary fibrosis model using wild-type (WT) and TIM-3 transgenic (TIM-3-TG) mice. Macrophage cells, RAW264.7, were then applied to investigate the effect of macrophage TIM-3 under BLM exposure in vitro. Macrophage depletion and adoptive-transfer experiments were finally performed to examine lung morphology and profibrotic molecules. TIM-3 expression was increased both in patients with IPF and in our BLM-induced mouse model. TIM-3-TG mice developed more serious pathological changes in lung tissue and higher expressions of TGF-β1 (transforming growth factor-β1) and IL-10 than WT mice. After BLM treatment, TGF-β1 and IL-10 expression was significantly decreased in RAW264.7 cells after TIM-3 knock-out, whereas it was increased in TIM-3-TG peritoneal macrophages. The scores of pulmonary fibrosis in WT and TIM-3-TG mice were significantly reduced, and there was no difference between them after macrophage depletion. Furthermore, WT mice receiving adoptive macrophages from TIM-3-TG mice also had more serious lung fibrosis and increased expression of TGF-β1 and IL-10 than those receiving macrophages from WT mice. Our findings revealed that overexpressed TIM-3 in alveolar macrophages aggravated pulmonary fibrosis.
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Affiliation(s)
- Yu Wang
- Beijing Institute of Transfusion Medicine, Beijing, China
| | - Qiyuan Kuai
- Beijing Institute of Transfusion Medicine, Beijing, China
| | - Fenghua Gao
- Beijing Institute of Transfusion Medicine, Beijing, China
| | - Yanbing Wang
- Beijing Institute of Transfusion Medicine, Beijing, China.,School of Life Sciences, Jilin University, Changchun, China
| | - Min He
- Beijing Institute of Transfusion Medicine, Beijing, China
| | - Hong Zhou
- Beijing Institute of Transfusion Medicine, Beijing, China
| | - Gencheng Han
- Institute of Beijing Brain Sciences, Beijing, China; and
| | - Xingwei Jiang
- Beijing Institute of Transfusion Medicine, Beijing, China
| | - Suping Ren
- Beijing Institute of Transfusion Medicine, Beijing, China.,Beijing Advanced Innovation Centre for Big Data-Based Precision Medicine, Beihang University, Beijing, China
| | - Qun Yu
- Beijing Institute of Transfusion Medicine, Beijing, China.,Beijing Advanced Innovation Centre for Big Data-Based Precision Medicine, Beihang University, Beijing, China
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14
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Li X, Liu R, Wang Y, Zhu W, Zhao D, Wang X, Yang H, Gurley EC, Chen W, Hylemon PB, Zhou H. Cholangiocyte-Derived Exosomal lncRNA H19 Promotes Macrophage Activation and Hepatic Inflammation under Cholestatic Conditions. Cells 2020; 9:E190. [PMID: 31940841 PMCID: PMC7016679 DOI: 10.3390/cells9010190] [Citation(s) in RCA: 81] [Impact Index Per Article: 16.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2019] [Revised: 01/07/2020] [Accepted: 01/08/2020] [Indexed: 02/07/2023] Open
Abstract
Activation of hepatic macrophages represents the critical driving force to promote cholestatic liver injury. Exosomes, as important small extracellular vesicles released by almost all types of cells, contribute to intercellular communication. We previously reported that cholangiocyte-derived exosomal long noncoding RNA (lncRNA) H19 plays a vital role in disrupting bile acid homeostasis in hepatocytes and promoting the activation of hepatic stellate cells (HSCs). Exosomal H19 derived from cholangiocytes was rapidly taken up by Kupffer cells. However, the mechanistic links between exosomal lncRNA H19 and macrophage-driven inflammation in cholestasis remain unclear. Here, we reported that the hepatic H19 level was closely correlated with macrophage activation and hepatic fibrosis in both Mdr2-/- and bile duct ligation (BDL) cholestatic mouse models, as well as in human primary sclerosing cholangitis (PSC) and primary biliary cholangitis (PBC) patients. Exosomal H19 significantly induced the expression and secretion of chemokine (C-C motif) ligand 2 (CCL-2) and interleukin 6 (IL-6) in Kupffer cells. H19-enriched exosomes enhanced the activation M1 polarization of Kupffer cells and promoted the recruitment and differentiation of bone marrow-derived macrophages, which were inhibited by a CCL-2 pharmacological inhibitor. In conclusion, Cholangiocyte-derived exosomal H19 played a critical role in macrophage activation, differentiation, and chemotaxis through CCL-2/CCR-2 signaling pathways, which represent a therapeutic target for cholestatic liver diseases.
