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Liu H, Yang R, Zhong H, Zhang Y, Wang S, Guo K, Jiang Z, He J, Huang Y, Lin Y, Chen X, Lin J. Mechanism of Qingjie Fuzheng Granules in inhibiting colitis associated colorectal cancer by regulating TLR4 and IL-4R mediated macrophage polarization. JOURNAL OF ETHNOPHARMACOLOGY 2025; 344:119511. [PMID: 39978444 DOI: 10.1016/j.jep.2025.119511] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/15/2024] [Revised: 02/14/2025] [Accepted: 02/15/2025] [Indexed: 02/22/2025]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Qingjie Fuzheng Granules (QFG), a herbal formula, has been employed as an adjuvant therapy for colitis-associated colorectal cancer (CAC), yet the underlying mechanisms by which QFG operates remain unclear. AIMS OF THE STUDY The aim of this study is to investigate whether the potential mechanism of QFG against CAC is associated with macrophage polarization. MATERIALS AND METHODS Non-targeted metabolomics and molecular docking assessed potential compounds of QFG to interact with targets associated with macrophage polarization. A model of AOM/DSS-induced CAC mice was established to analyze the effects of QFG on macrophage polarization using flow cytometry and immunohistochemical staining. In vitro experiments involved models of Ana-1 macrophages, either induced by varying QFG concentrations or with MD2 knockdown, to analyze M1-like phenotype. Meanwhile, M2-like macrophages models induced by IL-4 or culture supernatant of CT26 cells were utilized to assess the effects of QFG on M2-like macrophages. Finally, the mRNA expression of M1-like phenotype related to TLR4 pathways and the protein expression in IL-4R-mediated pathways were analyzed using RT-qPCR and Western blot, respectively. RESULTS Molecular docking confirmed the presence of binding sites between the ingredients of QFG and IL-4R or TLR4/MD2 receptor complex. QFG could induce a shift in macrophages towards an M1-like phenotype while inhibiting an M2-like phenotype in the colon with CAC mice and Ana-1 macrophages. QFG resulted in the upregulation of iNOS, IL-6, IL-1β, and TNF-α mRNA expression, which could be counteracted by TAK242, SR11302, INH14, PDTC, and LY294002, or by the knockdown of MD2. Meanwhile, QFG inhibited IL-4R-induced phosphorylation of STAT 6 and Akt. CONCLUSION Various monomer components within QFG can bind to MD2 or IL-4R, respectively, thereby inducing macrophages towards an M1-like phenotype through TLR4-mediated NF-κB, MAPK, and PI3K/Akt pathway activation, or inhibiting macrophages towards an M2-like phenotype via IL-4R-mediated JAKs pathway inhibition, ultimately exerting an inhibitory effect on the occurrence and development of CAC.
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Affiliation(s)
- Haiqin Liu
- College of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian Province, 350122, China; Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian Province, 350122, China; Fujian Key Laboratory of Integrative Medicine on Geriatrics, Fuzhou, Fujian Province, 350122, China
| | - Ruiming Yang
- College of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian Province, 350122, China; Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian Province, 350122, China; Fujian Key Laboratory of Integrative Medicine on Geriatrics, Fuzhou, Fujian Province, 350122, China
| | - Hangyan Zhong
- College of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian Province, 350122, China; Department of Proctology, Shanghang Hospital of Traditional Chinese Medicine, Longyan, Fujian Province, 364200, China
| | - Youquan Zhang
- The Second People's Hospital Affiliated to Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian Province, 350001, China
| | - Shunyong Wang
- College of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian Province, 350122, China
| | - Kangyue Guo
- College of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian Province, 350122, China
| | - Zhishan Jiang
- College of Pharmacy, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian Province, 350122, China
| | - Jiajun He
- College of Pharmacy, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian Province, 350122, China
| | - Yunmei Huang
- College of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian Province, 350122, China; Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian Province, 350122, China; Fujian Key Laboratory of Integrative Medicine on Geriatrics, Fuzhou, Fujian Province, 350122, China
| | - Ying Lin
- Shengli Clinical Medical College of Fujian Medical University, Fuzhou, Fujian Province, 350001, China; Department of Pathology, Fuzhou University Affiliated Provincial Hospital, Fuzhou, Fujian Province, 350001, China
| | - Xuzheng Chen
- College of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian Province, 350122, China; Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian Province, 350122, China; Fujian Key Laboratory of Integrative Medicine on Geriatrics, Fuzhou, Fujian Province, 350122, China.
| | - Jiumao Lin
- College of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian Province, 350122, China; Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian Province, 350122, China; Fujian Key Laboratory of Integrative Medicine on Geriatrics, Fuzhou, Fujian Province, 350122, China.
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Zhang YW, Sun L, Wang YN, Zhan SY. Role of macrophage polarization in diabetic foot ulcer healing: A bibliometric study. World J Diabetes 2025; 16:99755. [PMID: 39817209 PMCID: PMC11718451 DOI: 10.4239/wjd.v16.i1.99755] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/02/2024] [Revised: 10/28/2024] [Accepted: 11/18/2024] [Indexed: 11/29/2024] Open
Abstract
BACKGROUND Diabetic foot ulcers (DFUs) are a significant contributor to disability and mortality in diabetic patients. Macrophage polarization and functional regulation are promising areas of research and show therapeutic potential in the field of DFU healing. However, the complex mechanism, the difficulty in clinical translation, and the large heterogeneity present significant challenges. Hence, this study was to comprehensively analyze the publication status and trends of studies on macrophage polarization and DFU healing. AIM To examine the relevant literature on macrophage polarization in DFU healing. METHODS A bibliometric analysis was conducted using the Web of Science database. Relevant literature was retrieved from the Web of Science Core Collection database between 2013 to 2023 using literature visualization and analysis software (VOSviewer and CiteSpace) and bibliometric online platforms. The obtained literature was then subjected to visualization and analysis of different countries/regions, institutions, journals, authors, and keywords to reveal the research's major trends and focus. RESULTS The number of publications on the role of macrophage polarization in DFU healing increased rapidly from 2013 to 2023, especially in the latter period. Chinese researchers were the most prolific in this field, with 217 publications, while American researchers had been engaged in this field for a longer period. Qian Tan of Nanjing Drum Tower Hospital and Qian Ding of Nanjing University were the first to publish in this field. Shanghai Jiao Tong University was the institution with the most publications (27). The keywords "bone marrow", "adjustment, replacement, response, tissue repair", and "activation, repair, differentiation" appeared more frequently. The study of macrophage polarization in DFU healing focused on the regulatory mechanism, gene expression, and other aspects. CONCLUSION This study through the bibliometric method reveals the research trends and development trends in this field of macrophage polarization in DFU healing from 2013 to 2023 in the Web of Science Core Collection database. The key hotspots in this field mainly include the regulation of macrophage activation, gene expression, wound tissue repair, and new wound materials. This study provides references for future research directions.
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Affiliation(s)
- You-Wen Zhang
- Department of Peripheral Vascular Disease, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan 250014, Shandong Province, China
| | - Lei Sun
- Department of Surgery, The Second Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan 250001, Shandong Province, China
| | - Yan-Nan Wang
- Department of Peripheral Vascular Disease, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan 250014, Shandong Province, China
| | - Shi-Yu Zhan
- Department of Surgery, Longkou Traditional Chinese Medicine Hospital, Yantai 265701, Shandong Province, China
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Huang Y, Tian Z, Bi J. Intracellular checkpoints for NK cell cancer immunotherapy. Front Med 2024; 18:763-777. [PMID: 39340588 DOI: 10.1007/s11684-024-1090-6] [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: 02/08/2024] [Accepted: 05/17/2024] [Indexed: 09/30/2024]
Abstract
Natural killer (NK) cells are key innate immune lymphocytes, which play important roles against tumors. However, tumor-infiltrating NK cells are always hypofunctional/exhaustive. On the one hand, this state is contributed by context-dependent interactions between inhibitory NK cell checkpoint receptors and their ligands, which usually vary in different tumor types and stages during tumor development. On the other hand, the inhibitory functions of intracellular checkpoint molecules of NK cells are more similar across different tumor types, representing common mechanisms limiting the potential of NK cell therapy. In this review, representative NK cell intracellular checkpoint molecules in different aspects of NK cell biology were reviewed, and therapeutic potentials were discussed by targeting these molecules to promote antitumor NK cell therapy.
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Affiliation(s)
- Yingying Huang
- CAS Key Laboratory of Quantitative Engineering Biology, Shenzhen Institute of Synthetic Biology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 518055, China
- Department of Urology, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, China
- Center for Genomic and Personalized Medicine, Guangxi Medical University, Nanning, 530021, China
- Guangxi Collaborative Innovation Center for Genomic and Personalized Medicine, Nanning, 530021, China
- Guangxi Key Laboratory for Genomic and Personalized Medicine, Guangxi Key Laboratory of Colleges and Universities, Nanning, 530021, China
- Collaborative Innovation Center of Regenerative Medicine and Medical BioResource Development and Application, Guangxi Medical University, Nanning, 530021, China
| | - Zhigang Tian
- CAS Key Laboratory of Quantitative Engineering Biology, Shenzhen Institute of Synthetic Biology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 518055, China
- The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230027, China
- Institute of Immunology, University of Science and Technology of China, Hefei, 230027, China
- Research Unit of NK Cell Study, Chinese Academy of Medical Sciences, Beijing, 100864, China
| | - Jiacheng Bi
- CAS Key Laboratory of Quantitative Engineering Biology, Shenzhen Institute of Synthetic Biology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 518055, China.
