|
1
|
Huang S, Shi J, Shen J, Fan X. Metabolic reprogramming of neutrophils in the tumor microenvironment: Emerging therapeutic targets. Cancer Lett 2025; 612:217466. [PMID: 39862916 DOI: 10.1016/j.canlet.2025.217466] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2024] [Revised: 01/12/2025] [Accepted: 01/13/2025] [Indexed: 01/27/2025]
Abstract
Neutrophils are pivotal in the immune system and have been recognized as significant contributors to cancer development and progression. These cells undergo metabolic reprogramming in response to various stimulus, including infections, diseases, and the tumor microenvironment (TME). Under normal conditions, neutrophils primarily rely on aerobic glucose metabolism for energy production. However, within the TME featured by hypoxic and nutrient-deprived conditions, they shift to altered anaerobic glycolysis, lipid metabolism, mitochondrial metabolism and amino acid metabolism to perform their immunosuppressive functions and facilitate tumor progression. Targeting neutrophils within the TME is a promising therapeutic approach. Yet, focusing on their metabolic pathways presents a novel strategy to enhance cancer immunotherapy. This review synthesizes the current understanding of neutrophil metabolic reprogramming in the TME, with an emphasis on the underlying molecular mechanisms and signaling pathways. Studying neutrophil metabolism in the TME poses challenges, such as their short lifespan and the metabolic complexity of the environment, necessitating the development of advanced research methodologies. This review also discusses emerging solutions to these challenges. In conclusion, given their integral role in the TME, targeting the metabolic pathways of neutrophils could offer a promising avenue for cancer therapy.
Collapse
Affiliation(s)
- Shiyun Huang
- Department of Ophthalmology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China; Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, 200025, China.
| | - Jiahao Shi
- Department of Ophthalmology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China; Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, 200025, China.
| | - Jianfeng Shen
- Department of Ophthalmology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China; Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, 200025, China.
| | - Xianqun Fan
- Department of Ophthalmology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China; Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, 200025, China.
| |
Collapse
|
|
2
|
Yu K, Wang Y, Yu C, Han L, Li K, Miao K, Ni L, Wen Z, Chen C, Rao X, Wang DW, Zhou L, Zhao C. Regulatory effect of rapamycin on recruitment and function of myeloid-derived suppressor cells in heart failure. Int Immunopharmacol 2024; 141:112965. [PMID: 39186836 DOI: 10.1016/j.intimp.2024.112965] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2024] [Revised: 07/30/2024] [Accepted: 08/15/2024] [Indexed: 08/28/2024]
Abstract
BACKGROUND Immune response and inflammation play important roles in the physiological and pathophysiological processes of heart failure (HF). In our previous study, myeloid-derived suppressor cells (MDSCs), a heterogeneous group of immature myeloid cells with anti-inflammatory and immunosuppressive functions, were shown to exert cardioprotective effects in HF. The pharmacological targeting of MDSCs using rapamycin may emerge as a promising strategy for the prevention and treatment of HF. However, the specific mechanisms underlying rapamycin-induced MDSC accumulation remain unclear. Our study aimed to clarify the effects of rapamycin on the recruitment and function of MDSCs in HF, exploring new therapeutic options for the prevention and treatment of HF. METHODS We used transverse aortic constriction surgery and isoproterenol injection to establish HF models. Flow cytometry, reverse transcription polymerase chain reaction, transcriptomics and western blot were used to explore the regulation of rapamycin on recruitment and function of MDSCs in HF. Furthermore, rapamycin and granulocyte-macrophage colony-stimulating factor (GM-CSF) were combined to induce exogenous MDSCs from bone marrow cells. RESULTS Rapamycin promotes the recruitment of MDSCs by inhibiting their maturation and differentiation via suppression of the Wnt signaling in HF mice and enhanced the immunosuppressive function of MDSCs via the NF-κB signaling. Furthermore, exogenous MDSCs induced by rapamycin and GM-CSF can significantly alleviate transverse aortic constriction-induced cardiac dysfunction. CONCLUSIONS The pharmacological targeting of MDSCs using rapamycin is a promising strategy for the prevention and treatment of HF.
Collapse
Affiliation(s)
- Kun Yu
- Division of Cardiology, Departments of Internal Medicine and Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Yinhui Wang
- Division of Cardiology, Departments of Internal Medicine and Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Chengxin Yu
- GI Cancer Research Institute, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Liang Han
- Department of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, TongJi Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Ke Li
- Division of Cardiology, Departments of Internal Medicine and Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Kun Miao
- Division of Cardiology, Departments of Internal Medicine and Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Li Ni
- Division of Cardiology, Departments of Internal Medicine and Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Zheng Wen
- Division of Cardiology, Departments of Internal Medicine and Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Chen Chen
- Division of Cardiology, Departments of Internal Medicine and Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Xiaoquan Rao
- Division of Cardiology, Departments of Internal Medicine and Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Dao Wen Wang
- Division of Cardiology, Departments of Internal Medicine and Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Ling Zhou
- Division of Cardiology, Departments of Internal Medicine and Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
| | - Chunxia Zhao
- Division of Cardiology, Departments of Internal Medicine and Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
| |
Collapse
|
|
3
|
Ren Y, Dong X, Liu Y, Kang H, Guan L, Huang Y, Zhu X, Tian J, Chen B, Jiang B, He Y. Rapamycin antagonizes angiogenesis and lymphangiogenesis through myeloid-derived suppressor cells in corneal transplantation. Am J Transplant 2023; 23:1359-1374. [PMID: 37225089 DOI: 10.1016/j.ajt.2023.05.017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2022] [Revised: 04/22/2023] [Accepted: 05/18/2023] [Indexed: 05/26/2023]
Abstract
Rapamycin is an immunosuppressive drug that is widely used in the postsurgery management of transplantation. To date, the mechanism by which rapamycin reduces posttransplant neovascularization has not been fully understood. Given the original avascularity and immune privilege of the cornea, corneal transplantation is considered as an ideal model to investigate neovascularization and its effects on allograft rejection. Previously, we found that myeloid-derived suppressor cells (MDSC) prolong corneal allograft survival through suppression of angiogenesis and lymphangiogenesis. Here, we show that depletion of MDSC abolished rapamycin-mediated suppression of neovascularization and elongation of corneal allograft survival. RNA-sequencing analysis revealed that rapamycin dramatically enhanced the expression of arginase 1 (Arg1). Furthermore, an Arg1 inhibitor also completely abolished the rapamycin-mediated beneficial effects after corneal transplantation. Taken together, these findings indicate that MDSC and elevated Arg1 activity are essential for the immunosuppressive and antiangiogenic functions of rapamycin.
Collapse
Affiliation(s)
- Yuerong Ren
- Department of Ophthalmology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China; Hunan Clinical Research Center of Ophthalmic Disease, Changsha, Hunan, China
| | - Xiaonan Dong
- State Key Laboratory of Respiratory Disease, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, Guangdong 510120, China; Guangzhou National Laboratory, Guangzhou, Guangdong 510005, China
| | - Yingyi Liu
- Department of Ophthalmology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China; Hunan Clinical Research Center of Ophthalmic Disease, Changsha, Hunan, China
| | - Huanmin Kang
- Department of Ophthalmology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China; Hunan Clinical Research Center of Ophthalmic Disease, Changsha, Hunan, China
| | - Lingling Guan
- State Key Laboratory of Respiratory Disease, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, Guangdong 510120, China; Guangzhou National Laboratory, Guangzhou, Guangdong 510005, China
| | - Yumin Huang
- Guangzhou National Laboratory, Guangzhou, Guangdong 510005, China
| | - Xinqi Zhu
- Guangzhou National Laboratory, Guangzhou, Guangdong 510005, China
| | - Jing Tian
- Department of Rheumatology and Immunology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Baihua Chen
- Department of Ophthalmology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China; Hunan Clinical Research Center of Ophthalmic Disease, Changsha, Hunan, China
| | - Bing Jiang
- Department of Ophthalmology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China; Hunan Clinical Research Center of Ophthalmic Disease, Changsha, Hunan, China
| | - Yan He
- Department of Ophthalmology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China; Hunan Clinical Research Center of Ophthalmic Disease, Changsha, Hunan, China.
| |
Collapse
|
|
4
|
Ahmadi M, Ali-Hassanzadeh M, Hosseini MS, Gharesi-Fard B. In vitro-Generated MDSCs Reduce the Pregnancy Complications in an Abortion-Prone Murine Model. Reprod Sci 2023; 30:1217-1228. [PMID: 35851683 DOI: 10.1007/s43032-022-00995-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2022] [Accepted: 05/31/2022] [Indexed: 11/27/2022]
Abstract
Recurrent spontaneous abortion (RSA) is one of the major pregnancy-related complications. The roles of different immune cells have been studied in pregnancy complications. The current study aimed to investigate myeloid-derived suppressor cells (MDSCs) in a murine abortion model and introduce a therapeutic approach by using in vitro-generated MDSCs in this model. CBA/J × DBA/2 (abortion prone) and CBA/J × Balb/C (normal pregnancy) mice were used. The frequency of granulocytic MDSCs, monocytic MDSCs, and Tregs was checked in the bone marrow and uteroplacental tissue of mice on three gestational days (gd9.5, gd13.5, and gd17.5) using the flow cytometry approach. MDSCs were generated in vitro from bone marrow-isolated cells using GM-CSF and IL-6 cytokines. Abortion-prone mice were injected intravenously with in vitro-generated MDSCs at gd0.5, and pregnancy outcomes were recorded in treated mice. The frequency of G-MDSCs and M-MDSCs in the bone marrow of abortion-prone mice was decreased at gd9.5 (p = 0.026 and p = 0.05, respectively). In uteroplacental tissue, the frequency of G-MDSCs was significantly lower at gd9.5 and gd13.5 (p = 0.001, p = 0.029, respectively), while M-MDSCs only showed decreased number at gd9.5 (p = 0.05) in abortion-prone mice. Injection of in vitro-generated MDSCs resulted in the increased fetus and placenta weights (p = 0.049 and p = 0.012, respectively) but showed no effect on the number of live fetuses and abortion rate. The reduced frequency of both G-MDSCs and M-MDSCs in the bone marrow and at the feto-maternal interface is associated with pregnancy complications. In vitro-generated MDSCs could be considered as a potential approach to reduce these complications.
Collapse
Affiliation(s)
- Moslem Ahmadi
- Department of Immunology, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Mohammad Ali-Hassanzadeh
- Department of Immunology, School of Medicine, Jiroft University of Medical Sciences, Jiroft, Iran
| | | | - Behrouz Gharesi-Fard
- Department of Immunology, Shiraz University of Medical Sciences, Shiraz, Iran.