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Affiliation(s)
- Xiaojiaoyang Li
- Department of Microbiology and Immunology and McGuire Veterans Affairs Medical Center, Virginia Commonwealth University, Richmond, VA 23298, USA; (X.L.); (R.L.); (Y.W.); (W.Z.); (D.Z.); (X.W.); (H.Y.); (E.C.G.); (P.B.H.)
- Division of Gastroenterology, Hepatology and Nutrition and McGuire Veterans Affairs Medical Center, Virginia Commonwealth University, Richmond, VA 23298, USA
| | - Runping Liu
- Department of Microbiology and Immunology and McGuire Veterans Affairs Medical Center, Virginia Commonwealth University, Richmond, VA 23298, USA; (X.L.); (R.L.); (Y.W.); (W.Z.); (D.Z.); (X.W.); (H.Y.); (E.C.G.); (P.B.H.)
- Division of Gastroenterology, Hepatology and Nutrition and McGuire Veterans Affairs Medical Center, Virginia Commonwealth University, Richmond, VA 23298, USA
| | - Yanyan Wang
- Department of Microbiology and Immunology and McGuire Veterans Affairs Medical Center, Virginia Commonwealth University, Richmond, VA 23298, USA; (X.L.); (R.L.); (Y.W.); (W.Z.); (D.Z.); (X.W.); (H.Y.); (E.C.G.); (P.B.H.)
| | - Weiwei Zhu
- Department of Microbiology and Immunology and McGuire Veterans Affairs Medical Center, Virginia Commonwealth University, Richmond, VA 23298, USA; (X.L.); (R.L.); (Y.W.); (W.Z.); (D.Z.); (X.W.); (H.Y.); (E.C.G.); (P.B.H.)
| | - Derrick Zhao
- Department of Microbiology and Immunology and McGuire Veterans Affairs Medical Center, Virginia Commonwealth University, Richmond, VA 23298, USA; (X.L.); (R.L.); (Y.W.); (W.Z.); (D.Z.); (X.W.); (H.Y.); (E.C.G.); (P.B.H.)
- Division of Gastroenterology, Hepatology and Nutrition and McGuire Veterans Affairs Medical Center, Virginia Commonwealth University, Richmond, VA 23298, USA
| | - Xuan Wang
- Department of Microbiology and Immunology and McGuire Veterans Affairs Medical Center, Virginia Commonwealth University, Richmond, VA 23298, USA; (X.L.); (R.L.); (Y.W.); (W.Z.); (D.Z.); (X.W.); (H.Y.); (E.C.G.); (P.B.H.)
- Division of Gastroenterology, Hepatology and Nutrition and McGuire Veterans Affairs Medical Center, Virginia Commonwealth University, Richmond, VA 23298, USA
| | - Hang Yang
- Department of Microbiology and Immunology and McGuire Veterans Affairs Medical Center, Virginia Commonwealth University, Richmond, VA 23298, USA; (X.L.); (R.L.); (Y.W.); (W.Z.); (D.Z.); (X.W.); (H.Y.); (E.C.G.); (P.B.H.)
| | - Emily C. Gurley
- Department of Microbiology and Immunology and McGuire Veterans Affairs Medical Center, Virginia Commonwealth University, Richmond, VA 23298, USA; (X.L.); (R.L.); (Y.W.); (W.Z.); (D.Z.); (X.W.); (H.Y.); (E.C.G.); (P.B.H.)
- Division of Gastroenterology, Hepatology and Nutrition and McGuire Veterans Affairs Medical Center, Virginia Commonwealth University, Richmond, VA 23298, USA
| | - Weidong Chen
- School of Pharmaceutical Science, Anhui University of Chinese Medicine, Hefei 230031, China;
| | - Phillip B. Hylemon
- Department of Microbiology and Immunology and McGuire Veterans Affairs Medical Center, Virginia Commonwealth University, Richmond, VA 23298, USA; (X.L.); (R.L.); (Y.W.); (W.Z.); (D.Z.); (X.W.); (H.Y.); (E.C.G.); (P.B.H.)