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Matsui M, Kajikuri J, Kito H, Elboray EE, Suzuki T, Ohya S. Downregulation of IL-8 and IL-10 by LRRC8A Inhibition through the NOX2-Nrf2-CEBPB Transcriptional Axis in THP-1-Derived M 2 Macrophages. Int J Mol Sci 2024; 25:9612. [PMID: 39273558 PMCID: PMC11395230 DOI: 10.3390/ijms25179612] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2024] [Revised: 08/30/2024] [Accepted: 09/02/2024] [Indexed: 09/15/2024] Open
Abstract
M2-polarized, tumor-associated macrophages (TAMs) produce pro-tumorigenic and angiogenic mediators, such as interleukin-8 (IL-8) and IL-10. Leucine-rich repeat-containing protein 8 members (LRRC8s) form volume-regulated anion channels and play an important role in macrophage functions by regulating cytokine and chemokine production. We herein examined the role of LRRC8A in IL-8 and IL-10 expression in THP-1-differentiated M2-like macrophages (M2-MACs), which are a useful tool for investigating TAMs. In M2-MACs, the pharmacological inhibition of LRRC8A led to hyperpolarizing responses after a transient depolarization phase, followed by a slight elevation in the intracellular concentration of Ca2+. Both the small interfering RNA-mediated and pharmacological inhibition of LRRC8A repressed the transcriptional expression of IL-8 and IL-10, resulting in a significant reduction in their secretion. The inhibition of LRRC8A decreased the nuclear translocation of phosphorylated nuclear factor-erythroid 2-related factor 2 (Nrf2), while the activation of Nrf2 reversed the LRRC8A inhibition-induced transcriptional repression of IL-8 and IL-10 in M2-MACs. We identified the CCAAT/enhancer-binding protein isoform B, CEBPB, as a downstream target of Nrf2 signaling in M2-MACs. Moreover, among several upstream candidates, the inhibition of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 2 (NOX2) suppressed the Nrf2-CEBPB transcriptional axis in M2-MACs. Collectively, the present results indicate that the inhibition of LRRC8A repressed IL-8 and IL-10 transcription in M2-MACs through the NOX2-Nrf2-CEBPB axis and suggest that LRRC8A inhibitors suppress the IL-10-mediated evasion of tumor immune surveillance and IL-8-mediated metastasis and neovascularization in TAMs.
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Affiliation(s)
- Miki Matsui
- Department of Pharmacology, Graduate School of Medical Sciences, Nagoya City University, Nagoya 467-8601, Japan; (M.M.); (J.K.); (H.K.)
| | - Junko Kajikuri
- Department of Pharmacology, Graduate School of Medical Sciences, Nagoya City University, Nagoya 467-8601, Japan; (M.M.); (J.K.); (H.K.)
| | - Hiroaki Kito
- Department of Pharmacology, Graduate School of Medical Sciences, Nagoya City University, Nagoya 467-8601, Japan; (M.M.); (J.K.); (H.K.)
| | - Elghareeb E. Elboray
- Department of Complex Molecular Chemistry, SANKEN, Osaka University, Osaka 560-0043, Japan; (E.E.E.); (T.S.)
- Department of Chemistry, Faculty of Science, South Valley University, Qena 83523, Egypt
| | - Takayoshi Suzuki
- Department of Complex Molecular Chemistry, SANKEN, Osaka University, Osaka 560-0043, Japan; (E.E.E.); (T.S.)
| | - Susumu Ohya
- Department of Pharmacology, Graduate School of Medical Sciences, Nagoya City University, Nagoya 467-8601, Japan; (M.M.); (J.K.); (H.K.)
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Qin Z, Han Y, Du Y, Zhang Y, Bian Y, Wang R, Wang H, Guo F, Yuan H, Pan Y, Jin J, Zhou Q, Wang Y, Han F, Xu Y, Jiang J. Bioactive materials from berberine-treated human bone marrow mesenchymal stem cells promote alveolar bone regeneration by regulating macrophage polarization. SCIENCE CHINA. LIFE SCIENCES 2024; 67:1010-1026. [PMID: 38489007 DOI: 10.1007/s11427-023-2454-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/15/2023] [Accepted: 09/19/2023] [Indexed: 03/17/2024]
Abstract
Alveolar bone regeneration has been strongly linked to macrophage polarization. M1 macrophages aggravate alveolar bone loss, whereas M2 macrophages reverse this process. Berberine (BBR), a natural alkaloid isolated and refined from Chinese medicinal plants, has shown therapeutic effects in treating metabolic disorders. In this study, we first discovered that culture supernatant (CS) collected from BBR-treated human bone marrow mesenchymal stem cells (HBMSCs) ameliorated periodontal alveolar bone loss. CS from the BBR-treated HBMSCs contained bioactive materials that suppressed the M1 polarization and induced the M2 polarization of macrophages in vivo and in vitro. To clarify the underlying mechanism, the bioactive materials were applied to different animal models. We discovered macrophage colony-stimulating factor (M-CSF), which regulates macrophage polarization and promotes bone formation, a key macromolecule in the CS. Injection of pure M-CSF attenuated experimental periodontal alveolar bone loss in rats. Colony-stimulating factor 1 receptor (CSF1R) inhibitor or anti-human M-CSF (M-CSF neutralizing antibody, Nab) abolished the therapeutic effects of the CS of BBR-treated HBMSCs. Moreover, AKT phosphorylation in macrophages was activated by the CS, and the AKT activator reversed the negative effect of the CSF1R inhibitor or Nab. These results suggest that the CS of BBR-treated HBMSCs modulates macrophage polarization via the M-CSF/AKT axis. Further studies also showed that CS of BBR-treated HBMSCs accelerated bone formation and M2 polarization in rat teeth extraction sockets. Overall, our findings established an essential role of BBR-treated HBMSCs CS and this might be the first report to show that the products of BBR-treated HBMSCs have active effects on alveolar bone regeneration.
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Affiliation(s)
- Ziyue Qin
- Department of Oral and Maxillofacial Surgery, The Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, 210029, China
- Jiangsu Province Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing, 210029, China
- Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Nanjing, 210029, China
| | - Yanxing Han
- State Key Laboratory of Bioactive Substances and Function of Natural Medicine, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China
| | - Yifei Du
- Department of Oral and Maxillofacial Surgery, The Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, 210029, China
- Jiangsu Province Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing, 210029, China
- Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Nanjing, 210029, China
| | - Yixuan Zhang
- Gusu school, Nanjing medical university, Suzhou, 215002, China
- Key Laboratory of Cardiovascular & Cerebrovascular Medicine, Drug Target and Drug Discovery Center, School of Pharmacy, Nanjing Medical University, Nanjing, 211166, China
| | - Yifeng Bian
- Department of Oral and Maxillofacial Surgery, The Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, 210029, China
- Jiangsu Province Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing, 210029, China
- Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Nanjing, 210029, China
| | - Ruyu Wang
- Department of Oral and Maxillofacial Surgery, The Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, 210029, China
- Jiangsu Province Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing, 210029, China
- Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Nanjing, 210029, China
| | - Haoran Wang
- Department of Oral and Maxillofacial Surgery, The Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, 210029, China
- Jiangsu Province Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing, 210029, China
- Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Nanjing, 210029, China
| | - Fanyi Guo
- Department of Oral and Maxillofacial Surgery, The Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, 210029, China
- Jiangsu Province Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing, 210029, China
- Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Nanjing, 210029, China
| | - Hua Yuan
- Department of Oral and Maxillofacial Surgery, The Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, 210029, China
- Jiangsu Province Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing, 210029, China
- Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Nanjing, 210029, China
| | - Yongchu Pan
- Jiangsu Province Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing, 210029, China
- Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Nanjing, 210029, China
- Department of Orthodontics, The Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, 210029, China
| | - Jianliang Jin
- Department of Human Anatomy, Research Centre for Bone and Stem Cells, Key Laboratory for Aging & Disease, The State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, 211166, China
| | - Qigang Zhou
- Department of Clinical Pharmacology, School of Pharmacy, Nanjing Medical University, Nanjing Jiangsu, 211166, China
| | - Yuli Wang
- Department of Oral and Maxillofacial Surgery, The Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, 210029, China.
- Jiangsu Province Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing, 210029, China.
- Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Nanjing, 210029, China.
| | - Feng Han
- Key Laboratory of Cardiovascular & Cerebrovascular Medicine, Drug Target and Drug Discovery Center, School of Pharmacy, Nanjing Medical University, Nanjing, 211166, China.
| | - Yan Xu
- Jiangsu Province Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing, 210029, China.
- Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Nanjing, 210029, China.
- Department of Periodontology, The Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, 210029, China.
| | - Jiandong Jiang
- Department of Virology, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China
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Li Y, Yin C, Jiang J, Yang H, Zhang F, Xing Y, Wang W, Lu C. Tumor necrosis factor α-induced protein 8-like-2 controls microglia phenotype via metabolic reprogramming in BV2 microglial cells and responses to neuropathic pain. Int J Biochem Cell Biol 2024; 169:106541. [PMID: 38309648 DOI: 10.1016/j.biocel.2024.106541] [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: 06/16/2023] [Revised: 01/07/2024] [Accepted: 01/28/2024] [Indexed: 02/05/2024]
Abstract
Microglial are major players in neuroinflammation that have recently emerged as potential therapeutic targets for neuropathic pain. Glucose metabolic programming has been linked to differential activation state and function in microglia. Tumor necrosis factor α-induced protein 8-like-2 (TNFAIP8L2) is an important component in regulating the anti-inflammatory response. However, the role of TNFAIP8L2 in microglia differential state during neuropathic pain and its interplay with glucose metabolic reprogramming in microglia has not yet been determined. Thus, we aimed to investigate the role of TNFAIP8L2 in the status of microglia in vitro and in vivo. BV2 microglial cells were treated with lipopolysaccharides plus interferon-gamma (LPS/IFNγ) or interleukin-4 (IL-4) to induce the two different phenotypes of microglia in vitro. In vivo experiments were conducted by chronic constriction injury of the sciatic nerve (CCI). We investigated whether TNFAIP8L2 regulates glucose metabolic programming in BV2 microglial cells. The data in vitro showed that TNFAIP8L2 lowers glycolysis and increases mitochondrial oxidative phosphorylation (OXPHOS) in inflammatory microglia. Blockade of glycolytic pathway abolished TNFAIP8L2-mediated differential activation of microglia. TNFAIP8L2 suppresses inflammatory microglial activation and promotes restorative microglial activation in BV2 microglial cells and in spinal cord microglia after neuropathic pain. Furthermore, TNFAIP8L2 controls differential activation of microglia and glucose metabolic reprogramming through the MAPK/mTOR/HIF-1α signaling axis. This study reveals that TNFAIP8L2 plays a critical role in neuropathic pain, providing important insights into glucose metabolic reprogramming and microglial phenotypic transition, which indicates that TNFAIP8L2 may be used as a potential drug target for the prevention of neuropathic pain.
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Affiliation(s)
- Yeqi Li
- School of Anesthesiology, Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Cui Yin
- School of Anesthesiology, Xuzhou Medical University, Xuzhou, Jiangsu, China; Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Jinhong Jiang
- School of Anesthesiology, Xuzhou Medical University, Xuzhou, Jiangsu, China; Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Huan Yang
- School of Anesthesiology, Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Feifei Zhang
- School of Anesthesiology, Xuzhou Medical University, Xuzhou, Jiangsu, China; Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Yanhong Xing
- School of Anesthesiology, Xuzhou Medical University, Xuzhou, Jiangsu, China; Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Wuyang Wang
- School of Anesthesiology, Xuzhou Medical University, Xuzhou, Jiangsu, China; Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical University, Xuzhou, Jiangsu, China.
| | - Chen Lu
- School of Anesthesiology, Xuzhou Medical University, Xuzhou, Jiangsu, China; Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical University, Xuzhou, Jiangsu, China.