- Infertility Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.
| |
Collapse
|
|
5
|
Tan L, Shi G, Zhao J, Xia X, Li D, Wang S, Liang J, Hou Y, Dou H. MDSCs participate in the pathogenesis of diffuse pulmonary hemorrhage in murine lupus through mTOR-FoxO1 signaling. Biochem Biophys Rep 2022; 32:101351. [PMID: 36164563 PMCID: PMC9507990 DOI: 10.1016/j.bbrep.2022.101351] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2022] [Revised: 09/14/2022] [Accepted: 09/15/2022] [Indexed: 11/29/2022] Open
Affiliation(s)
- Liping Tan
- The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology, Medical School, Nanjing University, Nanjing, 210093, PR China
- Jiangsu Key Laboratory of Molecular Medicine, Nanjing, 210093, PR China
| | - Guoping Shi
- The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology, Medical School, Nanjing University, Nanjing, 210093, PR China
- Jiangsu Key Laboratory of Molecular Medicine, Nanjing, 210093, PR China
| | - Junyu Zhao
- The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology, Medical School, Nanjing University, Nanjing, 210093, PR China
- Jiangsu Key Laboratory of Molecular Medicine, Nanjing, 210093, PR China
| | - Xiaoyu Xia
- The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology, Medical School, Nanjing University, Nanjing, 210093, PR China
- Jiangsu Key Laboratory of Molecular Medicine, Nanjing, 210093, PR China
| | - Dan Li
- The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology, Medical School, Nanjing University, Nanjing, 210093, PR China
- Jiangsu Key Laboratory of Molecular Medicine, Nanjing, 210093, PR China
| | - Saiwen Wang
- The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology, Medical School, Nanjing University, Nanjing, 210093, PR China
- Jiangsu Key Laboratory of Molecular Medicine, Nanjing, 210093, PR China
| | - Jun Liang
- Department of Rheumatology and Immunology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, 210008, PR China
| | - Yayi Hou
- The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology, Medical School, Nanjing University, Nanjing, 210093, PR China
- Jiangsu Key Laboratory of Molecular Medicine, Nanjing, 210093, PR China
- Corresponding author. The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology, Medical School, Nanjing University, Nanjing, 210093, PR China.
| | - Huan Dou
- The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology, Medical School, Nanjing University, Nanjing, 210093, PR China
- Jiangsu Key Laboratory of Molecular Medicine, Nanjing, 210093, PR China
- Corresponding author. The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology, Medical School, Nanjing University, Nanjing, 210093, PR China.
| |
Collapse
|
|
6
|
van Geffen C, Heiss C, Deißler A, Kolahian S. Pharmacological modulation of myeloid-derived suppressor cells to dampen inflammation. Front Immunol 2022; 13:933847. [PMID: 36110844 PMCID: PMC9468781 DOI: 10.3389/fimmu.2022.933847] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2022] [Accepted: 07/26/2022] [Indexed: 11/13/2022] Open
Abstract
Myeloid-derived suppressor cells (MDSCs) are a heterogeneous cell population with potent suppressive and regulative properties. MDSCs’ strong immunosuppressive potential creates new possibilities to treat chronic inflammation and autoimmune diseases or induce tolerance towards transplantation. Here, we summarize and critically discuss different pharmacological approaches which modulate the generation, activation, and recruitment of MDSCs in vitro and in vivo, and their potential role in future immunosuppressive therapy.
Collapse
|
|
7
|
Dual mTORC1/2 inhibitor AZD2014 diminishes myeloid-derived suppressor cells accumulation in ovarian cancer and delays tumor growth. Cancer Lett 2021; 523:72-81. [PMID: 34560229 DOI: 10.1016/j.canlet.2021.09.017] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2021] [Revised: 09/04/2021] [Accepted: 09/09/2021] [Indexed: 02/08/2023]
Abstract
Mechanistic target of rapamycin (mTOR) forms two distinct complexes, mTOR complex 1 (mTORC1) and mTORC2. Here we investigated the antitumor effect of dual mTORC1/2 inhibitor AZD2014 on epithelial ovarian cancer (EOC) and its potential effect on immunosuppressive myeloid-derived suppressor cells (MDSCs). Immunohistochemical analysis of mTORC1 and mTORC2 was performed on a human ovarian cancer tissue microarray. High mTORC2 expression level was associated with shorter survival in EOC, whereas mTORC1 was not correlate with patients' prognosis. AZD2014 suppressed mTOR signaling pathway in ovarian cancer cells, inhibited proliferation and induced G1-phase cell cycle arrest and apoptosis. In tumor-bearing mice, AZD2014 treatment limited tumor growth, reduced peritoneal ascites, and prolonged survival. AZD2014 specifically reduced MDSCs migration and accumulation in EOC peritoneal fluid but not in the spleen. Moreover, subsequent AZD2014 treatment after cisplatin chemotherapy delayed EOC recurrence. Collectively, we observed that high mTORC2 expression level in EOC indicated a poor prognosis. Remarkably, in tumor-bearing mice, AZD2014 diminished MDSC accumulation and delayed tumor growth and recurrence.
Collapse
|
|
8
|
Li X, Li Y, Yu Q, Xu L, Fu S, Wei C, Wang L, Luo Y, Shi J, Qian P, Huang H, Lin Y. mTOR Signaling Regulates the Development and Therapeutic Efficacy of PMN-MDSCs in Acute GVHD. Front Cell Dev Biol 2021; 9:741911. [PMID: 35004668 PMCID: PMC8733691 DOI: 10.3389/fcell.2021.741911] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2021] [Accepted: 11/19/2021] [Indexed: 12/13/2022] Open
Abstract
Myeloid-derived suppressor cells (MDSCs) represent a population of heterogeneous myeloid cells, which are characterized by their remarkable ability to suppress T cells and natural killer cells. MDSCs have been proven to play a positive role in protecting acute graft-versus-host disease (aGVHD). Here, we aimed to describe the mechanism behind how mTOR signaling regulates MDSCs' generation and explore its prophylactic and therapeutic potential in aGVHD. Reducing mTOR expression retains myeloid cells with immature characteristics and promotes polymorphonuclear MDSC (PMN-MDSC) immunosuppressive function through STAT3-C/EBPβ pathway. Prophylactic transfusion of mTORKO PMN-MDSCs could alleviate aGVHD while maintaining the graft-versus-leukemia (GVL) effect, which could downregulate the Th1/Th2 ratio, decrease serum proinflammatory cytokines, and increase the proportion of regulatory T cells (Tregs) in aGVHD models at the early stage after transplantation. Moreover, transfusion therapy could promote the reconstruction and function of donor-derived PMN-MDSCs. Not only the percentage and the absolute number of donor-derived PMN-MDSCs significantly increased but also the immunosuppressive ability was much more robust compared to other groups. Altogether, these findings indicated that mTOR is an intrinsic regulator for PMN-MDSCs' differentiation and immunosuppressive function. Together, mTORKO PMN-MDSC transfusion can play a protective role in alleviating cytokine storm at the initial stage and promoting the quantitative and functional recoveries of donor-derived PMN-MDSCs in aGVHD.
Collapse
Affiliation(s)
- Xiaoqing Li
- Bone Marrow Transplantation Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou, China
- Zhejiang Province Engineering Laboratory for Stem Cell and Immunity Therapy, Hangzhou, China
- Institute of Hematology, Zhejiang University, Hangzhou, China
| | - Yixue Li
- Bone Marrow Transplantation Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou, China
- Zhejiang Province Engineering Laboratory for Stem Cell and Immunity Therapy, Hangzhou, China
- Institute of Hematology, Zhejiang University, Hangzhou, China
| | - Qinru Yu
- Bone Marrow Transplantation Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou, China
- Zhejiang Province Engineering Laboratory for Stem Cell and Immunity Therapy, Hangzhou, China
- Institute of Hematology, Zhejiang University, Hangzhou, China
| | - Lin Xu
- Bone Marrow Transplantation Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou, China
- Zhejiang Province Engineering Laboratory for Stem Cell and Immunity Therapy, Hangzhou, China
- Institute of Hematology, Zhejiang University, Hangzhou, China
| | - Shan Fu
- Bone Marrow Transplantation Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou, China
- Zhejiang Province Engineering Laboratory for Stem Cell and Immunity Therapy, Hangzhou, China
- Institute of Hematology, Zhejiang University, Hangzhou, China
| | - Cong Wei
- Bone Marrow Transplantation Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou, China
- Zhejiang Province Engineering Laboratory for Stem Cell and Immunity Therapy, Hangzhou, China
- Institute of Hematology, Zhejiang University, Hangzhou, China
| | - Limengmeng Wang
- Bone Marrow Transplantation Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou, China
- Zhejiang Province Engineering Laboratory for Stem Cell and Immunity Therapy, Hangzhou, China
- Institute of Hematology, Zhejiang University, Hangzhou, China
| | - Yi Luo
- Bone Marrow Transplantation Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou, China
- Zhejiang Province Engineering Laboratory for Stem Cell and Immunity Therapy, Hangzhou, China
- Institute of Hematology, Zhejiang University, Hangzhou, China
| | - Jimin Shi
- Bone Marrow Transplantation Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou, China
- Zhejiang Province Engineering Laboratory for Stem Cell and Immunity Therapy, Hangzhou, China
- Institute of Hematology, Zhejiang University, Hangzhou, China
| | - Pengxu Qian
- Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou, China
- Zhejiang Province Engineering Laboratory for Stem Cell and Immunity Therapy, Hangzhou, China
- Institute of Hematology, Zhejiang University, Hangzhou, China
| | - He Huang
- Bone Marrow Transplantation Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou, China
- Zhejiang Province Engineering Laboratory for Stem Cell and Immunity Therapy, Hangzhou, China
- Institute of Hematology, Zhejiang University, Hangzhou, China
| | - Yu Lin
- Bone Marrow Transplantation Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou, China
- Zhejiang Province Engineering Laboratory for Stem Cell and Immunity Therapy, Hangzhou, China
- Institute of Hematology, Zhejiang University, Hangzhou, China
| |
Collapse
|
|
9
|
Fu H, Liu X, Jin L, Lang J, Hu Z, Mao W, Cheng C, Shou Q. Safflower yellow reduces DEN-induced hepatocellular carcinoma by enhancing liver immune infiltration through promotion of collagen degradation and modulation of gut microbiota. Food Funct 2021; 12:10632-10643. [PMID: 34585698 DOI: 10.1039/d1fo01321a] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Safflower yellow (SY) is the main active ingredient isolated from the traditional Chinese medicine Carthamus tinctorius, which is a valuable natural edible pigment that is widely used to treat cerebrovascular and cardiovascular diseases. However, the effect of SY on hepatocellular carcinoma (HCC) remains unclear. In this study, we showed that SY decreased the degree of injury and inhibited the release of inflammatory factors in the liver of a diethylnitrosamine (DEN)-induced HCC mouse model. Flow cytometry and immunoblotting showed that SY increased the infiltration of CD8+ T cells and Gr-1+ macrophages to improve the immune microenvironment by affecting the expression of collagen fibers. Further cellular experiments showed that SY degraded the collagens in the liver cells through the TGF-β/Smad signalling pathway. SY also regulated the gut microbiota which may contribute to the immune microenvironment. In conclusion, SY exhibited a potent effect on the development of HCC by enhancing liver immune infiltration by promoting collagen degradation and modulating the gut microbiota. This study provides novel insights into the mechanism of SY as a candidate for the treatment of HCC in the future.