- Division of Gastroenterology, Hepatology and Nutrition and McGuire Veterans Affairs Medical Center, Virginia Commonwealth University, Richmond, VA 23298, USA
| | - Huiping Zhou
- Department of Microbiology and Immunology and McGuire Veterans Affairs Medical Center, Virginia Commonwealth University, Richmond, VA 23298, USA; (X.L.); (R.L.); (Y.W.); (W.Z.); (D.Z.); (X.W.); (H.Y.); (E.C.G.); (P.B.H.)
- Division of Gastroenterology, Hepatology and Nutrition and McGuire Veterans Affairs Medical Center, Virginia Commonwealth University, Richmond, VA 23298, USA
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15
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Liu M, Li W, Wang H, Yin L, Ye B, Tang Y, Huang C. CTRP9 Ameliorates Atrial Inflammation, Fibrosis, and Vulnerability to Atrial Fibrillation in Post-Myocardial Infarction Rats. J Am Heart Assoc 2019; 8:e013133. [PMID: 31623508 PMCID: PMC6898814 DOI: 10.1161/jaha.119.013133] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Background Inflammation and fibrosis play an important role in the pathogenesis of atrial fibrillation (AF) after myocardial infarction (MI). CTRP9 (C1q/tumor necrosis factor‐related protein‐9) as a secreted glycoprotein can reverse left ventricle remodeling post‐MI, but its effects on MI‐induced atrial inflammation, fibrosis, and associated AF are unknown. Methods and Results MI model rats received adenoviral supplementation of CTRP9 (Ad‐CTRP9) by jugular‐vein injection. Cardiac function, inflammatory, and fibrotic indexes and related signaling pathways, electrophysiological properties, and AF inducibility of atria in vivo and ex vivo were detected in 3 or 7 days after MI. shCTRP9 (short hairpin CTRP9) and shRNA were injected into rat and performed similar detection at day 5 or 10. Adverse atrial inflammation and fibrosis, cardiac dysfunction were induced in both MI and Ad‐GFP (adenovirus‐encoding green fluorescent protein)+MI rats. Systemic CTRP9 treatment improved cardiac dysfunction post‐MI. CTRP9 markedly ameliorated macrophage infiltration and attenuated the inflammatory responses by downregulating interleukin‐1β and interleukin‐6, and upregulating interleukin‐10, in 3 days post‐MI; depressed left atrial fibrosis by decreasing the expressions of collagen types I and III, α‐SMA, and transforming growth factor β1 in 7 days post‐MI possibly through depressing the Toll‐like receptor 4/nuclear factor‐κB and Smad2/3 signaling pathways. Electrophysiologic recordings showed that increased AF inducibility and duration, and prolongation of interatrial conduction time induced by MI were attenuated by CTRP9; moreover, CTRP9 was negatively correlated with interleukin‐1β and AF duration. Downregulation of CTRP9 aggravated atrial inflammation, fibrosis, susceptibility of AF and prolonged interatrial conduction time, without affecting cardiac function. Conclusions CTRP9 is effective at attenuating atrial inflammation and fibrosis, possibly via its inhibitory effects on the Toll‐like receptor 4/nuclear factor‐κB and Smad2/3 signaling pathways, and may be an original upstream therapy for AF in early phase of MI.