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Xu L, Pan F, Guo Z. TIPE2: A Candidate for Targeting Antitumor Immunotherapy. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2024; 212:755-763. [PMID: 38377476 DOI: 10.4049/jimmunol.2300433] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/07/2023] [Accepted: 12/18/2023] [Indexed: 02/22/2024]
Abstract
TNF-α-induced protein 8-like 2 (TIPE2 or TNFAIP8L2) is a recently discovered negative regulator of innate and adaptive immunity. TIPE2 is expressed in a wide range of tissues, both immune and nonimmune, and is implicated in the maintenance of immune homeostasis within the immune system. Furthermore, TIPE2 has been shown to play a pivotal role in the regulation of inflammation and the development of tumor. This review focuses on the structural characteristics, expression patterns, and functional roles of TIPE proteins, with a particular emphasis on the role and underlying mechanisms of TIPE2 in immune regulation and its involvement in different diseases. However, the current body of evidence is still limited in providing a comprehensive understanding of the complex role of TIPE2 in the human body, warranting further investigation to elucidate the possible mechanisms and functions of TIPE2 in diverse disease contexts.
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Affiliation(s)
- Luxia Xu
- Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing, China
| | - Feiyan Pan
- Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing, China
| | - Zhigang Guo
- Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing, China
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Fan X, Zheng S, Chen C, Lin L, Wang H, Shen Y, Pan Y, Li C. Sialidase facilitates Porphyromonas gingivalis immune evasion by reducing M1 polarization, antigen presentation, and phagocytosis of infected macrophages. Front Cell Infect Microbiol 2023; 13:1173899. [PMID: 37325520 PMCID: PMC10266273 DOI: 10.3389/fcimb.2023.1173899] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2023] [Accepted: 05/15/2023] [Indexed: 06/17/2023] Open
Abstract
Background Porphyromonas gingivalis (P. gingivalis), a major pathogen of periodontitis, can evade host immune defenses. Previously, we found that P. gingivalis W83 sialidase gene mutant strain (ΔPG0352) was more easily cleared by macrophages. The aims of this study were to investigate the effects of sialidase in P. gingivalis on the polarization, antigen presentation, and phagocytosis of infected macrophages and to clarify the mechanism of P. gingivalis immune evasion. Methods Human monocytes U937 were differentiated to macrophages and infected with P. gingivalis W83, ΔPG0352, comΔPG0352, and Escherichia coli (E. coli). The phagocytosis of macrophages was observed by transmission electron microscopy and flow cytometry. ELISA or Griess reaction were used to examine the levels of interleukin-12 (IL-12), inducible nitric oxide synthase (iNOS) and interleukin-10 (IL-10), and the expressions of CD68, CD80 and CD206 were determined by flow cytometry. The expression of major histocompatibility complex-II (MHC-II) was detected by immunofluorescence. A rat periodontitis model was established to determine the M1 and M2 polarization of macrophages. Results Compare with P. gingivalis W83, ΔPG0352 increased the levels of IL-12, iNOS, CD80, and MHC-II and inhibited the levels of IL-10 and CD206. Macrophages phagocytosed 75.4% of ΔPG0352 and 59.5% of P. gingivalis W83. In the rat periodontitis model, the levels of M1 and M2 macrophages in P. gingivalis W83 group were both higher than those in ΔPG0352 group, while the ratio of M1/M2 was higher in the ΔPG0352 group. Alveolar bone absorption was lower in ΔPG0352 group. Conclusion Sialidase facilitates P. gingivalis immune evasion by reducing M1 polarization, antigen presentation, and phagocytosis of infected macrophages.
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Affiliation(s)
- Xiaomiao Fan
- Department of Periodontology, School and Hospital of Stomatology, China Medical University, Liaoning Provincial Key Laboratory of Oral Disease, Shenyang, Liaoning, China
- Department of Periodontics, Affiliated Stomatology Hospital of Guangzhou Medical University, Guangdong Engineering Research Center of Oral Restoration and Reconstruction, Guangzhou Key Laboratory of Basic and Applied Research of Oral Regenerative Medicine, Guangzhou, Guangdong, China
| | - Shaowen Zheng
- Department of Periodontology, School and Hospital of Stomatology, China Medical University, Liaoning Provincial Key Laboratory of Oral Disease, Shenyang, Liaoning, China
| | - Chen Chen
- Department of Periodontology, School and Hospital of Stomatology, China Medical University, Liaoning Provincial Key Laboratory of Oral Disease, Shenyang, Liaoning, China
| | - Li Lin
- Department of Periodontology, School and Hospital of Stomatology, China Medical University, Liaoning Provincial Key Laboratory of Oral Disease, Shenyang, Liaoning, China
| | - Hongyan Wang
- Department of Periodontology, School and Hospital of Stomatology, China Medical University, Liaoning Provincial Key Laboratory of Oral Disease, Shenyang, Liaoning, China
| | - Yuqin Shen
- Department of Periodontics, Affiliated Stomatology Hospital of Guangzhou Medical University, Guangdong Engineering Research Center of Oral Restoration and Reconstruction, Guangzhou Key Laboratory of Basic and Applied Research of Oral Regenerative Medicine, Guangzhou, Guangdong, China
| | - Yaping Pan
- Department of Periodontology, School and Hospital of Stomatology, China Medical University, Liaoning Provincial Key Laboratory of Oral Disease, Shenyang, Liaoning, China
| | - Chen Li
- Department of Periodontology, School and Hospital of Stomatology, China Medical University, Liaoning Provincial Key Laboratory of Oral Disease, Shenyang, Liaoning, China
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9
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Zhang L, Guo D, Shen J, Zheng Y, Zhai J, Li R, He D, Zhang B. Tissue mechanics modulate PCNP expression in oral squamous cell carcinomas with different differentiation. Front Oncol 2023; 12:1072276. [PMID: 36703786 PMCID: PMC9873348 DOI: 10.3389/fonc.2022.1072276] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2022] [Accepted: 12/19/2022] [Indexed: 01/11/2023] Open
Abstract
Background PEST-containing nuclear protein (PCNP), a novel zinc finger protein, participates in cell cycle regulation. Previous studies have confirmed that PCNP plays a role in mediating cellular development and invasion in a variety of cancer types. However, the relationship between PCNP expression and the occurrence and development of oral squamous cell carcinoma (OSCC) requires further exploration. In this study, we used biological atomic force microscopy to examine the histomorphological and mechanical properties of OSCC to explore the relationship between PCNP expression and differentiation of OSCC. Methods Seventy-seven OSCC samples with varying degrees of differentiation were selected for hematoxylin and eosin staining, immunohistochemistry, and cellular mechanical measurement. The expression of PCNP and the mechanical properties such as stiffness and roughness of the tissue interface in OSCC samples were investigated. The Kaplan-Meier survival curve was utilized to assess the relationship of PCNP expression with patient survival. Results The level of PCNP was significantly higher in well-differentiated OSCC than in moderately and poorly differentiated OSCC (P < 0.001). High expression of PCNP was specifically associated with higher tumor differentiation, lack of lymph node metastasis, and lower tumor node metastasis stage (all P < 0.05). Patients with high PCNP expression had a higher survival rate than those with low PCNP expression. The average variation of stiffness within a single tissue ranged from 347 kPa to 539 kPa. The mean surface roughness of highly, moderately, and poorly differentiated OSCC and paraneoplastic tissues were 795.53 ± 47.2 nm, 598.37 ± 45.76 nm, 410.16 ± 38.44 nm, and 1010.94 ± 119.07 nm, respectively. Pearson correlation coefficient demonstrated a positive correlation between PCNP expression and tissue stiffness of OSCC (R = 0.86, P < 0.001). Conclusion The expression of PCNP was positively correlated with patient survival, tumor differentiation, and mechanical properties of tissue interfaces. PCNP is a potential biomarker for the early diagnosis and staging of OSCC. Furthermore, determination of the mechanical properties of the tissue interface could provide further useful information required for the detection and differentiation of OSCC.
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Affiliation(s)
- Leyang Zhang
- School (Hospital) of Stomatology Lanzhou University, Lanzhou, China,The First Hospital of Lanzhou University, Lanzhou, China
| | - Dingcheng Guo
- School (Hospital) of Stomatology Lanzhou University, Lanzhou, China
| | - Junjie Shen
- School (Hospital) of Stomatology Lanzhou University, Lanzhou, China
| | - Yayuan Zheng
- School (Hospital) of Stomatology Lanzhou University, Lanzhou, China
| | - Junkai Zhai
- School (Hospital) of Stomatology Lanzhou University, Lanzhou, China
| | - Ruiping Li
- School (Hospital) of Stomatology Lanzhou University, Lanzhou, China,Gansu Province Key Lab of Maxillofacial Reconstruction and Intelligent Manufacturing, Lanzhou University, Lanzhou, China,*Correspondence: Ruiping Li, ; Dengqi He, ; Baoping Zhang,
| | - Dengqi He
- The First Hospital of Lanzhou University, Lanzhou, China,*Correspondence: Ruiping Li, ; Dengqi He, ; Baoping Zhang,
| | - Baoping Zhang
- School (Hospital) of Stomatology Lanzhou University, Lanzhou, China,Gansu Province Key Lab of Maxillofacial Reconstruction and Intelligent Manufacturing, Lanzhou University, Lanzhou, China,Gansu Provincial Clinical Research Center for Oral Disease, Lanzhou University, Lanzhou, China,Institute of Biomechanics and Medical Engineering, Lanzhou University, Lanzhou, China,Key Laboratory of Mechanics on Disaster and Environment in Western China, Ministry of Education, College of Civil Engineering and Mechanics, Lanzhou University, Lanzhou, China,*Correspondence: Ruiping Li, ; Dengqi He, ; Baoping Zhang,
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10
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Wang L, He C. Nrf2-mediated anti-inflammatory polarization of macrophages as therapeutic targets for osteoarthritis. Front Immunol 2022; 13:967193. [PMID: 36032081 PMCID: PMC9411667 DOI: 10.3389/fimmu.2022.967193] [Citation(s) in RCA: 100] [Impact Index Per Article: 33.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2022] [Accepted: 07/27/2022] [Indexed: 12/14/2022] Open
Abstract
Macrophages are the most abundant immune cells within the synovial joints, and also the main innate immune effector cells triggering the initial inflammatory responses in the pathological process of osteoarthritis (OA). The transition of synovial macrophages between pro-inflammatory and anti-inflammatory phenotypes can play a key role in building the intra-articular microenvironment. The pro-inflammatory cascade induced by TNF-α, IL-1β, and IL-6 is closely related to M1 macrophages, resulting in the production of pro-chondrolytic mediators. However, IL-10, IL1RA, CCL-18, IGF, and TGF are closely related to M2 macrophages, leading to the protection of cartilage and the promoted regeneration. The inhibition of NF-κB signaling pathway is central in OA treatment via controlling inflammatory responses in macrophages, while the nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway appears not to attract widespread attention in the field. Nrf2 is a transcription factor encoding a large number of antioxidant enzymes. The activation of Nrf2 can have antioxidant and anti-inflammatory effects, which can also have complex crosstalk with NF-κB signaling pathway. The activation of Nrf2 can inhibit the M1 polarization and promote the M2 polarization through potential signaling transductions including TGF-β/SMAD, TLR/NF-κB, and JAK/STAT signaling pathways, with the regulation or cooperation of Notch, NLRP3, PI3K/Akt, and MAPK signaling. And the expression of heme oxygenase-1 (HO-1) and the negative regulation of Nrf2 for NF-κB can be the main mechanisms for promotion. Furthermore, the candidates of OA treatment by activating Nrf2 to promote M2 phenotype macrophages in OA are also reviewed in this work, such as itaconate and fumarate derivatives, curcumin, quercetin, melatonin, mesenchymal stem cells, and low-intensity pulsed ultrasound.