Collapse
Affiliation(s)
- Huiying Fu
- Affiliated Secondary Hospital, Zhejiang Chinese Medical University, Hangzhou, China. .,Zhejiang Provincial Key Laboratory of Sexual Function of Integrated Traditional Chinese and Western Medicine, Hangzhou 310053, PR China
| | - Xia Liu
- Affiliated Secondary Hospital, Zhejiang Chinese Medical University, Hangzhou, China. .,Zhejiang Provincial Key Laboratory of Sexual Function of Integrated Traditional Chinese and Western Medicine, Hangzhou 310053, PR China
| | - Lu Jin
- Affiliated Secondary Hospital, Zhejiang Chinese Medical University, Hangzhou, China. .,Zhejiang Provincial Key Laboratory of Sexual Function of Integrated Traditional Chinese and Western Medicine, Hangzhou 310053, PR China
| | - Jiali Lang
- Affiliated Secondary Hospital, Zhejiang Chinese Medical University, Hangzhou, China.
| | - Zhiming Hu
- Department of Hepatobiliary and Pancreatic Surgery, Zhejiang Provincial People's Hospital, Hangzhou, China.
| | - Wen Mao
- Affiliated Secondary Hospital, Zhejiang Chinese Medical University, Hangzhou, China.
| | - Changpei Cheng
- First Clinical Medical College, Guizhou University of Traditional Chinese Medicine, Guiyang, China
| | - Qiyang Shou
- Affiliated Secondary Hospital, Zhejiang Chinese Medical University, Hangzhou, China. .,Zhejiang Provincial Key Laboratory of Sexual Function of Integrated Traditional Chinese and Western Medicine, Hangzhou 310053, PR China
| |
Collapse
|
|
10
|
The kinase AKT1 potentiates the suppressive functions of myeloid-derived suppressor cells in inflammation and cancer. Cell Mol Immunol 2021; 18:1074-1076. [PMID: 33462382 DOI: 10.1038/s41423-020-00610-7] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2020] [Accepted: 11/26/2020] [Indexed: 11/08/2022] Open
|
|
11
|
Dong L, He Y, Cao Y, Wang Y, Jia A, Wang Y, Yang Q, Li W, Bi Y, Liu G. Functional differentiation and regulation of follicular T helper cells in inflammation and autoimmunity. Immunology 2020; 163:19-32. [PMID: 33128768 DOI: 10.1111/imm.13282] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2020] [Revised: 10/16/2020] [Accepted: 10/21/2020] [Indexed: 12/12/2022] Open
Abstract
Follicular T helper (TFH ) cells are specialized T cells that support B cells, which are essential for humoral immunity. TFH cells express the transcription factor B-cell lymphoma 6 (Bcl-6), chemokine (C-X-C motif) receptor (CXCR) 5, the surface receptors programmed cell death protein 1 (PD-1) and inducible T-cell costimulator (ICOS), the cytokine IL-21 and other molecules. The activation, proliferation and differentiation of TFH cells are closely related to dynamic changes in cellular metabolism. In this review, we summarize the progress made in understanding the development and functional differentiation of TFH cells. Specifically, we focus on the regulatory mechanisms of TFH cell functional differentiation, including regulatory signalling pathways and the metabolic regulatory mechanisms of TFH cells. In addition, TFH cells are closely related to immune-associated diseases, including infections, autoimmune diseases and cancers.
Collapse
Affiliation(s)
- Lin Dong
- Key Laboratory of Cell Proliferation and Regulation Biology, Ministry of Education, Institute of Cell Biology, College of Life Sciences, Beijing Normal University, Beijing, China
| | - Ying He
- Key Laboratory of Cell Proliferation and Regulation Biology, Ministry of Education, Institute of Cell Biology, College of Life Sciences, Beijing Normal University, Beijing, China
| | - Yejin Cao
- Key Laboratory of Cell Proliferation and Regulation Biology, Ministry of Education, Institute of Cell Biology, College of Life Sciences, Beijing Normal University, Beijing, China
| | - Yuexin Wang
- Key Laboratory of Cell Proliferation and Regulation Biology, Ministry of Education, Institute of Cell Biology, College of Life Sciences, Beijing Normal University, Beijing, China
| | - Anna Jia
- Key Laboratory of Cell Proliferation and Regulation Biology, Ministry of Education, Institute of Cell Biology, College of Life Sciences, Beijing Normal University, Beijing, China
| | - Yufei Wang
- Key Laboratory of Cell Proliferation and Regulation Biology, Ministry of Education, Institute of Cell Biology, College of Life Sciences, Beijing Normal University, Beijing, China
| | - Qiuli Yang
- Key Laboratory of Cell Proliferation and Regulation Biology, Ministry of Education, Institute of Cell Biology, College of Life Sciences, Beijing Normal University, Beijing, China
| | - Wanjie Li
- Key Laboratory of Cell Proliferation and Regulation Biology, Ministry of Education, Institute of Cell Biology, College of Life Sciences, Beijing Normal University, Beijing, China
| | - Yujing Bi
- State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing, China
| | - Guangwei Liu
- Key Laboratory of Cell Proliferation and Regulation Biology, Ministry of Education, Institute of Cell Biology, College of Life Sciences, Beijing Normal University, Beijing, China
| |
Collapse
|
|
12
|
Yang X, Lu Y, Hang J, Zhang J, Zhang T, Huo Y, Liu J, Lai S, Luo D, Wang L, Hua R, Lin Y. Lactate-Modulated Immunosuppression of Myeloid-Derived Suppressor Cells Contributes to the Radioresistance of Pancreatic Cancer. Cancer Immunol Res 2020; 8:1440-1451. [PMID: 32917658 DOI: 10.1158/2326-6066.cir-20-0111] [Citation(s) in RCA: 155] [Impact Index Per Article: 31.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2020] [Revised: 06/11/2020] [Accepted: 09/04/2020] [Indexed: 11/16/2022]
Abstract
The mechanisms responsible for radioresistance in pancreatic cancer have yet to be elucidated, and the suppressive tumor immune microenvironment must be considered. We investigated whether the radiotherapy-augmented Warburg effect helped myeloid cells acquire an immunosuppressive phenotype, resulting in limited treatment efficacy of pancreatic ductal adenocarcinoma (PDAC). Radiotherapy enhanced the tumor-promoting activity of myeloid-derived suppressor cells (MDSC) in pancreatic cancer. Sustained increase in lactate secretion, resulting from the radiation-augmented Warburg effect, was responsible for the enhanced immunosuppressive phenotype of MDSCs after radiotherapy. Hypoxia-inducible factor-1α (HIF-1α) was essential for tumor cell metabolism and lactate-regulated activation of MDSCs via the G protein-coupled receptor 81 (GPR81)/mTOR/HIF-1α/STAT3 pathway. Blocking lactate production in tumor cells or deleting Hif-1α in MDSCs reverted antitumor T-cell responses and effectively inhibited tumor progression after radiotherapy in pancreatic cancer. Our investigation highlighted the importance of radiation-induced lactate in regulating the inhibitory immune microenvironment of PDAC. Targeting lactate derived from tumor cells and the HIF-1α signaling in MDSCs may hold distinct promise for clinical therapies to alleviate radioresistance in PDAC.
Collapse
Affiliation(s)
- Xuguang Yang
- Cancer Institute, Department of Oncology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai, China
- Department of Oncology, Shanghai Cancer Institute, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Yun Lu
- Cancer Institute, Department of Oncology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Junjie Hang
- Department of Oncology, Changzhou No.2 People's Hospital, Nanjing Medical University, Changzhou, China
| | - Junfeng Zhang
- Department of Biliary-Pancreatic Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Tiening Zhang
- Oncology Center, Shanghai General Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Yanmiao Huo
- Department of Biliary-Pancreatic Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Jun Liu
- Oncology Center, Shanghai General Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Songtao Lai
- Department of Radiation Oncology, Shanghai Cancer Center, Shanghai Medical College, Fudan University, Shanghai, China
| | - Dawei Luo
- Oncology Center, Shanghai General Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Liwei Wang
- Department of Oncology, Shanghai Cancer Institute, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
| | - Rong Hua
- Department of Biliary-Pancreatic Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
| | - Yuli Lin
- Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai, China.
| |
Collapse
|
|
13
|
Scheurer J, Reisser T, Leithäuser F, Messmann JJ, Holzmann K, Debatin KM, Strauss G. Rapamycin-based graft-versus-host disease prophylaxis increases the immunosuppressivity of myeloid-derived suppressor cells without affecting T cells and anti-tumor cytotoxicity. Clin Exp Immunol 2020; 202:407-422. [PMID: 32681646 PMCID: PMC7670162 DOI: 10.1111/cei.13496] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2020] [Revised: 06/30/2020] [Accepted: 07/07/2020] [Indexed: 12/16/2022] Open
Abstract
The immunosuppressant rapamycin (RAPA) inhibits mammalian target of rapamycin (mTOR) functions and is applied after allogeneic bone marrow transplantation (BMT) to attenuate the development of graft‐versus‐host disease (GVHD), although the cellular targets of RAPA treatment are not well defined. Allogeneic T cells are the main drivers of GVHD, while immunoregulatory myeloid‐derived suppressor cells (MDSCs) were recently identified as potent disease inhibitors. In this study, we analyzed whether RAPA prevents the deleterious effects of allogeneic T cells or supports the immunosuppressive functions of MDSCs in a BMT model with major histocompatibility complex (MHC) classes I and II disparities. RAPA treatment efficiently attenuated clinical and histological GVHD and strongly decreased disease‐induced mortality. Although splenocyte numbers increased during RAPA treatment, the ratio of effector T cells to MDSCs was unaltered. However, RAPA treatment induced massive changes in the genomic landscape of MDSCs preferentially up‐regulating genes responsible for uptake or signal transduction of lipopeptides and lipoproteins. Most importantly, MDSCs from RAPA‐treated mice exhibited increased immunosuppressive potential, which was primarily inducible nitric oxide synthase (iNOS)‐dependent. Surprisingly, RAPA treatment had no impact on the genomic landscape of T cells, which was reflected by unchanged expression of activation and exhaustion markers and cytokine profiles in T cells from RAPA‐treated and untreated mice. Similarly, T cell cytotoxicity and the graft‐versus‐tumor effect were maintained as co‐transplanted tumor cells were efficiently eradicated, indicating that the immunosuppressant RAPA might be an attractive approach to strengthen the immunosuppressive function of MDSCs without affecting T cell immunity.
Collapse
Affiliation(s)
- J Scheurer
- Department of Pediatrics and Adolescent Medicine, University Medical Center Ulm, Ulm, Germany
| | - T Reisser
- Department of Pediatrics and Adolescent Medicine, University Medical Center Ulm, Ulm, Germany
| | - F Leithäuser
- Institute of Pathology, University Ulm, Ulm, Germany
| | - J J Messmann
- Department of Pediatrics and Adolescent Medicine, University Medical Center Ulm, Ulm, Germany
| | - K Holzmann
- Genomic-Core Facility, University Ulm, Ulm, Germany
| | - K-M Debatin
- Department of Pediatrics and Adolescent Medicine, University Medical Center Ulm, Ulm, Germany
| | - G Strauss
- Department of Pediatrics and Adolescent Medicine, University Medical Center Ulm, Ulm, Germany
| |
Collapse
|
|
14
|
Yang T, Li J, Li R, Yang C, Zhang W, Qiu Y, Yang C, Rong R. Correlation between MDSC and Immune Tolerance in Transplantation: Cytokines, Pathways and Cell-cell Interaction. Curr Gene Ther 2020; 19:81-92. [PMID: 31237207 DOI: 10.2174/1566523219666190618093707] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2019] [Revised: 05/06/2019] [Accepted: 05/24/2019] [Indexed: 11/22/2022]
Abstract
MDSCs play an important role in the induction of immune tolerance. Cytokines and chemokines (GM-CSF, IL-6) contributed to the expansion, accumulation of MDSCs, and MDSCs function through iNOS, arginase and PD-L1. MDSCs are recruited and regulated through JAK/STAT, mTOR and Raf/MEK/ERK signaling pathways. MDSCs' immunosuppressive functions were realized through Tregs-mediated pathways and their direct suppression of immune cells. All of the above contribute to the MDSC-related immune tolerance in transplantation. MDSCs have huge potential in prolonging graft survival and reducing rejection through different ways and many other factors worthy to be further investigated are also introduced.