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Affiliation(s)
- Mingxin Liu
- Department of Cardiology Renmin Hospital of Wuhan University Hubei China.,Cardiovascular Research Institute of Wuhan University Hubei China.,Hubei Key Laboratory of Cardiology Hubei China
| | - Wei Li
- Department of Cardiology Renmin Hospital of Wuhan University Hubei China.,Cardiovascular Research Institute of Wuhan University Hubei China.,Hubei Key Laboratory of Cardiology Hubei China
| | - Huibo Wang
- Department of Cardiology Renmin Hospital of Wuhan University Hubei China.,Cardiovascular Research Institute of Wuhan University Hubei China.,Hubei Key Laboratory of Cardiology Hubei China
| | - Lin Yin
- Department of Cardiology Renmin Hospital of Wuhan University Hubei China.,Cardiovascular Research Institute of Wuhan University Hubei China.,Hubei Key Laboratory of Cardiology Hubei China
| | - Bingjie Ye
- Department of Cardiology Renmin Hospital of Wuhan University Hubei China.,Cardiovascular Research Institute of Wuhan University Hubei China.,Hubei Key Laboratory of Cardiology Hubei China
| | - Yanhong Tang
- Department of Cardiology Renmin Hospital of Wuhan University Hubei China.,Cardiovascular Research Institute of Wuhan University Hubei China.,Hubei Key Laboratory of Cardiology Hubei China
| | - Congxin Huang
- Department of Cardiology Renmin Hospital of Wuhan University Hubei China.,Cardiovascular Research Institute of Wuhan University Hubei China.,Hubei Key Laboratory of Cardiology Hubei China
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16
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Gong T, Dong Z, Fu Y, Gong T, Deng L, Zhang Z. Hyaluronic acid modified doxorubicin loaded Fe 3O 4 nanoparticles effectively inhibit breast cancer metastasis. J Mater Chem B 2019; 7:5861-5872. [PMID: 31512706 DOI: 10.1039/c9tb01250h] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Tumor-associated macrophages (TAMs) play a critical role in tumor survival and metastasis. Iron(ii,iii) oxide (Fe3O4) nanoparticles have been shown to induce M1 macrophage polarization to initiate antitumor immunity and inhibit tumor metastasis. Hyaluronic acid (HA) modified doxorubicin (DOX) loaded Fe3O4 nanoparticles (Fe3O4-DOX-HA) have been constructed to mediate specific delivery of Fe3O4 nanoparticles to CD44-positive 4T1 tumor cells and tumor associated macrophages. Covalent conjugation of HA with DOX rendered nanoparticles with pH sensitivity, and further contributed to the prolonged circulation and enhanced tumor-specific accumulation in vivo. Furthermore, combining the M1 polarization effect of the Fe3O4 nanoparticles and enhanced cytotoxicity, Fe3O4-DOX-HA demonstrated enhanced antitumor and anti-metastasis effects both in vitro and in vivo.
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Affiliation(s)
- Ting Gong
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu, 610064, China.
| | - Zhanglu Dong
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu, 610064, China.
| | - Yao Fu
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu, 610064, China.
| | - Tao Gong
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu, 610064, China.
| | - Li Deng
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu, 610064, China.
| | - Zhirong Zhang
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu, 610064, China.
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17
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Hans CP, Sharma N, Sen S, Zeng S, Dev R, Jiang Y, Mahajan A, Joshi T. Transcriptomics Analysis Reveals New Insights into the Roles of Notch1 Signaling on Macrophage Polarization. Sci Rep 2019; 9:7999. [PMID: 31142802 PMCID: PMC6541629 DOI: 10.1038/s41598-019-44266-4] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2018] [Accepted: 01/29/2019] [Indexed: 12/24/2022] Open
Abstract
Naïve macrophages (Mφ) polarize in response to various environmental cues to a spectrum of cells that have distinct biological functions. The extreme ends of the spectrum are classified as M1 and M2 macrophages. Previously, we demonstrated that Notch1 deficiency promotes Tgf-β2 dependent M2-polarization in a mouse model of abdominal aortic aneurysm. The present studies aimed to characterize the unique set of genes regulated by Notch1 signaling in macrophage polarization. Bone marrow derived macrophages isolated from WT or Notch1+/- mice (n = 12) were differentiated to Mφ, M1 or M2-phenotypes by 24 h exposure to vehicle, LPS/IFN-γ or IL4/IL13 respectively and total RNA was subjected to RNA-Sequencing (n = 3). Bioinformatics analyses demonstrated that Notch1 haploinsufficiency downregulated the expression of 262 genes at baseline level, 307 genes with LPS/IFN-γ and 254 genes with IL4/IL13 treatment. Among these, the most unique genes downregulated by Notch1 haploinsufficiency included fibromodulin (Fmod), caspase-4, Has1, Col1a1, Alpl and Igf. Pathway analysis demonstrated that extracellular matrix, macrophage polarization and osteogenesis were the major pathways affected by Notch1 haploinsufficiency. Gain and loss-of-function studies established a strong correlation between Notch1 haploinsufficiency and Fmod in regulating Tgf-β signaling. Collectively, our studies suggest that Notch1 haploinsufficiency increases M2 polarization through these newly identified genes.