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Affiliation(s)
- Lin Wang
- Institute of Rehabilitation Medicine, West China Hospital, Sichuan University, Chengdu, China,Key Laboratory of Rehabilitation Medicine, West China Hospital, Sichuan University, Chengdu, China
| | - Chengqi He
- Institute of Rehabilitation Medicine, West China Hospital, Sichuan University, Chengdu, China,Key Laboratory of Rehabilitation Medicine, West China Hospital, Sichuan University, Chengdu, China,*Correspondence: Chengqi He,
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11
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Lu Y, Liu S, Yang P, Kou Y, Li C, Liu H, Li M. Exendin-4 and eldecalcitol synergistically promote osteogenic differentiation of bone marrow mesenchymal stem cells through M2 macrophages polarization via PI3K/AKT pathway. Stem Cell Res Ther 2022; 13:113. [PMID: 35313964 PMCID: PMC8935829 DOI: 10.1186/s13287-022-02800-8] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2021] [Accepted: 12/24/2021] [Indexed: 01/18/2023] Open
Abstract
Background The incidence of diabetic osteoporosis is increasing. This article evaluates the effect of combination treatment with the hypoglycemic drug exendin-4 (Ex-4) and the vitamin D analog eldecalcitol (ED-71) on improving diabetic osteoporosis and explores the relevant mechanism of action. Method Micro-CT, HE staining, immunohistochemistry, qPCR and ELISA were used to evaluate the impact of Ex-4 and ED-71 on bone formation and macrophage polarization in a mouse model of diabetic osteoporosis in vivo. Immunofluorescence, flow cytometry and qPCR were used to characterize the polarization type of macrophages treated with Ex-4 and ED-71 in vitro. A co-culture system of BMSCs and macrophages was established. Subsequently, crystal violet staining, alkaline phosphatase staining and alizarin red staining were used to evaluate the migration and osteogenesis differentiation of BMSCs. Results Ex-4 combined with ED-71 significantly reduced blood glucose levels and enhanced bone formation in mice with diabetic osteoporosis. In addition, Ex-4 synergized with ED-71 to induce the polarization of macrophages into M2 through the PI3K/AKT pathway. Macrophages treated with the combination of Ex-4 and ED-71 can significantly induce the osteogenic differentiation of BMSCs. Conclusion Ex-4 synergized with ED-71 to reduce blood glucose levels significantly. And this combination therapy can synergistically induce osteogenic differentiation of BMSCs by promoting M2 macrophages polarization, thereby improving diabetic osteoporosis. Therefore, the combination of Ex-4 and ED-71 may be a new strategy for the treatment of diabetic osteoporosis.
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Affiliation(s)
- Yupu Lu
- Department of Bone Metabolism, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University and Shandong Key Laboratory of Oral Tissue Regeneration and Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, Wenhua West Road 44-1, Jinan, 250012, Shandong, China.,Center of Osteoporosis and Bone Mineral Research, Shandong University, Jinan, 250012, Shandong, China
| | - Shanshan Liu
- Department of Bone Metabolism, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University and Shandong Key Laboratory of Oral Tissue Regeneration and Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, Wenhua West Road 44-1, Jinan, 250012, Shandong, China.,Center of Osteoporosis and Bone Mineral Research, Shandong University, Jinan, 250012, Shandong, China
| | - Panpan Yang
- Department of Bone Metabolism, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University and Shandong Key Laboratory of Oral Tissue Regeneration and Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, Wenhua West Road 44-1, Jinan, 250012, Shandong, China.,Center of Osteoporosis and Bone Mineral Research, Shandong University, Jinan, 250012, Shandong, China
| | - Yuying Kou
- Department of Bone Metabolism, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University and Shandong Key Laboratory of Oral Tissue Regeneration and Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, Wenhua West Road 44-1, Jinan, 250012, Shandong, China.,Center of Osteoporosis and Bone Mineral Research, Shandong University, Jinan, 250012, Shandong, China
| | - Congshan Li
- Department of Bone Metabolism, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University and Shandong Key Laboratory of Oral Tissue Regeneration and Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, Wenhua West Road 44-1, Jinan, 250012, Shandong, China.,Center of Osteoporosis and Bone Mineral Research, Shandong University, Jinan, 250012, Shandong, China
| | - Hongrui Liu
- Department of Bone Metabolism, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University and Shandong Key Laboratory of Oral Tissue Regeneration and Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, Wenhua West Road 44-1, Jinan, 250012, Shandong, China.,Center of Osteoporosis and Bone Mineral Research, Shandong University, Jinan, 250012, Shandong, China
| | - Minqi Li
- Department of Bone Metabolism, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University and Shandong Key Laboratory of Oral Tissue Regeneration and Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, Wenhua West Road 44-1, Jinan, 250012, Shandong, China. .,Center of Osteoporosis and Bone Mineral Research, Shandong University, Jinan, 250012, Shandong, China.
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12
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Single-Cell RNA-Sequencing Identifies Infrapatellar Fat Pad Macrophage Polarization in Acute Synovitis/Fat Pad Fibrosis and Cell Therapy. Bioengineering (Basel) 2021; 8:bioengineering8110166. [PMID: 34821732 PMCID: PMC8615266 DOI: 10.3390/bioengineering8110166] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2021] [Revised: 10/22/2021] [Accepted: 10/26/2021] [Indexed: 12/13/2022] Open
Abstract
The pathogenesis and progression of knee inflammatory pathologies is modulated partly by residing macrophages in the infrapatellar fat pad (IFP), thus, macrophage polarization towards pro-inflammatory (M1) or anti-inflammatory (M2) phenotypes is important in joint disease pathologies. Alteration of M1/M2 balance contributes to the initiation and progression of joint inflammation and can be potentially altered with mesenchymal stem cell (MSC) therapy. In an acute synovial/IFP inflammation rat model a single intra-articular injection of IFP-MSC was performed, having as controls (1) diseased rats not receiving IFP-MSC and (2) non-diseased rats. After 4 days, cell specific transcriptional profiling via single-cell RNA-sequencing was performed on isolated IFP tissue from each group. Eight transcriptomically distinct cell populations were identified within the IFP across all three treatment groups with a noted difference in the proportion of myeloid cells across the groups. Largely myeloid cells consisted of macrophages (>90%); one M1 sub-cluster highly expressing pro-inflammatory markers and two M2 sub-clusters with one of them expressing higher levels of canonical M2 markers. Notably, the diseased samples (11.9%) had the lowest proportion of cells expressing M2 markers relative to healthy (14.8%) and MSC treated (19.4%) samples. These results suggest a phenotypic polarization of IFP macrophages towards the pro-inflammatory M1 phenotype in an acute model of inflammation, which are alleviated by IFP-MSC therapy inducing a switch towards an alternate M2 status. Understanding the IFP cellular heterogeneity and associated transcriptional programs may offer insights into novel therapeutic strategies for disabling joint disease pathologies.
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13
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Bi J, Cheng C, Zheng C, Huang C, Zheng X, Wan X, Chen YH, Tian Z, Sun H. TIPE2 is a checkpoint of natural killer cell maturation and antitumor immunity. SCIENCE ADVANCES 2021; 7:eabi6515. [PMID: 34524845 PMCID: PMC8443187 DOI: 10.1126/sciadv.abi6515] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 05/13/2023]
Abstract
The maturation process of NK cells determines their functionality during which IL-15 plays a critical role. However, very few checkpoints specifically targeting this process have been discovered. Here, we report that TIPE2 expression gradually increased during NK cell ontogenesis correlating to their maturation stages in both mice and humans. NK-specific TIPE2 deficiency increased mature NK cells in mice, and these TIPE2-deficient NK cells exhibited enhanced activation, cytotoxicity, and IFN-γ production upon stimulation and enhanced response to IL-15 for maturation. Moreover, TIPE2 suppressed IL-15–triggered mTOR activity in both human and murine NK cells. Consequently, blocking mTOR constrained the effect of TIPE2 deficiency on NK cell maturation in response to IL-15. Last, NK-specific TIPE2-deficient mice were resistant to tumor growth in vivo. Our results uncover a potent checkpoint in NK cell maturation and antitumor immunity in both mice and humans, suggesting a promising approach of targeting TIPE2 for NK cell–based immunotherapies.
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Affiliation(s)
- Jiacheng Bi
- CAS Key Laboratory of Quantitative Engineering Biology, Shenzhen Institute of Synthetic Biology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China
- Corresponding author. (J.B.); (H.S.)
| | - Chen Cheng
- CAS Key Laboratory of Quantitative Engineering Biology, Shenzhen Institute of Synthetic Biology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China
| | - Chaoyue Zheng
- CAS Key Laboratory of Quantitative Engineering Biology, Shenzhen Institute of Synthetic Biology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China
| | - Chen Huang
- CAS Key Laboratory of Quantitative Engineering Biology, Shenzhen Institute of Synthetic Biology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China
| | - Xiaohu Zheng
- Hefei National Laboratory for Physical Sciences at Microscale, The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, China
- Institute of Immunology, University of Science and Technology of China, Hefei 230027, China
| | - Xiaochun Wan
- Center for Protein and Cell-based Drugs, Institute of Biomedicine and Biotechnology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
| | - Youhai H. Chen
- Center for Cancer Immunology, Institute of Biomedicine and Biotechnology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
| | - Zhigang Tian
- CAS Key Laboratory of Quantitative Engineering Biology, Shenzhen Institute of Synthetic Biology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China
- Hefei National Laboratory for Physical Sciences at Microscale, The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, China
- Institute of Immunology, University of Science and Technology of China, Hefei 230027, China
- Research Unit of NK Cell Study, Chinese Academy of Medical Sciences, Beijing 100864, China
| | - Haoyu Sun
- Hefei National Laboratory for Physical Sciences at Microscale, The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, China
- Institute of Immunology, University of Science and Technology of China, Hefei 230027, China
- Corresponding author. (J.B.); (H.S.)