Collapse
Affiliation(s)
- Tianying Yang
- Department of Urology, ZhongShan Hospital, Fudan University, Shanghai, China.,Shanghai Key Laboratory of Organ Transplantation, Shanghai, China
| | - Jiawei Li
- Department of Urology, ZhongShan Hospital, Fudan University, Shanghai, China.,Shanghai Key Laboratory of Organ Transplantation, Shanghai, China
| | - Ruimin Li
- Shanghai Key Laboratory of Organ Transplantation, Shanghai, China.,Biomedical Research Center, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Chunchen Yang
- Department of Transfusion, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Weitao Zhang
- Department of Urology, ZhongShan Hospital, Fudan University, Shanghai, China.,Shanghai Key Laboratory of Organ Transplantation, Shanghai, China
| | - Yue Qiu
- Department of Critical Care Medicine, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Cheng Yang
- Department of Urology, ZhongShan Hospital, Fudan University, Shanghai, China.,Shanghai Key Laboratory of Organ Transplantation, Shanghai, China
| | - Ruiming Rong
- Department of Urology, ZhongShan Hospital, Fudan University, Shanghai, China.,Shanghai Key Laboratory of Organ Transplantation, Shanghai, China.,Department of Transfusion, Zhongshan Hospital, Fudan University, Shanghai, China
| |
Collapse
|
|
15
|
Liu Y, Feng M, Chen H, Yang G, Qiu J, Zhao F, Cao Z, Luo W, Xiao J, You L, Zheng L, Zhang T. Mechanistic target of rapamycin in the tumor microenvironment and its potential as a therapeutic target for pancreatic cancer. Cancer Lett 2020; 485:1-13. [PMID: 32428662 DOI: 10.1016/j.canlet.2020.05.003] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2019] [Revised: 04/21/2020] [Accepted: 05/04/2020] [Indexed: 02/07/2023]
Abstract
Pancreatic cancer(PC) is a devastating disease with a poor prognosis; however, few treatment options are available and the search continues for feasible molecular therapeutic targets, both in the tumor itself and in the tumor microenvironment. The mechanistic target of rapamycin (mTOR) signaling pathway has emerged as an attractive target due to its regulatory role in multiple cellular processes, including metabolism, proliferation, survival, and differentiation, under physiological and pathological conditions. Although mTOR-regulated events in tumor cells and the tumor microenvironment are known to restrict the development and growth of tumor cells, monotherapy with mTOR inhibitors has shown limited efficacy against PC to date, suggesting the need for alternative approaches. In this review, we describe the mechanisms by which mTOR modulates the PC microenvironment and suggest ways its function in immune cells might be exploited for the treatment of PC. We also discuss preclinical and clinical studies with mTOR inhibitors in combination with other therapeutic strategies, most notably immunotherapy. Finally, we highlight the promise that mTOR combinatorial therapy may hold for the treatment of PC in the near future.
Collapse
Affiliation(s)
- Yueze Liu
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China.
| | - Mengyu Feng
- Department of Gastrointestinal Surgery, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, 100142, China; Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China.
| | - Hao Chen
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China.
| | - Gang Yang
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China.
| | - Jiangdong Qiu
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China.
| | - Fangyu Zhao
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China.
| | - Zhe Cao
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China.
| | - Wenhao Luo
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China.
| | - Jianchun Xiao
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China.
| | - Lei You
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China.
| | - Lianfang Zheng
- Department of Nuclear Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China.
| | - Taiping Zhang
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China; Clinical Immunology Center, Chinese Academy of Medical Sciences, Beijing, 100730, China.
| |
Collapse
|
|
16
|
Emerging Role of Myeloid-derived Suppressor Cells in the Biology of Transplantation Tolerance. Transplantation 2020; 104:467-475. [DOI: 10.1097/tp.0000000000002996] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
|
|
17
|
Gharaie Fathabad S, Kurzhagen JT, Sadasivam M, Noel S, Bush E, Hamad ARA, Rabb H. T Lymphocytes in Acute Kidney Injury and Repair. Semin Nephrol 2020; 40:114-125. [PMID: 32303275 DOI: 10.1016/j.semnephrol.2020.01.003] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
Innate and adaptive immune systems participate in the pathogenesis of acute kidney injury (AKI). Considerable data from different research teams have shown the importance of T lymphocytes in the pathophysiology of AKI and, more recently, prevention and repair. T cells can generate or resolve inflammation by secreting specific cytokines and growth factors as well as interact with other immune and stromal cells to induce kidney injury or promote tissue repair. There also are emerging data on the role of T cells in the progression of AKI to chronic kidney disease and organ cross-talk in AKI. These data set the stage for immunomodulatory therapies for AKI. This review focuses on the major populations of T lymphocytes and their roles as mediators for AKI and repair.
Collapse
Affiliation(s)
| | - Johanna T Kurzhagen
- Division of Nephrology, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Mohanraj Sadasivam
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Sanjeev Noel
- Division of Nephrology, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Errol Bush
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Abdel R A Hamad
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Hamid Rabb
- Division of Nephrology, Johns Hopkins University School of Medicine, Baltimore, MD.
| |
Collapse
|
|
18
|
HIF1α-Dependent Metabolic Signals Control the Differentiation of Follicular Helper T Cells. Cells 2019; 8:cells8111450. [PMID: 31744227 PMCID: PMC6912655 DOI: 10.3390/cells8111450] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2019] [Revised: 11/14/2019] [Accepted: 11/15/2019] [Indexed: 12/12/2022] Open
Abstract
Follicular helper T (TFH) cells are critical for germinal center (GC) formation and are responsible for effective B cell-mediated immunity; metabolic signaling is an important regulatory mechanism for the differentiation of TFH cells. However, the precise roles of hypoxia inducible factor (HIF) 1α-dependent glycolysis and oxidative phosphorylation (OXPHOS) metabolic signaling remain unclear in TFH cell differentiation. Herein, we investigated the effects of glycolysis and OXPHOS on TFH cell differentiation and GC responses using a pharmacological approach in mice under a steady immune status or an activated immune status, which can be caused by foreign antigen stimulation and viral infection. GC and TFH cell responses are related to signals from glycolytic metabolism in mice of different ages. Foreign, specific antigen-induced GC, and TFH cell responses and metabolic signals are essential upon PR8 infection. Glycolysis and succinate-mediated OXPHOS are required for the GC response and TFH cell differentiation. Furthermore, HIF1α is responsible for glycolysis- and OXPHOS-induced alterations in the GC response and TFH cell differentiation under steady or activated conditions in vivo. Blocking glycolysis and upregulating OXPHOS signaling significantly recovered TFH cell differentiation upon PR8 infection and ameliorated inflammatory damage in mice. Thus, our data provide a comprehensive experimental basis for fully understanding the precise roles of HIF1α-mediated glycolysis and OXPHOS metabolic signaling in regulating the GC response and TFH cell differentiation during stable physiological conditions or an antiviral immune response.
Collapse
|
|
19
|
Han M, Cheng H, Wang J, Yu Y, Wang F, Zhu R, Wang W, Yang S, Li H. Abnormal aggregation of myeloid-derived suppressor cells in a mouse model of cyclophosphamide-induced premature ovarian failure. Gynecol Endocrinol 2019; 35:985-990. [PMID: 31124382 DOI: 10.1080/09513590.2019.1616173] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/26/2022] Open
Abstract
Oocytes are extremely sensitive to radiation and chemotherapy, and premature ovarian failure (POF) is one of the side effects of anti-tumor therapy. The pathogenesis of POF is very complex and still not fully elucidated. A mouse POF model was established after 14 days of cyclophosphamide injection. POF mice presented ovarian atrophy, destroyed follicular structure, a reduction in the number of primordial and mature follicles, and an decrease in the number of corpora luteal along with increased level of follicle-stimulating hormone (FSH), decreased levels of estradiol (E2), and anti-Mullerian hormone (AMH). Additionally, the proportion of bone marrow myeloid-derived suppressor cells (MDSCs) in peripheral blood, spleen, and ovarian tissue increased. MDSCs were mainly distributed around follicles and corpora luteal. Levels of mTOR and p-mTOR increased in ovarian tissue and inhibition of mTOR with rapamycin reduced the aggregation of MDSCs in peripheral blood, spleen, and ovarian tissue. This investigation sheds new light on the modulatory role of mTOR and demonstrates that an increase in MDSC number may play a key role in the pathological reaction during POF. Inhibition of mTOR and reduction of MDSCs in the ovary may represent a novel strategy for the treatment of POF.
Collapse
Affiliation(s)
- Mutian Han
- Center for Reproduction and Genetics, Nanjing Medical University Affiliated Suzhou Hospital , Suzhou , China
| | - Hongbo Cheng
- Center for Reproduction and Genetics, Nanjing Medical University Affiliated Suzhou Hospital , Suzhou , China
| | - Jiaxiong Wang
- Center for Reproduction and Genetics, Nanjing Medical University Affiliated Suzhou Hospital , Suzhou , China
| | - Yi Yu
- Center for Reproduction and Genetics, Nanjing Medical University Affiliated Suzhou Hospital , Suzhou , China
| | - Fuxin Wang
- Center for Reproduction and Genetics, Nanjing Medical University Affiliated Suzhou Hospital , Suzhou , China
| | - Rui Zhu
- Center for Reproduction and Genetics, Nanjing Medical University Affiliated Suzhou Hospital , Suzhou , China
| | - Wei Wang
- Center for Reproduction and Genetics, Nanjing Medical University Affiliated Suzhou Hospital , Suzhou , China
| | - Shenmin Yang
- Center for Reproduction and Genetics, Nanjing Medical University Affiliated Suzhou Hospital , Suzhou , China
| | - Hong Li
- Center for Reproduction and Genetics, Nanjing Medical University Affiliated Suzhou Hospital , Suzhou , China
| |
Collapse
|
|
20
|
Ochando J, Conde P, Utrero-Rico A, Paz-Artal E. Tolerogenic Role of Myeloid Suppressor Cells in Organ Transplantation. Front Immunol 2019; 10:374. [PMID: 30894860 PMCID: PMC6414442 DOI: 10.3389/fimmu.2019.00374] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2018] [Accepted: 02/14/2019] [Indexed: 01/10/2023] Open
Abstract
Myeloid-derived suppressor cells (MDSC) are a heterogeneous population of immature cells of myeloid origin with a specific immune inhibitory function that negatively regulates the adaptive immune response. Since MDSC participate in the promotion of tolerance in the context of organ transplantation, therapeutic strategies that regulate the induction and development of MDSC have been the center of scientist attention. Here we review literature regarding induction of MDSC with demonstrated suppressive function among different types of allografts and their mechanism of action. While manipulation of MDSC represents a potential therapeutic approach for the promotion of donor specific tolerance in solid organ transplantation, further characterization of their specific phenotype, which distinguishes MDSC from non-suppressive myeloid cells, and detailed evaluation of the inhibitory mechanism that determines their suppressive function, is necessary for the realistic application of MDSC as biomarkers in health and disease and their potential use as immune cell therapy in organ transplantation.