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Affiliation(s)
- Chetan P Hans
- Department of Cardiovascular Medicine, University of Missouri, Columbia, USA.
- Medical Pharmacology and Physiology, University of Missouri, Columbia, USA.
- Dalton Cardiovascular Research Center, University of Missouri, Columbia, USA.
| | - Neekun Sharma
- Department of Cardiovascular Medicine, University of Missouri, Columbia, USA
- Dalton Cardiovascular Research Center, University of Missouri, Columbia, USA
| | - Sidharth Sen
- MU Informatics Institute, University of Missouri, Columbia, USA
| | - Shuai Zeng
- Department of Electrical Engineering and Computer Science, University of Missouri, Columbia, USA
| | - Rishabh Dev
- Department of Cardiovascular Medicine, University of Missouri, Columbia, USA
- Dalton Cardiovascular Research Center, University of Missouri, Columbia, USA
| | - Yuexu Jiang
- Department of Electrical Engineering and Computer Science, University of Missouri, Columbia, USA
| | - Advitiya Mahajan
- Department of Cardiovascular Medicine, University of Missouri, Columbia, USA
| | - Trupti Joshi
- MU Informatics Institute, University of Missouri, Columbia, USA
- Department of Electrical Engineering and Computer Science, University of Missouri, Columbia, USA
- Department of Health Management and Informatics, School of Medicine, University of Missouri, Columbia, USA
- Christopher S. Bond Life Science Center, University of Missouri, Columbia, USA
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18
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Lakhdari O, Yamamura A, Hernandez GE, Anderson KK, Lund SJ, Oppong-Nonterah GO, Hoffman HM, Prince LS. Differential Immune Activation in Fetal Macrophage Populations. Sci Rep 2019; 9:7677. [PMID: 31118442 PMCID: PMC6531440 DOI: 10.1038/s41598-019-44181-8] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2019] [Accepted: 05/02/2019] [Indexed: 02/06/2023] Open
Abstract
Distinct macrophage subsets populate the developing embryo and fetus in distinct waves. However little is known about the functional differences between in utero macrophage populations or how they might contribute to fetal and neonatal immunity. Here we tested the innate immune response of mouse macrophages derived from the embryonic yolk sac and from fetal liver. When isolated from liver or lung, CD11bHI fetal liver derived macrophages responded to the TLR4 agonist LPS by expressing and releasing inflammatory cytokines. However F4/80HI macrophages from the yolk sac did not respond to LPS treatment. While differences in TLR4 expression did not appear to explain these data, F4/80HI macrophages had much lower NLRP3 inflammasome expression compared to CD11bHI macrophages. Gene expression profiling also demonstrated LPS-induced expression of inflammatory genes in CD11bHI macrophages, but not in F4/80HI cells. Genes expressed in LPS-treated CD11bHI macrophages were more likely to contain predicted NF-κB binding sites in their promoter regions. Our data show that CD11bHI macrophages derived from fetal liver are the major pro-inflammatory cells in the developing fetus. These findings could have important implications in better understanding the fetal inflammatory response and the unique features of neonatal immunity.
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Affiliation(s)
- Omar Lakhdari
- Department of Pediatrics, University of California, San Diego, La Jolla, CA, Rady Children's Hospital, San Diego, San Diego, CA, USA
| | - Asami Yamamura
- Department of Pediatrics, University of California, San Diego, La Jolla, CA, Rady Children's Hospital, San Diego, San Diego, CA, USA
| | - Gilberto E Hernandez
- Department of Pediatrics, University of California, San Diego, La Jolla, CA, Rady Children's Hospital, San Diego, San Diego, CA, USA
| | - Kathryn K Anderson
- Department of Pediatrics, University of California, San Diego, La Jolla, CA, Rady Children's Hospital, San Diego, San Diego, CA, USA
| | - Sean J Lund
- Department of Pediatrics, University of California, San Diego, La Jolla, CA, Rady Children's Hospital, San Diego, San Diego, CA, USA
| | - Gertrude O Oppong-Nonterah
- Department of Pediatrics, University of California, San Diego, La Jolla, CA, Rady Children's Hospital, San Diego, San Diego, CA, USA
| | - Hal M Hoffman
- Department of Pediatrics, University of California, San Diego, La Jolla, CA, Rady Children's Hospital, San Diego, San Diego, CA, USA
| | - Lawrence S Prince
- Department of Pediatrics, University of California, San Diego, La Jolla, CA, Rady Children's Hospital, San Diego, San Diego, CA, USA.