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14
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Xu J, Xu H, Ma K, Wang Y, Niu B, Zhang L, Li F. lncRNA Gm16410 Mediates PM 2. 5-Induced Macrophage Activation via PI3K/AKT Pathway. Front Cell Dev Biol 2021; 9:618045. [PMID: 33796524 PMCID: PMC8007886 DOI: 10.3389/fcell.2021.618045] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2020] [Accepted: 02/22/2021] [Indexed: 01/08/2023] Open
Abstract
PM2.5 refers to atmospheric particulate matters with a diameter of less than 2.5 μm. The deposit of PM2.5 in lung cells can cause oxidative stress, leading to changes in macrophage polarity, which can subsequently cause pulmonary inflammation. Long-chain non-coding RNA (lncRNA) is a class of transcripts that regulate biological processes through multiple mechanisms. However, the role of lncRNA in PM2.5-induced lung inflammation has not been established. In this study, the biological effects and associated mechanism of lncRNA in PM2.5-induced change in macrophage polarity were investigated. The lncRNA-mediated PM2.5-induced macrophage inflammation and lung inflammation-associated injury were also determined. Mice were exposed to chronic levels of PM2.5, and changes in the expression of lncRNA in the lung were measured by lncRNA microarray. lncRNAs that showed significant changes in expression in response to PM2.5 were identified. lncRNA showing the biggest change was subjected to further analysis to determine its functional roles and mechanisms with respect to macrophage activation. The result showed that a significant reduction in expression of one lncRNA, identified as lncGm16410, was observed in the lung of mice and RAW264.7 cells following exposure to PM2.5. lncGm16410 suppressed PM2.5-induced macrophage activation via the SRC protein-mediated PI3K/AKT signaling pathway. PM2.5 promoted lung inflammation by downregulating the expression of lncGm16410, enhancing the activation of macrophages. Thus, lncGm16410 might provide new insight into the prevention of PM2.5 injury.
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Affiliation(s)
- Jingbin Xu
- Laboratory Medicine College, Dalian Medical University, Dalian, China
| | - Henggui Xu
- Laboratory Medicine College, Dalian Medical University, Dalian, China
| | - Kexin Ma
- Laboratory Medicine College, Dalian Medical University, Dalian, China
| | - Yue Wang
- Laboratory Medicine College, Dalian Medical University, Dalian, China
| | - Ben Niu
- Laboratory Medicine College, Dalian Medical University, Dalian, China
| | - Li Zhang
- Department of Central Laboratory, Dalian Municipal Central Hospital Affiliated of Dalian Medical University, Dalian, China
| | - Fasheng Li
- Laboratory Medicine College, Dalian Medical University, Dalian, China
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15
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Zhou J, Zhang A, Fan L. HSPA12B Secreted by Tumor-Associated Endothelial Cells Might Induce M2 Polarization of Macrophages via Activating PI3K/Akt/mTOR Signaling. Onco Targets Ther 2020; 13:9103-9111. [PMID: 32982299 PMCID: PMC7494226 DOI: 10.2147/ott.s254985] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2020] [Accepted: 08/07/2020] [Indexed: 11/29/2022] Open
Abstract
Purpose The intratumoral microenvironment of head and neck squamous cell carcinoma (HNSC) is highly immunosuppressive. In this study, we explored the potential functional role of HSPA12B secreted by tumor-associated endothelial cells (TECs) in M2 polarization of macrophages. Materials and Methods Bulk-seq data from TCGA-HNSC and single-cell RNA-seq data from GSE103322 (with over 5000 cells from 18 primary HNSC cases) were used for bioinformatic analysis. RAW264.7 cell line was used for in vitro studies. Results TECs in HNSC had significantly higher expression and secretion of HSPA12B, compared to normal human umbilical vein endothelial cells (HUVECs). Exogenous HSPA12B treatment increased the expression of M2 macrophage marker CD163 and CD206 on RAW264.7 cells in a dose-dependent manner but had no significant influence on CD86, an M1 macrophage marker. OLR1, a known receptor of HSP70 proteins, was specifically expressed in tumor-associated macrophages (TAMs) in HNSC. OLR1 knockdown significantly impaired HSPA12B uptake by RAW264.7 cells and weakened HSPA12B-induced CD163 and CD206 upregulation. HSPA12B treatment increased the expression of p-PI3K, p-Akt and p-mTOR in a dose-dependent manner in RAW264.7 cells. OLR1 inhibition and LY294002 treatment significantly weakened the effects HSPA12B on activating the PI3K/Akt/mTOR signaling and M2 marker expression. Conclusion Based on these findings, we speculated that aberrantly expressed and secreted HSPA12B by TECs could be taken by macrophages partly via OLR1, leading to subsequent activation of the PI3K/Akt/mTOR signaling pathway and elevated expression of M2 markers. This mechanism shows a novel cross-talk between TECs and TAMs, which contributes to the intratumoral immunosuppressive microenvironment.
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Affiliation(s)
- Jingjie Zhou
- Department of Otorhinolaryngology-Head and Neck Surgery, Jingmen No. 1 People's Hospital, Jingmen, Hubei 448000, People's Republic of China
| | - Aiping Zhang
- Department of Otorhinolaryngology-Head and Neck Surgery, Jingmen No. 1 People's Hospital, Jingmen, Hubei 448000, People's Republic of China
| | - Liang Fan
- Department of Otorhinolaryngology-Head and Neck Surgery, Jingmen No. 1 People's Hospital, Jingmen, Hubei 448000, People's Republic of China
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16
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Liu PK, Wen YT, Lin W, Kapupara K, Tai M, Tsai RK. Neuroprotective effects of low-dose G-CSF plus meloxicam in a rat model of anterior ischemic optic neuropathy. Sci Rep 2020; 10:10351. [PMID: 32587280 PMCID: PMC7316837 DOI: 10.1038/s41598-020-66977-9] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2019] [Accepted: 05/19/2020] [Indexed: 11/29/2022] Open
Abstract
Non-arteritic anterior ischemic optic neuropathy (NAION) causes a sudden loss of vision and lacks effective treatment. Granulocyte colony-stimulating factor (G-CSF) provides neuroprotection against the experimental optic nerve injuries but also induce leukocytosis upon typical administration. We found synergetic neuroprotective effects of meloxicam and low dose G-CSF without leukocytosis in a rat model of anterior ischemic optic neuropathy (rAION). The WBC counts in the low-dose G-CSF-plus meloxicam-treated group were similar to the sham-operated group. Combination treatment of low-dose G-CSF plus meloxicam preserved RGCs survival and visual function, reduced RGC apoptosis and the macrophages infiltration, and promote more M2 phenotype of macrophage/microglial transition than the low-dose GCSF treatment or the meloxicam treatment. Moreover, the combination treatment induced higher serine/threonine kinase 1 (Akt1) expression. The combination treatment of low-dose G-CSF plus meloxicam lessened the leukocytotic side effect and provided neuroprotective effects via Akt1 activation in the rAION model. This approach provides crucial preclinical information for the development of alternative therapy in AION.
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Affiliation(s)
- Pei-Kang Liu
- Department of Ophthalmology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.,Department of Ophthalmology, Yuan's General Hospital, Kaohsiung, Taiwan.,Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung, Taiwan.,School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Yao-Tseng Wen
- Institute of Eye Research, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan
| | - Wei Lin
- Department of Optometry, Da-Yeh University, Changhwa, Taiwan
| | - Kishan Kapupara
- Institute of Eye Research, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan
| | - Minghong Tai
- Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung, Taiwan. .,Center for Neuroscience, National Sun Yat-Sen University, Kaohsiung, Taiwan. .,Graduate Program in Marine Biotechnology, National Sun Yat-Sen University, Kaohsiung, Taiwan.
| | - Rong-Kung Tsai
- Institute of Eye Research, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan. .,Institute of Medical Sciences, Tzu Chi University, Hualien, Taiwan.
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Human Cytomegalovirus Mediates Unique Monocyte-to-Macrophage Differentiation through the PI3K/SHIP1/Akt Signaling Network. Viruses 2020; 12:v12060652. [PMID: 32560319 PMCID: PMC7354488 DOI: 10.3390/v12060652] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2020] [Revised: 05/29/2020] [Accepted: 06/09/2020] [Indexed: 12/11/2022] Open
Abstract
Blood monocytes mediate the hematogenous dissemination of human cytomegalovirus (HCMV) in the host. However, monocytes have a short 48-hour (h) lifespan and are not permissive for viral replication. We previously established that HCMV infection drives differentiation of monocytes into long-lived macrophages to mediate viral dissemination, though the mechanism was unclear. Here, we found that HCMV infection promoted monocyte polarization into distinct macrophages by inducing select M1 and M2 differentiation markers and that Akt played a central role in driving differentiation. Akt's upstream positive regulators, PI3K and SHIP1, facilitated the expression of the M1/M2 differentiation markers with p110δ being the predominant PI3K isoform inducing differentiation. Downstream of Akt, M1/M2 differentiation was mediated by caspase 3, whose activity was tightly regulated by Akt in a temporal manner. Overall, this study highlights that HCMV employs the PI3K/SHIP1/Akt pathway to regulate caspase 3 activity and drive monocyte differentiation into unique macrophages, which is critical for viral dissemination.