Collapse
Affiliation(s)
- Jordi Ochando
- Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, United States.,Immunología de Trasplantes, Centro Nacional de Microbiología, Instituto de Salud Carlos III, Madrid, Spain
| | - Patricia Conde
- Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, United States.,Immunología de Trasplantes, Centro Nacional de Microbiología, Instituto de Salud Carlos III, Madrid, Spain
| | - Alberto Utrero-Rico
- Grupo de Inmunodeficiencias e Inmunología del Trasplante, Instituto de Investigación Sanitaria Hospital 12 de Octubre (imas12), Madrid, Spain
| | - Estela Paz-Artal
- Grupo de Inmunodeficiencias e Inmunología del Trasplante, Instituto de Investigación Sanitaria Hospital 12 de Octubre (imas12), Madrid, Spain.,School of Medicine, Complutense University, Madrid, Spain
| |
Collapse
|
|
21
|
Splenectomy Promotes Macrophage Polarization in a Mouse Model of Concanavalin A- (ConA-) Induced Liver Fibrosis. BIOMED RESEARCH INTERNATIONAL 2019; 2019:5756189. [PMID: 30723740 PMCID: PMC6339718 DOI: 10.1155/2019/5756189] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/02/2018] [Accepted: 12/24/2018] [Indexed: 12/11/2022]
Abstract
Background Splenectomy can improve liver function and survival in patients with autoimmune hepatitis (AIH) and liver cirrhosis. We investigated the underlying mechanism in a mouse model of concanavalin A- (ConA-) induced liver fibrosis. Methods We used ConA to induce immune liver fibrosis in BALB/c mice. Splenectomy was performed alone or with the administration of dexamethasone (DEX). Changes in blood and liver tissues were evaluated. Results Mice treated with ConA for 7 weeks developed advanced liver fibrosis, while splenectomy suppressed liver fibrosis. Although the populations of macrophages/monocytes and M1 macrophages decreased after splenectomy, the inflammatory factors associated with M2 macrophages increased after splenectomy. Furthermore, the population of circulating CD11b+Ly6Chigh myeloid-derived suppressor cells (MDSCs) increased after splenectomy. After ConA treatment, elevated levels of activated and total NF-kBp65/p50 combined with DNA were observed in hepatic tissues. In contrast, the levels of NF-κB p65/p50 decreased after splenectomy. Conclusions Splenectomy may promote the polarization of CD11b+Ly6Chigh MDSCs and the differentiation of M2 macrophages while restricting the level of NF-κB p65-p50 heterodimers. These factors may suppress the progression of liver fibrosis.
Collapse
|
|
22
|
Wei C, Wang Y, Ma L, Wang X, Chi H, Zhang S, Liu T, Li Z, Xiang D, Dong Y, Wu X, Shi W, Gao H. Rapamycin Nano-Micelle Ophthalmic Solution Reduces Corneal Allograft Rejection by Potentiating Myeloid-Derived Suppressor Cells' Function. Front Immunol 2018; 9:2283. [PMID: 30349533 PMCID: PMC6186809 DOI: 10.3389/fimmu.2018.02283] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2018] [Accepted: 09/14/2018] [Indexed: 12/12/2022] Open
Abstract
Allograft rejection is the major cause of corneal allograft failure. Rapamycin (RAPA) has been reported as an effective and novel immunosuppressive agent for patients undergoing corneal transplantation. However, its high water insolubility and low bioavailability have strongly constrained its clinical application. In this study, we successfully developed a RAPA nano-micelle ophthalmic solution and found that corneal allograft survival in recipients treated with RAPA nano-micelle ophthalmic solution was significantly prolonged for more than 2 months, with less inflammatory infiltration, decreased production of pro-inflammatory factors, and elevated recruitment of myeloid-derived suppressor cells (MDSCs). MDSCs from mice treated with RAPA nano-micelle ophthalmic solution could significantly inhibit the proliferation of CD4+T cells through increased expressions of inducible nitric oxidase (iNOS) and arginase-1 (Arg-1). The activity blockade of Arg-1 and iNOS pharmacologically reversed their immunosuppressive ability. Moreover, the effects of RAPA were antagonized by the administration of anti-Gr-1 antibody or by inhibiting the activity of iNOS pharmacologically. In addition, RAPA nano-micelle also effectively alleviated allograft rejection in high-risk rabbit penetrating keratoplasty (PKP) models with corneal vascularization. Collectively, our results demonstrate that RAPA nano-micelle ophthalmic solution could improve the immunosuppressive activity of MDSCs through elevated expression of Arg-1 and iNOS, which highlights the possible therapeutic applications of RAPA against corneal allograft rejection.
Collapse
Affiliation(s)
- Chao Wei
- State Key Laboratory Cultivation Base, Shandong Provincial Key Laboratory of Ophthalmology, Shandong Eye Institute, Shandong Academy of Medical Sciences, Qingdao, China
| | - Yuexin Wang
- State Key Laboratory Cultivation Base, Shandong Provincial Key Laboratory of Ophthalmology, Shandong Eye Institute, Shandong Academy of Medical Sciences, Qingdao, China
| | - Li Ma
- State Key Laboratory Cultivation Base, Shandong Provincial Key Laboratory of Ophthalmology, Shandong Eye Institute, Shandong Academy of Medical Sciences, Qingdao, China
| | - Xin Wang
- State Key Laboratory Cultivation Base, Shandong Provincial Key Laboratory of Ophthalmology, Shandong Eye Institute, Shandong Academy of Medical Sciences, Qingdao, China
| | - Hao Chi
- State Key Laboratory Cultivation Base, Shandong Provincial Key Laboratory of Ophthalmology, Shandong Eye Institute, Shandong Academy of Medical Sciences, Qingdao, China.,School of Medicine and Life Sciences, University of Jinan-Shandong Academy of Medical Sciences, Jinan, China
| | - Sai Zhang
- State Key Laboratory Cultivation Base, Shandong Provincial Key Laboratory of Ophthalmology, Shandong Eye Institute, Shandong Academy of Medical Sciences, Qingdao, China.,Qingdao University Medical College, Qingdao, China
| | - Ting Liu
- State Key Laboratory Cultivation Base, Shandong Provincial Key Laboratory of Ophthalmology, Shandong Eye Institute, Shandong Academy of Medical Sciences, Qingdao, China
| | - Zhiyuan Li
- State Key Laboratory Cultivation Base, Shandong Provincial Key Laboratory of Ophthalmology, Shandong Eye Institute, Shandong Academy of Medical Sciences, Qingdao, China
| | - Demeng Xiang
- State Key Laboratory Cultivation Base, Shandong Provincial Key Laboratory of Ophthalmology, Shandong Eye Institute, Shandong Academy of Medical Sciences, Qingdao, China
| | - Yanling Dong
- State Key Laboratory Cultivation Base, Shandong Provincial Key Laboratory of Ophthalmology, Shandong Eye Institute, Shandong Academy of Medical Sciences, Qingdao, China
| | - Xianggen Wu
- State Key Laboratory Cultivation Base, Shandong Provincial Key Laboratory of Ophthalmology, Shandong Eye Institute, Shandong Academy of Medical Sciences, Qingdao, China.,Department of Pharmacy, College of Chemical Engineering, Qingdao University of Science and Technology, Qingdao, China
| | - Weiyun Shi
- State Key Laboratory Cultivation Base, Shandong Provincial Key Laboratory of Ophthalmology, Shandong Eye Institute, Shandong Academy of Medical Sciences, Qingdao, China
| | - Hua Gao
- State Key Laboratory Cultivation Base, Shandong Provincial Key Laboratory of Ophthalmology, Shandong Eye Institute, Shandong Academy of Medical Sciences, Qingdao, China
| |
Collapse
|
|
23
|
Sendo S, Saegusa J, Morinobu A. Myeloid-derived suppressor cells in non-neoplastic inflamed organs. Inflamm Regen 2018; 38:19. [PMID: 30237829 PMCID: PMC6139938 DOI: 10.1186/s41232-018-0076-7] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2018] [Accepted: 06/26/2018] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND Myeloid-derived suppressor cells (MDSCs) are a highly heterogeneous population of immature myeloid cells with immunosuppressive function. Although their function in tumor-bearing conditions is well studied, less is known about the role of MDSCs in various organs under non-neoplastic inflammatory conditions. MAIN BODY MDSCs are divided into two subpopulations, G-MDSCs and M-MDSCs, and their distribution varies between organs. MDSCs negatively control inflammation in inflamed organs such as the lungs, joints, liver, kidneys, intestines, central nervous system (CNS), and eyes by suppressing T cells and myeloid cells. MDSCs also regulate fibrosis in the lungs, liver, and kidneys and help repair CNS injuries. MDSCs in organs are plastic and can differentiate into osteoclasts and tolerogenic dendritic cells according to the microenvironment under non-neoplastic inflammatory conditions. CONCLUSION This article summarizes recent findings about MDSCs under inflammatory conditions, especially with respect to their function and differentiation in specific organs.
Collapse
Affiliation(s)
- Sho Sendo
- Division of Rheumatology and Clinical Immunology, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-2 Kusunoki-cho, Chuo-ku, Kobe, 650-0017 Japan
| | - Jun Saegusa
- Division of Rheumatology and Clinical Immunology, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-2 Kusunoki-cho, Chuo-ku, Kobe, 650-0017 Japan
- Division of Laboratory Medicine, Kobe University Graduate School of Medicine, 7-5-2 Kusunoki-cho, Chuo-ku, Kobe, 650-0017 Japan
| | - Akio Morinobu
- Division of Rheumatology and Clinical Immunology, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-2 Kusunoki-cho, Chuo-ku, Kobe, 650-0017 Japan
| |
Collapse
|
|
24
|
Nakamura T, Ushigome H. Myeloid-Derived Suppressor Cells as a Regulator of Immunity in Organ Transplantation. Int J Mol Sci 2018; 19:ijms19082357. [PMID: 30103447 PMCID: PMC6121658 DOI: 10.3390/ijms19082357] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2018] [Accepted: 08/08/2018] [Indexed: 12/16/2022] Open
Abstract
Regulation of allo-immune responses is proposed as a topic for investigation in the current field of organ transplantation. As a regulator, regulatory T cells (Tregs) have received attention due to their ability to control allograft rejection. Concurrently, however, the independent action of Tregs is not enough to achieve tolerance status in many situations. Meanwhile, as a multi-functional regulator, myeloid-derived suppressor cells (MDSCs) can suppress effector T cells as well as induce Tregs or regulatory B cells (Bregs) in certain circumstances. Furthermore, the importance of a crosstalk between MDSCs and natural killer T cells to induce tolerance has been reported. Thus, orchestration between MDSCs, myeloid regulators, T/Bregs and other lymphoid/myeloid regulators can shed light on achieving allogeneic tolerance. Here, we review the current knowledge in terms of immunological regulatory function displayed by MDSCs in the context of organ transplantation. Ideal control of MDSCs would lead to a reduction of allograft rejection and subsequent long-term allograft acceptance.
Collapse
Affiliation(s)
- Tsukasa Nakamura
- Department of Organ Transplantation and General Surgery, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan.
| | - Hidetaka Ushigome
- Department of Organ Transplantation and General Surgery, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan.
| |
Collapse
|
|
25
|
Li S, Wang N, Tan HY, Hong M, Yuen MF, Li H, Feng Y. Expansion of Granulocytic, Myeloid-Derived Suppressor Cells in Response to Ethanol-Induced Acute Liver Damage. Front Immunol 2018; 9:1524. [PMID: 30072984 PMCID: PMC6060237 DOI: 10.3389/fimmu.2018.01524] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2018] [Accepted: 06/20/2018] [Indexed: 02/06/2023] Open
Abstract
The dual role of ethanol in regulating both pro-inflammatory and anti-inflammatory response has recently been reported. Myeloid-derived suppressor cells (MDSCs) are one of the major components in the immune suppressive network in both innate and adaptive immune responses. In this study, we aim to define the role of a population expressing CD11b+Ly6GhighLy6Cint with immunosuppressive function in response to ethanol-induced acute liver damage. We find this increased granulocytic-MDSCs (G-MDSCs) population in the blood, spleen, and liver of mice treated with ethanol. Depletion of these cells increases serum alanine aminotransferase and aspartate aminotransferase levels, while G-MDSCs population adoptive transfer can ameliorate liver damage induced by ethanol, indicating the protective role in the early stage of alcoholic liver disease. The significant changes of T-cell profiles after G-MDSCs populations adoptive transfer and anti-Gr1 injection signify that both cytotoxic T and T helper cells might be the targeted cells of G-MDSCs. In the in vitro study, we find that myeloid precursors preferentially generate G-MDSCs and improve their suppressive capacity via chemokine interaction and YAP signaling when exposed to ethanol. Furthermore, IL-6 serves as an important indirect factor in mediating the expansion of G-MDSCs populations after acute ethanol exposure. Collectively, we show that expansion of G-MDSCs in response to ethanol consumption plays a protective role in acute alcoholic liver damage. Our study provides novel evidence of the immune response to acute ethanol consumption.