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19
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The role of hepatic macrophages in nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. Lab Anim Res 2018; 34:133-139. [PMID: 30671098 PMCID: PMC6333604 DOI: 10.5625/lar.2018.34.4.133] [Citation(s) in RCA: 54] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2018] [Revised: 09/28/2018] [Accepted: 10/01/2018] [Indexed: 12/18/2022] Open
Abstract
Nonalcoholic steatohepatitis (NASH) is becoming common chronic liver disease because of the increasing global prevalence of obesity and consequently Nonalcoholic fatty liver disease (NAFLD). However, the mechanism for progression of NAFLD to NASH and then cirrhosis is not completely understood, yet. The triggering of these hepatic diseases is thought from hepatocyte injury caused by over-accumulated lipid toxicity. Injured hepatocytes release damage-associated molecular patterns (DAMPs), which can stimulate the Kupffer cells (KCs), liver-resident macrophages, to release pro-inflammatory cytokines and chemokines, and recruit monocyte-derived macrophages (MDMs). The increased activation of KCs and recruitment of MDMs accelerate the progression of NAFLD to NASH and cirrhosis. Therefore, characterization for activation of hepatic macrophages, both KCs and MDMs, is a baseline to figure out the progression of hepatic diseases. The purpose of this review is to discuss the current understanding of mechanisms of NAFLD and NASH, mainly focusing on characterization and function of hepatic macrophages and suggests the regulators of hepatic macrophages as the therapeutic target in hepatic diseases.
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Ballerie A, Lescoat A, Augagneur Y, Lelong M, Morzadec C, Cazalets C, Jouneau S, Fardel O, Vernhet L, Jégo P, Lecureur V. Efferocytosis capacities of blood monocyte-derived macrophages in systemic sclerosis. Immunol Cell Biol 2018; 97:340-347. [PMID: 30426551 DOI: 10.1111/imcb.12217] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2018] [Revised: 11/12/2018] [Accepted: 11/12/2018] [Indexed: 12/15/2022]
Abstract
A defect in the apoptotic cell clearance (efferocytosis) by phagocytic cells may participate in autoimmunity and chronic inflammation. The mechanisms leading to the emergence of autoimmunity in systemic sclerosis (SSc) are still to be determined. In this study, the efferocytosis capacities of blood monocyte-derived macrophages (MDM) from patients with SSc were evaluated. Blood monocytes obtained from patients with SSc and healthy donors (HD) were differentiated in vitro into macrophages. The capacities of MDM to engulf CFSE+ apoptotic Jurkat human T lymphocytes were compared between SSc MDM and HD using flow cytometry. The expression of classical engulfing receptors in SSc MDM and HD MDM was also evaluated and their involvement in the modulation of efferocytosis was confirmed using a siRNA approach. The mean phagocytic index (PI) reflecting efferocytosis capacities of SSc MDM (PI = 19.3 ± 3.0; n = 21) was significantly decreased in comparison with the PI of HD MDM (PI = 35.9 ± 3.0; n = 31; P < 0.001). In comparison with HD, SSc MDM exhibited a downregulated expression of scavenger receptor (SR)-B1, SR-A1 and integrin β5 (ITGβ5). In HD MDM, the extinction of these receptors was followed by a reduction of efferocytosis only for the repression of ITGβ5, suggesting a possible selective role of this integrin in the impaired efferocytosis observed in SSc. As efferocytosis may be at the crossroads of inflammation, autoimmunity and fibrosis, in showing impaired efferocytosis capacities of blood MDM in SSc, our study offers new pathogenesis considerations for the involvement of macrophages in the autoimmune processes driving this disorder.