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18
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Shi B, Hao Y, Li W, Dong H, Xu M, Gao P. The enigmatic role of TIPE2 in asthma. Am J Physiol Lung Cell Mol Physiol 2020; 319:L163-L172. [PMID: 32493031 DOI: 10.1152/ajplung.00069.2020] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023] Open
Abstract
Unlike other members of the tumor necrosis factor (TNF)-α-induced protein 8 (TNFAIP8/TIPE) family that play a carcinogenic role and regulate apoptosis, TNFAIP8-like 2 (TIPE2) can not only maintain immune homeostasis but also regulate inflammation. TIPE2 mainly restrains the activation of T cell receptor (TCR) and Toll-like receptors (TLR), regulating its downstream signaling pathways, thereby regulating inflammation. Interestingly, TIPE2 is abnormally expressed in many inflammatory diseases and may promote or inhibit inflammation in different diseases. This review summarizes the molecular target and cellular function of TIPE2 in immune cells and inflammatory diseases and the underlying mechanism by which TIPE2 regulates inflammation. The function and mechanism of TIPE2 in asthma is also explained in detail. TIPE2 is abnormally expressed in asthma and participates in the pathogenesis of different phenotypes of asthma through regulating multiple inflammatory cells' activity and function. Considering the indispensable role of TIPE2 in asthma, TIPE2 may be an effective therapeutic target in asthma. However, the available data are insufficient to provide a full understanding of the complex role of TIPE2 in human asthma. Further study is still necessary to explore the possible mechanism and functions of TIPE2 in different asthma phenotypes.
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Affiliation(s)
- Bingqing Shi
- Department of Respiratory Medicine, The Second Hospital of Jilin University, Changchun, Jilin, China
| | - Yuqiu Hao
- Department of Respiratory Medicine, The Second Hospital of Jilin University, Changchun, Jilin, China
| | - Wei Li
- Department of Respiratory Medicine, The Second Hospital of Jilin University, Changchun, Jilin, China
| | - Hongna Dong
- Department of Respiratory Medicine, The Second Hospital of Jilin University, Changchun, Jilin, China
| | - Mengting Xu
- Department of Respiratory Medicine, The Second Hospital of Jilin University, Changchun, Jilin, China
| | - Peng Gao
- Department of Respiratory Medicine, The Second Hospital of Jilin University, Changchun, Jilin, China
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19
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Wang F, Pan S, Yao G, Zhang D, Wei X, Jiang S, Guo Y, Yu L. TIPE2 Improves the immune tolerance of human amniotic mesenchymal stem cells. ALL LIFE 2020. [DOI: 10.1080/26895293.2020.1757517] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Affiliation(s)
- Feng Wang
- West China Hospital, Sichuan University, Chengdu, 610000, China
- The Senond Affiliated Hospital of Zunyi Medical University, Zunyi, 563000, China
| | - Sisi Pan
- The Affiliated Hospital of Guizhou Medical University, Guiyang, 550000, China
| | - Guanping Yao
- The Affiliated Hospital of Zunyi Medical University, Zunyi, 563000, China
| | - Dengshen Zhang
- The Affiliated Hospital of Zunyi Medical University, Zunyi, 563000, China
| | - Xiaodong Wei
- Minda Hospital of Hubei Minzu University, Enshi, 445000, China
| | - Shanshan Jiang
- The Affiliated Hospital of Zunyi Medical University, Zunyi, 563000, China
| | - Yingqiang Guo
- West China Hospital, Sichuan University, Chengdu, 610000, China
| | - Limei Yu
- The Affiliated Hospital of Zunyi Medical University, Zunyi, 563000, China
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20
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Tang D, Shi X, Guo H, Bai Y, Shen C, Zhang Y, Wang Z. Comparative transcriptome analysis of the gills of Procambarus clarkii provides novel insights into the immune-related mechanism of copper stress tolerance. FISH & SHELLFISH IMMUNOLOGY 2020; 96:32-40. [PMID: 31786343 DOI: 10.1016/j.fsi.2019.11.060] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/30/2019] [Revised: 10/19/2019] [Accepted: 11/25/2019] [Indexed: 06/10/2023]
Abstract
The red-swamp crayfish (Procambarus clarkii) is the most important economic shrimp species in China, and is an important model crustacean organism in many fields of research. In crustaceans, gills interface directly with the ambient environment and thus play a vital role in the toxicology. In the context of increasing environmental heavy metal pollution, the relationship between copper (Cu2+) stress and the immune response of P. clarkii has recently received considerable attention. However, impact of Cu2+ on the crayfish immune system is still not fully understood. In this study, we used Illumina sequencing technology to perform a transcriptome analysis of the gills of P. clarkii after 24 h of Cu2+ treatment. A total of 37,226,812 unigenes were assembled, and 1943 unigenes were significantly differentially expressed between the control and Cu2+ treatment groups. Functional categorization of differentially expressed genes (DEGs) revealed that genes related to antioxidant activity, detoxication, metabolic processes, biosynthetic processes, and immune system processes were differentially regulated during Cu2+ stress. In addition, DEGs in the immune system were classified as being related to the MAPK signaling pathway, purine metabolism, Toll and Imd signaling pathway, PI3K-Akt signaling pathway and Hippo signaling pathway. Five genes (CuZnSOD, CAT, IDH1, PHYH and DECR2) were significantly up-regulated in the peroxisome pathway, which plays an important role in reacting to oxidative stress. Importantly, qRT-PCR validation of the results for seven genes chosen at random (NDK, ATP6L, ATP5C1, RPS14, RPL22e, CTSF and HSP90A) confirmed the Illumina sequencing results. This study provides a valuable starting point for further studies to elucidate the molecular basis of the immune system's response to Cu2+ stress in crayfish.
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Affiliation(s)
- Dan Tang
- Jiangsu Key Laboratory for Bioresources of Saline Soils, Jiangsu Synthetic Innovation Center for Coastal Bio-agriculture, Jiangsu Provincial Key Laboratory of Coastal Wetland Bioresources and Environmental Protection, School of Ocean and Biological Engineering, Yancheng Teachers University, Yancheng, 224001, Jiangsu Province, People's Republic of China
| | - Xueling Shi
- Jiangsu Key Laboratory for Bioresources of Saline Soils, Jiangsu Synthetic Innovation Center for Coastal Bio-agriculture, Jiangsu Provincial Key Laboratory of Coastal Wetland Bioresources and Environmental Protection, School of Ocean and Biological Engineering, Yancheng Teachers University, Yancheng, 224001, Jiangsu Province, People's Republic of China
| | - Huayun Guo
- Jiangsu Key Laboratory for Bioresources of Saline Soils, Jiangsu Synthetic Innovation Center for Coastal Bio-agriculture, Jiangsu Provincial Key Laboratory of Coastal Wetland Bioresources and Environmental Protection, School of Ocean and Biological Engineering, Yancheng Teachers University, Yancheng, 224001, Jiangsu Province, People's Republic of China
| | - Yuze Bai
- Jiangsu Key Laboratory for Bioresources of Saline Soils, Jiangsu Synthetic Innovation Center for Coastal Bio-agriculture, Jiangsu Provincial Key Laboratory of Coastal Wetland Bioresources and Environmental Protection, School of Ocean and Biological Engineering, Yancheng Teachers University, Yancheng, 224001, Jiangsu Province, People's Republic of China
| | - Chenchen Shen
- Jiangsu Key Laboratory for Bioresources of Saline Soils, Jiangsu Synthetic Innovation Center for Coastal Bio-agriculture, Jiangsu Provincial Key Laboratory of Coastal Wetland Bioresources and Environmental Protection, School of Ocean and Biological Engineering, Yancheng Teachers University, Yancheng, 224001, Jiangsu Province, People's Republic of China
| | - Yiping Zhang
- Jiangsu Key Laboratory for Bioresources of Saline Soils, Jiangsu Synthetic Innovation Center for Coastal Bio-agriculture, Jiangsu Provincial Key Laboratory of Coastal Wetland Bioresources and Environmental Protection, School of Ocean and Biological Engineering, Yancheng Teachers University, Yancheng, 224001, Jiangsu Province, People's Republic of China
| | - Zhengfei Wang
- Jiangsu Key Laboratory for Bioresources of Saline Soils, Jiangsu Synthetic Innovation Center for Coastal Bio-agriculture, Jiangsu Provincial Key Laboratory of Coastal Wetland Bioresources and Environmental Protection, School of Ocean and Biological Engineering, Yancheng Teachers University, Yancheng, 224001, Jiangsu Province, People's Republic of China.
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21
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Nguyen Ngo Le MA, Wen YT, Ho YC, Kapupara K, Tsai RK. Therapeutic Effects of Puerarin Against Anterior Ischemic Optic Neuropathy Through Antiapoptotic and Anti-Inflammatory Actions. Invest Ophthalmol Vis Sci 2019; 60:3481-3491. [PMID: 31408114 DOI: 10.1167/iovs.19-27129] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
Purpose This study investigated the therapeutic effects of puerarin (PR) on a rat model of anterior ischemic optic neuropathy (rAION). Methods The neuroprotective effects of PR on rAION were evaluated using flash visual-evoked potentials (FVEP), retrograde labeling of retinal ganglion cells (RGCs), TUNEL assay of the retina, optical coherence tomography (OCT) images of optic nerve width, and ED1 staining of the optic nerve (ON). The inflammatory response of ON and Akt signaling pathways were analyzed through Western blot. M2 polarization was determined by immunostaining and immunoblotting in ONs. Results In FVEP analysis, the amplitude of P1-N2 and the RGC density in the PR-treated group were 2.3- and 1.6-fold higher than those in the PBS-treated group, respectively (P < 0.05). The number of apoptotic RGC in the PR-treated group was 2.8-fold lower than that in the PBS-treated group. OCT images demonstrated that PR treatment-reduced ON edema in the acute phase compared to PBS treatment (P < 0.05). Macrophage infiltration was reduced by 5.2-fold by PR treatment compared with the PBS treatment (P < 0.05). PR treatment inhibited the levels of iNOS, IL-1β, and TNF-α, induced the levels of IL-10, Arg1, and Fizz1 in the rAION model. The levels of p-Akt1 and C/EBPβ in the PR-treated group increased by 3.4-fold and 5.89-fold compared with those in the PBS-treated group (P < 0.05). Inhibition of Akt activation reduced the number of M2 macrophage in the PR-treated group (P < 0.05). Conclusions PR treatment provided the neuroprotective effects in the rAION model, which may lead to new clinical applications.