Collapse
Affiliation(s)
- Sha Li
- Li Ka Shing Faculty of Medicine, School of Chinese Medicine, The University of Hong Kong, Pokfulam, Hong Kong
| | - Ning Wang
- Li Ka Shing Faculty of Medicine, School of Chinese Medicine, The University of Hong Kong, Pokfulam, Hong Kong
| | - Hor-Yue Tan
- Li Ka Shing Faculty of Medicine, School of Chinese Medicine, The University of Hong Kong, Pokfulam, Hong Kong
| | - Ming Hong
- Li Ka Shing Faculty of Medicine, School of Chinese Medicine, The University of Hong Kong, Pokfulam, Hong Kong
| | - Man-Fung Yuen
- Division of Gastroenterology and Hepatology, Queen Mary Hospital, Department of Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong
| | - Huabin Li
- Guangdong Provincial Key Laboratory of Food, Nutrition and Health, School of Public Health, Sun Yat-sen University, Guangzhou, China
| | - Yibin Feng
- Li Ka Shing Faculty of Medicine, School of Chinese Medicine, The University of Hong Kong, Pokfulam, Hong Kong
| |
Collapse
|
|
26
|
The Effect of Immunosuppressive Drugs on MDSCs in Transplantation. J Immunol Res 2018; 2018:5414808. [PMID: 30057917 PMCID: PMC6051033 DOI: 10.1155/2018/5414808] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2018] [Accepted: 06/05/2018] [Indexed: 12/13/2022] Open
Abstract
Myeloid-derived suppressor cells (MDSCs) are a group of innate immune cells that regulates both innate and adaptive immune responses. In recent years, MDSCs were shown to play an important negative regulatory role in transplant immunology even upstream of regulatory T cells. In certain cases, MDSCs are closely involved in transplantation immune tolerance induction and maintenance. It is known that some immunosuppressant drugs negatively regulate MDSCs but others have positive effects on MDSCs in different transplant cases. We herein summarized our recent insights into the regulatory roles of MDSCs in transplantation specially focusing on the effects of immunosuppressive drugs on MDSCs and their mechanisms of action. Studies on the effects of immunosuppressive drugs on MDSCs will significantly expand our understanding of immunosuppressive drugs on immune regulatory cells in transplantation and offer new insights into transplant tolerance. We hope to emphasize our concern for the negative effects of immunosuppressive agents on MDSCs, which may potentially attenuate the immune tolerance induction in transplanted recipients.
Collapse
|
|
27
|
Zhou L, Miao K, Yin B, Li H, Fan J, Zhu Y, Ba H, Zhang Z, Chen F, Wang J, Zhao C, Li Z, Wang DW. Cardioprotective Role of Myeloid-Derived Suppressor Cells in Heart Failure. Circulation 2018; 138:181-197. [PMID: 29437117 DOI: 10.1161/circulationaha.117.030811] [Citation(s) in RCA: 71] [Impact Index Per Article: 10.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/01/2017] [Accepted: 01/16/2018] [Indexed: 11/16/2022]
Abstract
BACKGROUND Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of cells that expand in cancer, inflammation, and infection and negatively regulate inflammation and the immune response. Heart failure (HF) is a complex clinical syndrome wherein inflammation induction and incomplete resolution can potentially contribute to HF development and progression. However, the role of MDSCs in HF remains unclear. METHODS The percentage of MDSCs in patients with HF and in mice with pressure overload-induced HF using isoproterenol infusion or transverse aortic constriction (TAC) was detected by flow cytometry. The effects of MDSCs on isoproterenol- or TAC-induced HF were observed on depleting MDSCs with 5-fluorouracil (50 mg/kg) or gemcitabine (120 mg/kg), transferring purified MDSCs, or enhancing endogenous MDSCs with rapamycin (2 mg·kg-1·d-1). Hypertrophic markers and inflammatory factors were detected by ELISA, real-time polymerase chain reaction, or Western blot. Cardiac functions were determined by echocardiography and hemodynamic analysis. RESULTS The percentage of human leukocyte antigen-D-related (HLA-DR)-CD33+CD11b+ MDSCs in the blood of patients with HF was significantly increased and positively correlated with disease severity and increased plasma levels of cytokines, including interleukin-6, interleukin-10, and transforming growth factor-β. Furthermore, MDSCs derived from patients with HF inhibited T-cell proliferation and interferon-γ secretion. Similar results were observed in TAC- and isoproterenol-induced HF in mice. Pharmaceutical depletion of MDSCs significantly exacerbated isoproterenol- and TAC-induced pathological cardiac remodeling and inflammation, whereas adoptive transfer of MDSCs prominently rescued isoproterenol- and TAC-induced HF. Consistently, administration of rapamycin significantly increased endogenous MDSCs by suppressing their differentiation and improved isoproterenol- and TAC-induced HF, but MDSC depletion mostly blocked beneficial rapamycin-mediated effects. Mechanistically, MDSC-secreted molecules suppressed isoproterenol-induced hypertrophy and proinflammatory gene expression in cardiomyocytes in a coculture system. Neutralization of interleukin-10 blunted both monocytic MDSC- and granulocytic MDSC-mediated anti-inflammatory and antihypertrophic effects, but treatment with a nitric oxide inhibitor only partially blocked the antihypertrophic effect of monocytic MDSCs. CONCLUSIONS Our findings revealed a cardioprotective role of MDSCs in HF by their antihypertrophic effects on cardiomyocytes and anti-inflammatory effects through interleukin-10 and nitric oxide. Pharmacological targeting of MDSCs by rapamycin constitutes a promising therapeutic strategy for HF.
Collapse
Affiliation(s)
- Ling Zhou
- Division of Cardiology, Department of Internal Medicine and Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiologic Disorders, Tongji Hospital (L.Z., K.M., H.L., J.F., C.Z., D.W.W.)
| | - Kun Miao
- Division of Cardiology, Department of Internal Medicine and Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiologic Disorders, Tongji Hospital (L.Z., K.M., H.L., J.F., C.Z., D.W.W.)
| | - Bingjiao Yin
- Division of Cardiology, Department of Internal Medicine and Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiologic Disorders, Tongji Hospital (L.Z., K.M., H.L., J.F., C.Z., D.W.W.).,Department of Immunology, School of Basic Medicine (B.Y., Y.Z., H.B., Z.Z., F.C., J.W., and Z.L.), Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Huaping Li
- Division of Cardiology, Department of Internal Medicine and Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiologic Disorders, Tongji Hospital (L.Z., K.M., H.L., J.F., C.Z., D.W.W.)
| | - Jiahui Fan
- Division of Cardiology, Department of Internal Medicine and Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiologic Disorders, Tongji Hospital (L.Z., K.M., H.L., J.F., C.Z., D.W.W.)
| | - Yazhen Zhu
- Division of Cardiology, Department of Internal Medicine and Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiologic Disorders, Tongji Hospital (L.Z., K.M., H.L., J.F., C.Z., D.W.W.).,Department of Immunology, School of Basic Medicine (B.Y., Y.Z., H.B., Z.Z., F.C., J.W., and Z.L.), Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Hongping Ba
- Division of Cardiology, Department of Internal Medicine and Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiologic Disorders, Tongji Hospital (L.Z., K.M., H.L., J.F., C.Z., D.W.W.).,Department of Immunology, School of Basic Medicine (B.Y., Y.Z., H.B., Z.Z., F.C., J.W., and Z.L.), Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Zunyue Zhang
- Division of Cardiology, Department of Internal Medicine and Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiologic Disorders, Tongji Hospital (L.Z., K.M., H.L., J.F., C.Z., D.W.W.).,Department of Immunology, School of Basic Medicine (B.Y., Y.Z., H.B., Z.Z., F.C., J.W., and Z.L.), Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Fang Chen
- Division of Cardiology, Department of Internal Medicine and Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiologic Disorders, Tongji Hospital (L.Z., K.M., H.L., J.F., C.Z., D.W.W.).,Department of Immunology, School of Basic Medicine (B.Y., Y.Z., H.B., Z.Z., F.C., J.W., and Z.L.), Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jing Wang
- Division of Cardiology, Department of Internal Medicine and Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiologic Disorders, Tongji Hospital (L.Z., K.M., H.L., J.F., C.Z., D.W.W.).,Department of Immunology, School of Basic Medicine (B.Y., Y.Z., H.B., Z.Z., F.C., J.W., and Z.L.), Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Chunxia Zhao
- Division of Cardiology, Department of Internal Medicine and Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiologic Disorders, Tongji Hospital (L.Z., K.M., H.L., J.F., C.Z., D.W.W.)
| | - Zhuoya Li
- Division of Cardiology, Department of Internal Medicine and Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiologic Disorders, Tongji Hospital (L.Z., K.M., H.L., J.F., C.Z., D.W.W.) .,Department of Immunology, School of Basic Medicine (B.Y., Y.Z., H.B., Z.Z., F.C., J.W., and Z.L.), Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Dao Wen Wang
- Division of Cardiology, Department of Internal Medicine and Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiologic Disorders, Tongji Hospital (L.Z., K.M., H.L., J.F., C.Z., D.W.W.)
| |
Collapse
|
|
28
|
Nakao T, Nakamura T, Masuda K, Matsuyama T, Ushigome H, Ashihara E, Yoshimura N. Dexamethasone Prolongs Cardiac Allograft Survival in a Murine Model Through Myeloid-derived Suppressor Cells. Transplant Proc 2018; 50:299-304. [DOI: 10.1016/j.transproceed.2017.11.014] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2017] [Accepted: 11/03/2017] [Indexed: 01/21/2023]
|
|
29
|
Lin Y, Wang B, Shan W, Tan Y, Feng J, Xu L, Wang L, Han B, Zhang M, Yu J, Yu X, Huang H. mTOR inhibitor rapamycin induce polymorphonuclear myeloid-derived suppressor cells mobilization and function in protecting against acute graft-versus-host disease after bone marrow transplantation. Clin Immunol 2017; 187:122-131. [PMID: 29132870 DOI: 10.1016/j.clim.2017.11.005] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2017] [Revised: 10/23/2017] [Accepted: 11/09/2017] [Indexed: 01/07/2023]
Abstract
The mammalian target of rapamycin (mTOR) inhibitor rapamycin (RAPA) has been shown to be an effective immunosuppressor in the management of acute graft-versus-host disease (aGVHD) after bone marrow transplantation. Myeloid-derived suppressor cells (MDSCs) also have a protective effect in aGVHD regulation. However, the relationship between RAPA and MDSCs in aGVHD models is unclear. Meanwhile, the effect of RAPA on different subgroups of MDSCs is also less well described. In this study, we demonstrate that in vivo administration of RAPA results in the expansion and functional enhancement of polymorphonuclear MDSCs (PMN-MDSCs) in a murine model of aGVHD. RAPA treatment can enhance the suppressive function of PMN-MDSCs via up-regulation of arginase1 (Arg1) and induced nitric oxide synthase (iNOS) at later time points. Moreover, RAPA can also induce a strong immunosuppressive function in PMN-MDSCs from murine bone marrow in vitro, but has a contrary effect on monocytic MDSCs (M-MDSCs). We found that RAPA-treated PMN-MDSCs can restrain the differentiation of Th1/Th2 cells and promote induction of regulatory T cells in in vitro studies.