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Affiliation(s)
- Alice Ballerie
- Univ Rennes, CHU Rennes, INSERM, EHESP, IRSET (Institut de recherche en santé, environnement et travail) - UMR_S 1085, 35000, Rennes, France.,Department of Internal Medicine, Rennes University Hospital, 35000, Rennes, France
| | - Alain Lescoat
- Univ Rennes, CHU Rennes, INSERM, EHESP, IRSET (Institut de recherche en santé, environnement et travail) - UMR_S 1085, 35000, Rennes, France.,Department of Internal Medicine, Rennes University Hospital, 35000, Rennes, France
| | - Yu Augagneur
- Univ Rennes, CHU Rennes, INSERM, EHESP, IRSET (Institut de recherche en santé, environnement et travail) - UMR_S 1085, 35000, Rennes, France
| | - Marie Lelong
- Univ Rennes, CHU Rennes, INSERM, EHESP, IRSET (Institut de recherche en santé, environnement et travail) - UMR_S 1085, 35000, Rennes, France
| | - Claudie Morzadec
- Univ Rennes, CHU Rennes, INSERM, EHESP, IRSET (Institut de recherche en santé, environnement et travail) - UMR_S 1085, 35000, Rennes, France
| | - Claire Cazalets
- Department of Internal Medicine, Rennes University Hospital, 35000, Rennes, France
| | - Stéphane Jouneau
- Univ Rennes, CHU Rennes, INSERM, EHESP, IRSET (Institut de recherche en santé, environnement et travail) - UMR_S 1085, 35000, Rennes, France.,Department of Respiratory Diseases, Rennes University Hospital, 35000, Rennes, France
| | - Olivier Fardel
- Univ Rennes, CHU Rennes, INSERM, EHESP, IRSET (Institut de recherche en santé, environnement et travail) - UMR_S 1085, 35000, Rennes, France.,Pôle Biologie, Rennes University Hospital, 35033, Rennes, France
| | - Laurent Vernhet
- Univ Rennes, CHU Rennes, INSERM, EHESP, IRSET (Institut de recherche en santé, environnement et travail) - UMR_S 1085, 35000, Rennes, France
| | - Patrick Jégo
- Univ Rennes, CHU Rennes, INSERM, EHESP, IRSET (Institut de recherche en santé, environnement et travail) - UMR_S 1085, 35000, Rennes, France.,Department of Internal Medicine, Rennes University Hospital, 35000, Rennes, France
| | - Valérie Lecureur
- Univ Rennes, CHU Rennes, INSERM, EHESP, IRSET (Institut de recherche en santé, environnement et travail) - UMR_S 1085, 35000, Rennes, France
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Veremeyko T, Yung AWY, Anthony DC, Strekalova T, Ponomarev ED. Early Growth Response Gene-2 Is Essential for M1 and M2 Macrophage Activation and Plasticity by Modulation of the Transcription Factor CEBPβ. Front Immunol 2018; 9:2515. [PMID: 30443252 PMCID: PMC6221966 DOI: 10.3389/fimmu.2018.02515] [Citation(s) in RCA: 65] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2018] [Accepted: 10/11/2018] [Indexed: 12/24/2022] Open
Abstract
The process of macrophage polarization is involved in many pathologies such as anti-cancer immunity and autoimmune diseases. Polarized macrophages exhibit various levels of plasticity when M2/M(IL-4) macrophages are reprogrammed into an M1-like phenotype following treatment with IFNγ and/or LPS. At the same time, M1 macrophages are resistant to reprogramming in the presence of M2-like stimuli. The molecular mechanisms responsible for the macrophages polarization, plasticity of M2 macrophages, and lack of plasticity in M1 macrophages remain unknown. Here, we explored the role of Egr2 in the induction and maintenance of macrophage M1 and M2 polarization in the mouse in vitro and in vivo models of inflammation. Egr2 knockdown with siRNA treatment fail to upregulate either M1 or M2 markers upon stimulation, and the overexpression of Egr2 potentiated M1 or M2 marker expression following polarization. Polarisation with M2-like stimuli (IL-4 or IL-13) results in increased Egr2 expression, but macrophages stimulated with M1-like stimuli (IFNγ, LPS, IL-6, or TNF) exhibit a decrease in Egr2 expression. Egr2 was critical for the expression of transcription factors CEBPβ and PPARγ in M2 macrophages, and CEBPβ was highly expressed in M1-polarized macrophages. In siRNA knockdown studies the transcription factor CEBPβ was found to negatively regulate Egr2 expression and is likely to be responsible for the maintenance of the M1-like phenotype and lack plasticity. During thioglycolate-induced peritonitis, adoptively transferred macrophages with Egr2 knockdown failed to become activated as determined by upregulation of MHC class II and CD86. Thus, our study indicates that Egr2 expression is associated with the ability of unstimulated or M2 macrophages to respond to stimulation with inflammatory stimuli, while low levels of Egr2 expression is associated with non-responsiveness of macrophages to their activation.