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Affiliation(s)
- Minh-Anh Nguyen Ngo Le
- Institute of Medical Sciences, Tzu Chi University, Hualien, Taiwan.,Institute of Eye Research, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan
| | - Yao-Tseng Wen
- Institute of Eye Research, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan
| | - Yu-Chieh Ho
- Institute of Eye Research, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan.,Master Program in Medical Physiology, School of Medicine, Tzu Chi University, Hualien, Taiwan
| | - Kishan Kapupara
- Institute of Eye Research, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan
| | - Rong-Kung Tsai
- Institute of Medical Sciences, Tzu Chi University, Hualien, Taiwan.,Institute of Eye Research, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan
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Ji J, Zhang YY, Fan YC. TIPE2 as a potential therapeutic target in chronic viral hepatitis. Expert Opin Ther Targets 2019; 23:485-493. [PMID: 30995133 DOI: 10.1080/14728222.2019.1608948] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2018] [Accepted: 04/15/2019] [Indexed: 01/05/2023]
Abstract
Tumor necrosis factor-α-induced protein-8 like-2 (TIPE2) is a novel negative regulator of innate and adaptive immune responses by binding to caspase-8. The binding of TIPE2 and caspase-8 can inhibit the activity of activating protein-1(AP-1) and nuclear factor-κB (NF-κB), ultimately promoting Fas-induced apoptosis in immune cells. Therefore, TIPE2-caspase-8-NF-κB signaling might serve as a biomarker and a potential target for therapeutic intervention. Areas covered: This review summarizes the biological functions of TIPE2 in the regulation of immune homeostasis and the underlying mechanism by which TIPE2 is regulated in the human immune response. The molecular pathway of TIPE2-caspase-8 signaling in chronic infections of hepatitis B virus and hepatitis C virus is also explained. Expert opinion: Considering the essential role of TIPE2 in linking immunity and inflammation, this protein may be a promising therapeutic target in chronic viral hepatitis. However, studies are necessary to elucidate the molecular mechanism of TIPE2 in the immunogenesis of viral hepatitis and to develop potential interventions for breaking immune tolerance in chronic hepatitis B virus infection. Additional studies are required to understand how TIPE2 binds to caspase-8.
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Affiliation(s)
- Jian Ji
- a Department of Clinical Laboratory, Qilu Hospital , Shandong University , Jinan , China
| | - Yuan-Yuan Zhang
- b Department of Neurology , Jinan Central Hospital affiliated to Shandong University , Jinan , China
| | - Yu-Chen Fan
- c Department of Hepatology , Qilu Hospital of Shandong University , Jinan , China
- d Department of Immunology , Shandong University School of Basic Medical Science , Jinan , China
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23
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Li D, Tan Y. TIPE2 suppresses atherosclerosis by exerting a protective effect on macrophages via the inhibition of the Akt signaling pathway. Exp Ther Med 2019; 17:2937-2944. [PMID: 30936963 PMCID: PMC6434246 DOI: 10.3892/etm.2019.7316] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2018] [Accepted: 11/30/2018] [Indexed: 12/19/2022] Open
Abstract
Macrophage apoptosis and inflammation serve pivotal roles in the occurrence of atherosclerosis. However, the detailed underlying mechanism of macrophage action during atherosclerosis is poorly understood. Tumor necrosis factor-α-induced protein 8-like 2 (TIPE2) is a well-known negative regulator of the immune response. The current study assessed the association between TIPE2 and apoptosis-associated molecules in macrophages during atherosclerosis, as well as the role of TIPE2 in macrophage inflammation. RAW264.7 macrophages were subsequently transfected with a TIPE2 expression plasmid. Following oxidized low-density lipoprotein (oxLDL) induction (100 µg/m1) for 48 h, macrophage apoptosis was assessed via Annexin V/propidium iodide dual staining. The apoptosis-associated factors and Akt signaling pathway-associated factors were also evaluated via western blot analysis. The expression of inflammatory factors was determined via a reverse transcription-quantitative polymerase chain reaction assay and western blotting. Furthermore, a transwell assay was performed to test cell invasion ability. NF-κB phosphorylation and nuclear translocation were also assessed via western blotting. The results demonstrated that TIPE2 overexpression may promote oxLDL-induced RAW264.7 macrophage apoptosis by inhibiting the protein kinase B (Akt) signaling pathway. Furthermore, it was demonstrated that TIPE2 significantly reduced oxLDL-induced tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6) and monocyte chemoattractant protein 1 expression (MCP-1), and increased IL-10 expression by suppressing NF-κB phosphorylation and nuclear translocation in RAW264.7 macrophages. These results indicated that TIPE2 serves a protective role in oxLDL-induced RAW264.7 macrophages, and its mechanism may partly be exerted via the inhibition of the PI3K/Akt signaling pathway and the reduction of the macrophage inflammatory response achieved via the suppression of NF-κB signal activation.
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Affiliation(s)
- Dan Li
- Department of Geriatrics, The Second Xiangya Hospital of Central South University, Changsha, Hunan 410011, P.R. China
| | - Ying Tan
- Department of Cardiovascular Medicine, The First Affiliated Hospital of University of South China, Hengyang, Hunan 421000, P.R. China
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24
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Liu R, Liu C, Liu C, Fan T, Geng W, Ruan Q. TIPE2 in dendritic cells inhibits the induction of pTregs in the gut mucosa. Biochem Biophys Res Commun 2019; 509:911-917. [DOI: 10.1016/j.bbrc.2019.01.008] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2018] [Accepted: 01/03/2019] [Indexed: 02/08/2023]
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25
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Zhang YY, Huang NN, Zhao YX, Li YS, Wang D, Fan YC, Li XH. Elevated Tumor Necrosis Factor-a-induced Protein 8-like 2 mRNA from Peripheral Blood Mononuclear Cells in Patients with Acute Ischemic Stroke. Int J Med Sci 2018; 15:1713-1722. [PMID: 30588195 PMCID: PMC6299423 DOI: 10.7150/ijms.27817] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/11/2018] [Accepted: 10/18/2018] [Indexed: 12/23/2022] Open
Abstract
Background: Tumor necrosis factor-a-induced protein 8-like 2 (TIPE2) is a novel regulator of immunity and protects against experimental stroke. However, the expression and function of TIPE2 in patients with acute ischemic stroke has not been well demonstrated. Methods: A total of 182 consecutive patients with acute ischemic stroke and 40 healthy controls were included during November 2015 to June 2016. The mRNA levels of TIPE2, interleukin(IL)-1β, IL-10, IL-6, nuclear factor(NF)-κβ, activator protein(AP)-1, interferon(IFN)-γ and tumor necrosis factor(TNF)-α from peripheral blood mononuclear cells were determined using real time quantitative reverse transcriptase polymerase chain reaction. The severity of stroke was assessed using the National Institutes of Health Stroke Scale (NIHSS) score. Results: The median mRNA levels of TIPE2, TNF-α, AP-1, IFN-γ and NF-κβ in patients with acute ischemic stroke were significantly higher than healthy controls (all P<0.001, respectively). Of note, TIPE2 mRNA showed an increasing trend on a time-dependent manner after the onset of stroke. Furthermore, TIPE2 mRNA was negatively associated with lesion volumes (r=-0.23, P<0.01), NIHSS(r=-0.15, P<0.05), TNF-α(r=-0.33,P<0.001), AP-1(r=-0.28,P<0.001), IFN-γ (r=-0.16, P<0.05) and NF-κβ (r=-0.13, P<0.05), but positively associated with IL-6(r=0.14, P<0.05) and IL-10(r=-0.31, P<0.001). Hierarchy cluster analysis showed that TIPE2 mRNA has nearest membership with TNF-α, followed by IL-6, NF-κβ, AP-1, IL-10, IL-1β and IFN-γ. In addition, TIPE2 mRNA in survivals (n=149) was significantly higher than nonsurvivals (n=33) (P<0.001), and showed a great odd ratio (0.52, 95% confidence interval: 0.349-0.760, P<0.001) on 3-month mortality. Conclusions: TIPE2 mRNA contributed to the immune response of stroke and might be a potential biomarker for the mortality of acute ischemic stroke.
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Affiliation(s)
- Yuan-Yuan Zhang
- Department of Neurology, Jinan Central Hospital affiliated to Shandong University, Jinan 250013, China
| | - Na-Na Huang
- Department of Neurology, Jinan Central Hospital affiliated to Shandong University, Jinan 250013, China
| | - Yan-Xin Zhao
- Department of Neurology, Jinan Central Hospital affiliated to Shandong University, Jinan 250013, China
| | - Yan-Shuang Li
- Department of Neurology, Jinan Central Hospital affiliated to Shandong University, Jinan 250013, China
| | - Dong Wang
- Department of Neurology, Jinan Central Hospital affiliated to Shandong University, Jinan 250013, China
| | - Yu-Chen Fan
- Department of Hepatology, Qilu Hospital of Shandong University, Jinan 250012, China
| | - Xiao-Hong Li
- Department of Neurology, Jinan Central Hospital affiliated to Shandong University, Jinan 250013, China
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26
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Bhattacharya S, Aggarwal A. M2 macrophages and their role in rheumatic diseases. Rheumatol Int 2018; 39:769-780. [DOI: 10.1007/s00296-018-4120-3] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2018] [Accepted: 08/02/2018] [Indexed: 12/21/2022]
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27
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Lin Z, Liu W, Xiao C, Fan Y, Zhuang G, Qi Z. TIPE2 inhibits GC via regulation of cell proliferation, apoptosis and inflammation. Oncol Rep 2018; 40:1307-1316. [PMID: 30015980 PMCID: PMC6072396 DOI: 10.3892/or.2018.6576] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2017] [Accepted: 07/02/2018] [Indexed: 12/26/2022] Open
Abstract
Gastric cancer (GC), a type of gastric mucosal epithelium disease caused by common malignant tumors, has become a major threat to human health and survival. Tumor necrosis factor-α-induced protein-8 like-2 (TIPE2) is a negative immune regulatory factor that is selectively expressed in immune organs, immune cells and various epithelial cells and serves an important role in the maintenance of human physiological immune homeostasis. In our preliminary study, we found that the expression of TIPE2 was downregulated or absent in GC tissues compared with normal gastric mucosa tissues, indicating that TIPE2 may play a significant role in the development of GC. To clarify the role of TIPE2 in the progression of human GC and to elucidate the underlying mechanism, the association between TIPE2 and phosphatidylinositol 3-kinase (PI3K)/AKT, the cell cycle, the caspase-related apoptosis pathway and the NF-κB signaling pathway were investigated through western blot and flow cytometric analysis. It was determined that TIPE2 inhibited GC cell proliferation mainly by reducing the expression of phosphorylated AKT and ERK, which caused subsequent inhibition of the PI3K-AKT and Ras-Raf-MEK-ERK1/2 signaling pathways. Additionally, we investigated the relationship between TIPE2 and GC and discovered that TIPE2 inhibited tumor progression via growth, apoptosis and inflammatory pathways. The results of the present study provided a theoretical basis for the development and application of TIPE2 as an antitumor agent.