Collapse
Affiliation(s)
- Yu Lin
- Bone Marrow Transplantation Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China; Institute of Hematology, Zhejiang University, Hangzhou, China
| | - Binsheng Wang
- Bone Marrow Transplantation Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Wei Shan
- Bone Marrow Transplantation Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Yamin Tan
- Bone Marrow Transplantation Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Jingjing Feng
- Bone Marrow Transplantation Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Lin Xu
- Bone Marrow Transplantation Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Limengmeng Wang
- Bone Marrow Transplantation Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China; Institute of Hematology, Zhejiang University, Hangzhou, China
| | - Biqing Han
- Bone Marrow Transplantation Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Mingming Zhang
- Bone Marrow Transplantation Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Jian Yu
- Bone Marrow Transplantation Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Xiaohong Yu
- Bone Marrow Transplantation Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - He Huang
- Bone Marrow Transplantation Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China; Institute of Hematology, Zhejiang University, Hangzhou, China.
| |
Collapse
|
|
30
|
Hamdani S, Thiolat A, Naserian S, Grondin C, Moutereau S, Hulin A, Calderaro J, Grimbert P, Cohen JL, Azoulay D, Pilon C. Delayed and short course of rapamycin prevents organ rejection after allogeneic liver transplantation in rats. World J Gastroenterol 2017; 23:6962-6972. [PMID: 29097869 PMCID: PMC5658314 DOI: 10.3748/wjg.v23.i38.6962] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2017] [Revised: 04/06/2017] [Accepted: 06/01/2017] [Indexed: 02/06/2023] Open
Abstract
AIM To test whether a delayed and short course of rapamycin would induce immunosuppressive effects following allogeneic orthotopic liver transplantation (OLT) in rats.
METHODS Allogeneic OLTs were performed using Dark Agouti livers transplanted into Lewis recipients, and syngeneic OLTs were performed using the Lewis rat strain. Rapamycin (1 mg/kg per day) was administered by gavage from day 4 to day 11 post-transplantation. Lymphocyte cellular compartments were analyzed by flow cytometry in draining lymph nodes, non-draining lymph nodes and the spleen at days 11 and 42 in rapamycin-treated rats, untreated control rats and syngeneic grafted rats. Skin grafts from Dark agouti or from F344 RT were performed at day 30 on liver grafted rats treated with rapamycin.
RESULTS An 8-d course of rapamycin treatment initiated 4 d following transplantation resulted in the survival of grafted rats for more than 100 d. In contrast, untreated rats died of liver failure within 13 to 21 d. The analysis of the cellular compartment revealed an increase in two cellular subpopulations, specifically myeloid-derived suppressor cells (MDSCs) and CD8+CD45RClow T cells, without major modifications in the regulatory T cell (Treg) compartment in treated rats in the early stages after grafting. We evaluated the ability of treated rats to reject third-party allogeneic skin grafts to confirm their immune competence. In contrast, when skin was collected from rats syngeneic to the grafted liver, it was not rejected.
CONCLUSION Our results demonstrate that short and delayed rapamycin treatment allows for tolerance in allogeneic OLT. The results also allowed for the identification of the mechanisms of tolerance induced by rapamycin by identifying MDSCs and CD8+CD45RClow T cells as associated with the state of tolerance.
Collapse
Affiliation(s)
- Salim Hamdani
- Université Paris-Est, UMR_S955, UPEC, Inserm, U955, Equipe 21, F-94000 Créteil, France
| | - Allan Thiolat
- Université Paris-Est, UMR_S955, UPEC, Inserm, U955, Equipe 21, F-94000 Créteil, France
| | - Sina Naserian
- Université Paris-Est, UMR_S955, UPEC, Inserm, U955, Equipe 21, F-94000 Créteil, France
| | - Cynthia Grondin
- Université Paris-Est, UMR_S955, UPEC, Inserm, U955, Equipe 21, F-94000 Créteil, France
| | - Stéphane Moutereau
- AP-HP, Laboratoire de Biochimie, Groupe Hospitalier Henri-Mondor Albert-Chenevier, F-94000 Créteil, France
| | - Anne Hulin
- AP-HP, Laboratoire de Pharmacologie-Toxicologie Biologiques, Groupe Hospitalier Henri-Mondor Albert-Chenevier, F-94000 Créteil, France
| | - Julien Calderaro
- AP-HP, Anatomie et Cytologie Pathologique, Groupe Hospitalier Henri-Mondor Albert-Chenevier, F-94000 Créteil, France
| | - Philippe Grimbert
- Université Paris-Est, UMR_S955, UPEC, Inserm, U955, Equipe 21, APHP, Inserm, CIC Biothérapie, Groupe Hospitalier Henri-Mondor Albert-Chenevier, F-94000 Créteil, France
| | - José Laurent Cohen
- Université Paris-Est, UMR_S955, UPEC, Inserm, U955, Equipe 21, APHP, Inserm, CIC Biothérapie, Groupe Hospitalier Henri-Mondor Albert-Chenevier, F-94000 Créteil, France
| | - Daniel Azoulay
- APHP, Service de Chirurgie HPB et Transplantation Hépatique, Groupe Hospitalier Henri-Mondor Albert-Chenevier, F-94000 Créteil, France
- Department of Hepato-Pancreato-Biliary Surgery and Liver Transplantation, Henri Mondor Hospital, 94010 Créteil, France
| | - Caroline Pilon
- Université Paris-Est, UMR_S955, UPEC, Inserm, U955, Equipe 21, APHP, Inserm, CIC Biothérapie, Groupe Hospitalier Henri-Mondor Albert-Chenevier, F-94000 Créteil, France
| |
Collapse
|
|
31
|
The mTOR signal regulates myeloid-derived suppressor cells differentiation and immunosuppressive function in acute kidney injury. Cell Death Dis 2017; 8:e2695. [PMID: 28333137 PMCID: PMC5386577 DOI: 10.1038/cddis.2017.86] [Citation(s) in RCA: 66] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2016] [Revised: 02/06/2017] [Accepted: 02/09/2017] [Indexed: 12/12/2022]
Abstract
The mammalian target of rapamycin (mTOR) signal controls innate and adaptive immune response in multiple immunoregulatory contexts. Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of myeloid cells of potent immunosuppressive capacity. In this study, we aimed to investigate the role of MDSCs in the protection of acute kidney injury (AKI) and the regulation of mTOR signal on MDSC's protective role in this context. In mice AKI model, rapamycin administration was associated with improved renal function, restored histological damage and decreased CD4+ and CD8+ T-cell infiltration in kidney tissue. MDSCs, especially CD11b+Ly6G+Ly6Clow G-MDSCs were recruited to the injured kidney following the interaction of CXCL1, CXCL2 and their receptor CXCR2 after inhibiting mTOR signal with rapamycin treatment. The adoptive transfer of rapamycin-treated MDSCs into the mice with AKI significantly improved the renal function, ameliorated histologic damages and limited the infiltration of T cells in kidney tissue. In addition, the expression of pro-inflammatory cytokines IL-1β and IFN-γ mRNA was downregulated while the expression of TGF-β1 and Foxp3 mRNA was upregulated in kidney tissue after transferring rapamycin-treated MDSCs. Adoptive transfer of rapamycin-treated MDSCs also downregulated the serum levels of IL-1β, IL-6 and IFN-γ and upregulated the serum levels of TGF-β1 compared with the IR group and PBS-treated MDSC group. In in vitro study, inhibiting mTOR signal regulated the induction of MDSC towards the CD11b+Ly6G+Ly6Clow G-MDSC subset. The ability to suppress T-cell proliferation of both bone marrow–derived CD11b+Ly6G+Ly6Clow G-MDSCs and CD11b+Ly6G-Ly6Chigh M-MDSCs was enhanced by mTOR signal inhibition via upregulating the expression of Arginase-1 and iNOS. Accordingly, both G-MDSCs and M-MDSCs presented downregulated runx1 gene expression after rapamycin treatment. Taken together, our results demonstrated that MDSCs ameliorated AKI and the protective effect was enhanced by mTOR signal inhibition via promoting MDSCs recruitment, regulating the induction of MDSCs and strengthening their immunosuppressive activity.
Collapse
|
|
32
|
Li S, Hong M, Tan HY, Wang N, Feng Y. Insights into the Role and Interdependence of Oxidative Stress and Inflammation in Liver Diseases. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2016; 2016:4234061. [PMID: 28070230 PMCID: PMC5192343 DOI: 10.1155/2016/4234061] [Citation(s) in RCA: 224] [Impact Index Per Article: 24.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/07/2016] [Accepted: 11/02/2016] [Indexed: 02/06/2023]
Abstract
The crucial roles of oxidative stress and inflammation in the development of hepatic diseases have been unraveled and emphasized for decades. From steatosis to fibrosis, cirrhosis and liver cancer, hepatic oxidative stress, and inflammation are sustained and participated in this pathological progressive process. Notably, increasing evidences showed that oxidative stress and inflammation are tightly related, which are regarded as essential partners that present simultaneously and interact with each other in various pathological conditions, creating a vicious cycle to aggravate the hepatic diseases. Clarifying the interaction of oxidative stress and inflammation is of great importance to provide new directions and targets for developing therapeutic intervention. Herein, this review is concerned with the regulation and interdependence of oxidative stress and inflammation in a variety of liver diseases. In addition to classical mediators and signaling, particular emphasis is placed upon immune suppression, a potential linkage of oxidative stress and inflammation, to provide new inspiration for the treatment of liver diseases. Furthermore, since antioxidation and anti-inflammation have been extensively attempted as the strategies for treatment of liver diseases, the application of herbal medicines and their derived compounds that protect liver from injury via regulating oxidative stress and inflammation collectively were reviewed and discussed.
Collapse
Affiliation(s)
- Sha Li
- School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong
| | - Ming Hong
- School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong
| | - Hor-Yue Tan
- School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong
| | - Ning Wang
- School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong
| | - Yibin Feng
- School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong
| |
Collapse
|
|
33
|
Ito H, Ando T, Seishima M. Inhibition of iNOS activity enhances the anti-tumor effects of alpha-galactosylceramide in established murine cancer model. Oncotarget 2016; 6:41863-74. [PMID: 26496031 PMCID: PMC4747194 DOI: 10.18632/oncotarget.6172] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2015] [Accepted: 10/06/2015] [Indexed: 12/15/2022] Open
Abstract
Alpha-garactosylceramide (GalCer) has been shown to have anti-tumor effect in the basic research and clinical studies. However, anti-tumor effect of GalCer is limited. The administration of GalCer increases the production of IFN-γ which is involved in the suppression of tumor growth. On the other hand, the enhancement of IFN-γ production increases immunosuppressive factors such as nitric oxide. This suppressive action might impair the anti-tumor effect of GalCer. In the present study, we evaluated the anti-tumor effect of GalCer in the absence of inducible nitric oxide synthase (iNOS). In lung metastatic model, the number of tumor nodules in the lung of iNOS-KO mice treated with GalCer was significantly reduced compared with that of WT mice treated with GalCer. Moreover, L-NAME, which is the inhibitor for iNOS, enhanced the anti-tumor effect of GalCer in lung metastatic model. The frequency of CD8+ cells in bronchoalveolar lavage fluid increased in iNOS-KO mice treated with GalCer. The administration of GalCer increased the frequency of myeloid-derived suppressor cells (MDSCs) in the lung from tumor-bearing WT mice, but the increase of MDSCs in the lung was not induced in iNOS-KO mice. The subcutaneous tumor experiments revealed that the administration of GalCer in the absence of iNOS expression significantly enhanced the induction of tumor antigen-specific response. Finally, our results indicated that the inhibition of iNOS expression could enhance the therapeutic efficacy of GalCer via the increase of tumor antigen-specific immune response and the suppression of MDSCs.