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Affiliation(s)
- Tatyana Veremeyko
- Faculty of Medicine, School of Biomedical Sciences, The Chinese University of Hong Kong, Shatin, Hong Kong
| | - Amanda W Y Yung
- Faculty of Medicine, School of Biomedical Sciences, The Chinese University of Hong Kong, Shatin, Hong Kong
| | - Daniel C Anthony
- Department of Pharmacology, University of Oxford, Oxford, United Kingdom
| | - Tatyana Strekalova
- Department of Neuroscience, Maastricht University, Maastricht, Netherlands.,Institute of General Pathology and Pathophysiology, Moscow, Russia.,Laboratory of Psychiatric Neurobiology, Institute of Molecular Medicine and Department of Normal Physiology, Sechenov First Moscow State Medical University, Moscow, Russia
| | - Eugene D Ponomarev
- Faculty of Medicine, School of Biomedical Sciences, The Chinese University of Hong Kong, Shatin, Hong Kong.,Kunming Institute of Zoology-Chinese University of Hong Kong Joint Laboratory of Bioresources and Molecular Research of Common Diseases, Kunming, China
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Yu S, Ding L, Liang D, Luo L. Porphyromonas gingivalisinhibits M2 activation of macrophages by suppressing α-ketoglutarate production in mice. Mol Oral Microbiol 2018; 33:388-395. [PMID: 30007055 DOI: 10.1111/omi.12241] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/12/2018] [Indexed: 12/26/2022]
Affiliation(s)
- S. Yu
- School of Stomatology; Weifang Medical University; Weifang China
- Clinical Research Center; Shanghai Jiading Central Hospital; Shanghai China
| | - L. Ding
- School of Stomatology; Weifang Medical University; Weifang China
- Clinical Research Center; Shanghai Jiading Central Hospital; Shanghai China
| | - D. Liang
- Clinical Research Center; Shanghai Jiading Central Hospital; Shanghai China
| | - L. Luo
- Department of Periodontics; The Affiliated Stomatology Hospital; Tongji University; Shanghai China
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Schaefer L. Decoding fibrosis: Mechanisms and translational aspects. Matrix Biol 2018; 68-69:1-7. [PMID: 29679639 DOI: 10.1016/j.matbio.2018.04.009] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2018] [Accepted: 04/17/2018] [Indexed: 12/17/2022]
Abstract
Fibrosis, a complex process of abnormal tissue healing which inevitably leads to loss of physiological organ structure and function, is a worldwide leading cause of death. Despite a large body of research over the last two decades, antifibrotic approaches are mainly limited to organ replacement therapy generating high costs of medical care. In this translational issue, a unique group of basic and clinical researchers provide meaningful answers to a desperate call of society for effective antifibrotic treatments. Fortunately, a plethora of novel fibrogenic factors and biomarkers has been identified. Noninvasive diagnostic methods and drug delivery systems have been recently developed for the management of fibrosis. Consequently, a large number of exciting clinical trials addressing comprehensive, organ and stage-specific mechanisms of fibrogenesis are ongoing. By critically addressing previously unsuccessful and novel promising therapeutic strategies, we aim to spread hope for future treatments of the various forms of organ fibrosis.
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Affiliation(s)
- Liliana Schaefer
- Pharmazentrum Frankfurt, Institut für Allgemeine Pharmakologie und Toxikologie, Klinikum der Goethe-Universität Frankfurt am Main, Frankfurt am Main 60590, Germany.
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