Collapse
Affiliation(s)
- Hiroyasu Ito
- Department of Informative Clinical Medicine, Gifu University Graduate School of Medicine, Yanagido, Gifu, Japan
| | - Tatsuya Ando
- Department of Informative Clinical Medicine, Gifu University Graduate School of Medicine, Yanagido, Gifu, Japan
| | - Mitsuru Seishima
- Department of Informative Clinical Medicine, Gifu University Graduate School of Medicine, Yanagido, Gifu, Japan
| |
Collapse
|
|
34
|
Nakamura T, Nakao T, Yoshimura N, Ashihara E. Rapamycin Prolongs Cardiac Allograft Survival in a Mouse Model by Inducing Myeloid-Derived Suppressor Cells. Am J Transplant 2015; 15:2364-77. [PMID: 25943210 DOI: 10.1111/ajt.13276] [Citation(s) in RCA: 64] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2014] [Revised: 02/16/2015] [Accepted: 02/17/2015] [Indexed: 01/25/2023]
Abstract
Mammalian target of rapamycin (mTOR) inhibitors are the main immunosuppressive drugs for organ transplant recipients. Nevertheless, the mechanisms by which mTOR inhibitors induce immunosuppression is not fully understood. Myeloid-derived suppressor cells (MDSCs) maintain host immunity; however, the relationship between mTOR inhibitors and MDSCs is unclear. Here, the results from a murine cardiac transplantation model revealed that rapamycin treatment (3 mg/kg, intraperitoneally on postoperative days 0, 2, 4, and 6) led to the recruitment of MDSCs and increased their expression of inducible nitric oxide synthase (iNOS). Immunohistochemical analysis revealed that rapamycin induced the migration of iNOS-expressing MDSCs into the subintimal space within the allograft vessels, resulting in a significant prolongation of graft survival compared with that in the untreated group (67 days vs. 7 days, respectively). These effects were counterbalanced by the administration of an anti-Gr-1, which reduced allograft survival to 21 days. Moreover, adoptive transcoronary arterial transfer of MDSCs from rapamycin-treated recipients prolonged allograft survival; this increase was reversed by the anti-Gr-1 antibody. Finally, co-administration of rapamycin and a mitogen-activated protein kinase kinase (MEK) inhibitor trametinib reversed rapamycin-mediated MDSC recruitment. Thus, the mTOR and Raf/MEK/extracellular signal regulated kinase (ERK) signaling pathways appear to play an important role in MDSC expansion.
Collapse
Affiliation(s)
- T Nakamura
- Department of Transplantation and Regenerative Surgery, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kamigyo-Ku, Kyoto-Prefecture, Japan.,Department of Clinical and Translational Physiology, Kyoto Pharmaceutical University, Yamashina-ku, Kyoto, Japan
| | - T Nakao
- Department of Transplantation and Regenerative Surgery, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kamigyo-Ku, Kyoto-Prefecture, Japan.,Department of Clinical and Translational Physiology, Kyoto Pharmaceutical University, Yamashina-ku, Kyoto, Japan
| | - N Yoshimura
- Department of Transplantation and Regenerative Surgery, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kamigyo-Ku, Kyoto-Prefecture, Japan
| | - E Ashihara
- Department of Clinical and Translational Physiology, Kyoto Pharmaceutical University, Yamashina-ku, Kyoto, Japan
| |
Collapse
|
|
35
|
Hammerich L, Tacke F. Emerging roles of myeloid derived suppressor cells in hepatic inflammation and fibrosis. World J Gastrointest Pathophysiol 2015; 6:43-50. [PMID: 26301117 PMCID: PMC4540705 DOI: 10.4291/wjgp.v6.i3.43] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/09/2015] [Revised: 03/16/2015] [Accepted: 06/02/2015] [Indexed: 02/06/2023] Open
Abstract
Myeloid derived suppressor cells (MDSC) are a heterogeneous population of immune cells that are potent suppressors of immune responses. MDSC emerge in various compartments in the body, such as blood, bone marrow or spleen, especially in conditions of cancer, infections or inflammation. MDSC usually express CD11b, CD33, and low levels of human leukocyte antigen-DR in humans or CD11b and Gr1 (Ly6C/G) in mice, and they can be further divided into granulocytic or monocytic MDSC. The liver is an important organ for MDSC induction and accumulation in hepatic as well as extrahepatic diseases. Different hepatic cells, especially hepatic stellate cells, as well as liver-derived soluble factors, including hepatocyte growth factor and acute phase proteins (SAA, KC), can promote the differentiation of MDSC from myeloid cells. Importantly, hepatic myeloid cells like neutrophils, monocytes and macrophages fulfill essential roles in acute and chronic liver diseases. Recent data from patients with liver diseases and animal models linked MDSC to the pathogenesis of hepatic inflammation, fibrosis and hepatocellular carcinoma (HCC). In settings of acute hepatitis, MDSC can limit immunogenic T cell responses and subsequent tissue injury. In patients with chronic hepatitis C, MDSC increase and may favor viral persistence. Animal models of chronic liver injury, however, have not yet conclusively clarified the involvement of MDSC for hepatic fibrosis. In human HCC and mouse models of liver cancer, MDSC are induced in the tumor environment and suppress anti-tumoral immune responses. Thus, the liver is a primary site of MDSC in vivo, and modulating MDSC functionality might represent a promising novel therapeutic target for liver diseases.
Collapse
|
|
36
|
Sido JM, Nagarkatti PS, Nagarkatti M. Δ⁹-Tetrahydrocannabinol attenuates allogeneic host-versus-graft response and delays skin graft rejection through activation of cannabinoid receptor 1 and induction of myeloid-derived suppressor cells. J Leukoc Biol 2015; 98:435-47. [PMID: 26034207 DOI: 10.1189/jlb.3a0115-030rr] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2015] [Accepted: 05/06/2015] [Indexed: 12/18/2022] Open
Abstract
Immune cells have been shown to express cannabinoid receptors and to produce endogenous ligands. Moreover, activation of cannabinoid receptors on immune cells has been shown to trigger potent immunosuppression. Despite such studies, the role of cannabinoids in transplantation, specifically to prevent allograft rejection, has not, to our knowledge, been investigated previously. In the current study, we tested the effect of THC on the suppression of HvGD as well as rejection of skin allografts. To this end, we studied HvGD by injecting H-2(k) splenocytes into H-2(b) mice and analyzing the immune response in the draining ingLNs. THC treatment significantly reduced T cell proliferation and activation in draining LNs of the recipient mice and decreased early stage rejection-indicator cytokines, including IL-2 and IFN-γ. THC treatment also increased the allogeneic skin graft survival. THC treatment in HvGD mice led to induction of MDSCs. Using MDSC depletion studies as well as adoptive transfer experiments, we found that THC-induced MDSCs were necessary for attenuation of HvGD. Additionally, using pharmacological inhibitors of CB1 and CB2 receptors and CB1 and CB2 knockout mice, we found that THC was working preferentially through CB1. Together, our research shows, for the first time to our knowledge, that targeting cannabinoid receptors may provide a novel treatment modality to attenuate HvGD and prevent allograft rejection.
Collapse
Affiliation(s)
- Jessica M Sido
- *Department of Pathology, Microbiology, and Immunology, University of South Carolina School of Medicine, Columbia, South Carolina, USA; and William Jennings Bryan Dorn Veterans Affairs Medical Center, Columbia, South Carolina, USA
| | - Prakash S Nagarkatti
- *Department of Pathology, Microbiology, and Immunology, University of South Carolina School of Medicine, Columbia, South Carolina, USA; and William Jennings Bryan Dorn Veterans Affairs Medical Center, Columbia, South Carolina, USA
| | - Mitzi Nagarkatti
- *Department of Pathology, Microbiology, and Immunology, University of South Carolina School of Medicine, Columbia, South Carolina, USA; and William Jennings Bryan Dorn Veterans Affairs Medical Center, Columbia, South Carolina, USA
| |
Collapse
|
|
37
|
Lin D, Lei L, Zhang Y, Hu B, Bao G, Liu Y, Song Y, Liu C, Wu Y, Zhao L, Yu X, Liu H. Secreted IL-1α promotes T-cell activation and expansion of CD11b+Gr1+cells in carbon tetrachloride-induced liver injury in mice. Eur J Immunol 2015; 45:2084-98. [DOI: 10.1002/eji.201445195] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2014] [Revised: 03/05/2015] [Accepted: 04/10/2015] [Indexed: 01/28/2023]
Affiliation(s)
- Dandan Lin
- Laboratory of Cellular and Molecular Tumor Immunology; Jiangsu Key Laboratory of Infection and Immunity, Institutes of Biology and Medical Sciences, Soochow University; Suzhou Jiangsu China
| | - Lei Lei
- Laboratory of Cellular and Molecular Tumor Immunology; Jiangsu Key Laboratory of Infection and Immunity, Institutes of Biology and Medical Sciences, Soochow University; Suzhou Jiangsu China
| | - Yinsheng Zhang
- Laboratory of Cellular and Molecular Tumor Immunology; Jiangsu Key Laboratory of Infection and Immunity, Institutes of Biology and Medical Sciences, Soochow University; Suzhou Jiangsu China
| | - Bo Hu
- Laboratory of Cellular and Molecular Tumor Immunology; Jiangsu Key Laboratory of Infection and Immunity, Institutes of Biology and Medical Sciences, Soochow University; Suzhou Jiangsu China
| | - Guangming Bao
- Laboratory of Cellular and Molecular Tumor Immunology; Jiangsu Key Laboratory of Infection and Immunity, Institutes of Biology and Medical Sciences, Soochow University; Suzhou Jiangsu China
| | - Yonghao Liu
- Laboratory of Cellular and Molecular Tumor Immunology; Jiangsu Key Laboratory of Infection and Immunity, Institutes of Biology and Medical Sciences, Soochow University; Suzhou Jiangsu China
| | - Yuan Song
- Laboratory of Cellular and Molecular Tumor Immunology; Jiangsu Key Laboratory of Infection and Immunity, Institutes of Biology and Medical Sciences, Soochow University; Suzhou Jiangsu China
| | - Chunliang Liu
- Laboratory of Cellular and Molecular Tumor Immunology; Jiangsu Key Laboratory of Infection and Immunity, Institutes of Biology and Medical Sciences, Soochow University; Suzhou Jiangsu China
| | - Yan Wu
- Laboratory of Cellular and Molecular Tumor Immunology; Jiangsu Key Laboratory of Infection and Immunity, Institutes of Biology and Medical Sciences, Soochow University; Suzhou Jiangsu China
| | - Lixiang Zhao
- Laboratory of Cellular and Molecular Tumor Immunology; Jiangsu Key Laboratory of Infection and Immunity, Institutes of Biology and Medical Sciences, Soochow University; Suzhou Jiangsu China
| | - Xiao Yu
- Laboratory of Cellular and Molecular Tumor Immunology; Jiangsu Key Laboratory of Infection and Immunity, Institutes of Biology and Medical Sciences, Soochow University; Suzhou Jiangsu China
| | - Haiyan Liu
- Laboratory of Cellular and Molecular Tumor Immunology; Jiangsu Key Laboratory of Infection and Immunity, Institutes of Biology and Medical Sciences, Soochow University; Suzhou Jiangsu China
- Cyrus Tang Hematology Center; Department of Hematology, Collaborative Innovation Center of Hematology, the First Affiliated Hospital of Soochow University, Jiangsu Institute of Hematology and Key Laboratory of Thrombosis and Hemostasis Ministry of Health; Suzhou Jiangsu China
| |
Collapse
|
|
38
|
Wu T, Zhao Y, Zhao Y. The roles of myeloid-derived suppressor cells in transplantation. Expert Rev Clin Immunol 2014; 10:1385-94. [DOI: 10.1586/1744666x.2014.948424] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023]
|