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Affiliation(s)
- Zhenhe Lin
- Department of Gastroenterology, Zhongshan Hospital Affiliated to Xiamen University, Xiamen, Fujian 361004, P.R. China
| | - Wenming Liu
- Department of Gastroenterology, Zhongshan Hospital Affiliated to Xiamen University, Xiamen, Fujian 361004, P.R. China
| | - Chuanxing Xiao
- Department of Gastroenterology, Zhongshan Hospital Affiliated to Xiamen University, Xiamen, Fujian 361004, P.R. China
| | - Yanyun Fan
- Department of Gastroenterology, Zhongshan Hospital Affiliated to Xiamen University, Xiamen, Fujian 361004, P.R. China
| | - Guohong Zhuang
- Organ Transplantation Institute, Anti‑Cancer Research Center, Medical College of Xiamen University, Xiamen, Fujian 361102, P.R. China
| | - Zhongquan Qi
- Organ Transplantation Institute, Anti‑Cancer Research Center, Medical College of Xiamen University, Xiamen, Fujian 361102, P.R. China
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Zhang Y, Feng J, Fu H, Liu C, Yu Z, Sun Y, She X, Li P, Zhao C, Liu Y, Liu T, Liu Q, Liu Q, Li G, Wu M. Coagulation Factor X Regulated by CASC2c Recruited Macrophages and Induced M2 Polarization in Glioblastoma Multiforme. Front Immunol 2018; 9:1557. [PMID: 30034397 PMCID: PMC6043648 DOI: 10.3389/fimmu.2018.01557] [Citation(s) in RCA: 44] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2018] [Accepted: 06/25/2018] [Indexed: 12/18/2022] Open
Abstract
Tumor-associated macrophages (TAMs) constitute a major component of inflammatory cells in the glioblastoma multiforme (GBM) tumor microenvironment. TAMs have been implicated in GBM angiogenesis, invasion, local tumor recurrence, and immunosuppression. Coagulation factor X (FX) is a vitamin K-dependent plasma protein that plays a role in the regulation of blood coagulation. In this study, we first found that FX was highly expressed and positively correlated with TAM density in human GBM. FX exhibited a potent chemotactic capacity to recruit macrophages and promoted macrophages toward M2 subtype polarization, accelerating GBM growth. FX bound to extracellular signal-related kinase (ERK)1/2 and inhibited p-ERK1/2 in GBM cells. FX was secreted in the tumor microenvironment and increased the phosphorylation and activation of ERK1/2 and AKT in macrophages, which may have been responsible for the M2 subtype macrophage polarization. Moreover, although the lncRNA CASC2c has been verified to function as a miR-101 competing endogenous RNA (ceRNA) to promote miR-101 target genes in GBM cells, we first confirmed that CASC2c did not function as a miR-338-3p ceRNA to promote FX expression, and that FX was a target gene of miR-338-3p. CASC2c interacted with and reciprocally repressed miR-338-3p. Both CASC2c and miR-388-3p bound to FX and commonly inhibited its expression and secretion. CASC2c repressed M2 subtype macrophage polarization. Taken together, our findings revealed a novel mechanism highlighting CASC2c and FX as potential therapeutic targets to improve GBM patients by altering the GBM microenvironment.
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Affiliation(s)
- Yan Zhang
- Hunan Provincial Tumor Hospital and the Affiliated Tumor Hospital of Xiangya Medical School, Central South University, Changsha, China.,The Key Laboratory of Carcinogenesis of the Chinese Ministry of Health, The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, China
| | - Jianbo Feng
- Hunan Provincial Tumor Hospital and the Affiliated Tumor Hospital of Xiangya Medical School, Central South University, Changsha, China.,The Key Laboratory of Carcinogenesis of the Chinese Ministry of Health, The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, China
| | - Haijuan Fu
- Hunan Provincial Tumor Hospital and the Affiliated Tumor Hospital of Xiangya Medical School, Central South University, Changsha, China.,The Key Laboratory of Carcinogenesis of the Chinese Ministry of Health, The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, China
| | - Changhong Liu
- Hunan Provincial Tumor Hospital and the Affiliated Tumor Hospital of Xiangya Medical School, Central South University, Changsha, China.,The Key Laboratory of Carcinogenesis of the Chinese Ministry of Health, The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, China
| | - Zhibin Yu
- Hunan Provincial Tumor Hospital and the Affiliated Tumor Hospital of Xiangya Medical School, Central South University, Changsha, China.,The Key Laboratory of Carcinogenesis of the Chinese Ministry of Health, The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, China
| | - Yingnan Sun
- Hunan Provincial Tumor Hospital and the Affiliated Tumor Hospital of Xiangya Medical School, Central South University, Changsha, China
| | - Xiaoling She
- The Second Xiangya Hospital, Central South University, Changsha, China
| | - Peiyao Li
- Hunan Provincial Tumor Hospital and the Affiliated Tumor Hospital of Xiangya Medical School, Central South University, Changsha, China.,The Key Laboratory of Carcinogenesis of the Chinese Ministry of Health, The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, China
| | - Chunhua Zhao
- Hunan Provincial Tumor Hospital and the Affiliated Tumor Hospital of Xiangya Medical School, Central South University, Changsha, China.,The Key Laboratory of Carcinogenesis of the Chinese Ministry of Health, The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, China
| | - Yang Liu
- Hunan Provincial Tumor Hospital and the Affiliated Tumor Hospital of Xiangya Medical School, Central South University, Changsha, China.,The Key Laboratory of Carcinogenesis of the Chinese Ministry of Health, The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, China
| | - Tao Liu
- Hunan Provincial Tumor Hospital and the Affiliated Tumor Hospital of Xiangya Medical School, Central South University, Changsha, China.,The Key Laboratory of Carcinogenesis of the Chinese Ministry of Health, The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, China
| | - Qiang Liu
- The Third Xiangya Hospital, Central South University, Changsha, China
| | - Qing Liu
- The Xiangya Hospital, Central South University, Changsha, China
| | - Guiyuan Li
- Hunan Provincial Tumor Hospital and the Affiliated Tumor Hospital of Xiangya Medical School, Central South University, Changsha, China.,The Key Laboratory of Carcinogenesis of the Chinese Ministry of Health, The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, China
| | - Minghua Wu
- Hunan Provincial Tumor Hospital and the Affiliated Tumor Hospital of Xiangya Medical School, Central South University, Changsha, China.,The Key Laboratory of Carcinogenesis of the Chinese Ministry of Health, The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, China
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Bobade D, Khandare AV, Deval M, Shastry P, Deshpande P. Hemozoin-induced activation of human monocytes toward M2-like phenotype is partially reversed by antimalarial drugs-chloroquine and artemisinin. Microbiologyopen 2018; 8:e00651. [PMID: 29877619 PMCID: PMC6436431 DOI: 10.1002/mbo3.651] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2018] [Revised: 04/08/2018] [Accepted: 04/16/2018] [Indexed: 12/20/2022] Open
Abstract
Plasmodium falciparum malaria is the most severe form of malaria with several complications. The malaria pigment‐hemozoin (Hz) is associated with severe anemia, cytokine dysfunction, and immunosuppression, thus making it an interesting target for developing new strategies for antimalarial therapy. Monocytes (MO) in circulation actively ingest Hz released by Plasmodium parasites and secrete pro‐ and anti‐inflammatory cytokines. M1 and M2 types represent the two major forms of MO/macrophages (MQ) with distinct phenotypes and opposing functions. Imbalance in the polarization of these types is reported in many infectious diseases. Though the association of Hz with immunosuppression is well documented, its role in activation of MO in context of M1/M2 phenotypes remains to be addressed. We report here that natural Hz drives human MO toward M2‐like phenotype as evidenced by the expression of M2 signature markers. Hz‐fed MO showed elevated transcript and secreted level of IL‐10, CCL17, CCL1, expression of mannose‐binding lectin receptor (CD206), and arginase activity. Hz attenuated HLA‐DR expression, nitric oxide, and reactive oxygen species production, which are the features of M1 phenotype. Our data also implicate the involvement of p38 MAPK, PI3K/AKT, and NF‐κB signaling pathways in skewing of Hz‐fed MO toward M2‐like type and suppression of mitogen‐stimulated lymphocyte proliferation. Importantly, antimalarial drugs—chloroquine and artemisinin—partially reversed activation of Hz‐induced MO toward M2‐like phenotype. Considering the limitations in the current therapeutic options for malaria, we propose that these drugs may be re‐examined for their potential as immunomodulators and candidates for adjunctive treatment in malaria.
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Affiliation(s)
| | | | - Mangesh Deval
- National Centre for Cell Science (NCCS), Pune, India
| | - Padma Shastry
- National Centre for Cell Science (NCCS), Pune, India
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Shi-Bai Z, Rui-Min L, Ying-Chuan S, Jie Z, Chao J, Can-Hua Y, Xi C, Wen-Wei Q. TIPE2 expression is increased in peripheral blood mononuclear cells from patients with rheumatoid arthritis. Oncotarget 2017; 8:87472-87479. [PMID: 29152095 PMCID: PMC5675647 DOI: 10.18632/oncotarget.21267] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2017] [Accepted: 09/03/2017] [Indexed: 01/05/2023] Open
Abstract
We investigated the changes in mRNA and protein expression of tumor necrosis factor-α–induced protein 8-like 2 (TIPE2) and PEST-containing nuclear protein (PCNP) in peripheral blood lymphocytes from 54 patients with rheumatoid arthritis (RA) and the spleens of model mice with collagen-induced arthritis (CIA) to generate new ideas for clinical diagnosis and treatment. Expression levels of both TIPE2 and PCNP were higher in RA patients and CIA mice than in their respective controls. They were also higher in the 32 patients with active RA than in the 22 with inactive RA (P < 0.001 for both). After comprehensively treating patients with active RA with anti-inflammatory and antirheumatic drugs for 6 months, they were stable, and there was no difference in TIPE2 levels between the treated patients and those with inactive RA (P = 0.85). In addition, TIPE2 mRNA levels in peripheral blood correlated positively with PCNP (R2 = 0.744, P = 0.001). The DAS28 score correlated positively with peripheral blood TIPE2 levels in the RA patients (R2 = 0.945, P = 0.001). These findings suggest TIPE2 expression increases with the severity of RA.
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Affiliation(s)
- Zhu Shi-Bai
- Department of Orthopedic Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Science, Beijing, China
| | | | | | - Zhai Jie
- Department of Breast Surgery, Cancer Institute and Hospital, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Science, Beijing, China
| | - Jiang Chao
- Department of Orthopedic Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Science, Beijing, China
| | - Ye Can-Hua
- Department of Orthopedic Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Science, Beijing, China
| | - Chen Xi
- Department of Orthopedic Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Science, Beijing, China
| | - Qian Wen-Wei
- Department of Orthopedic Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Science, Beijing, China
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Sun Y, Wang X, Li Y, Sun H, Wan L, Wang X, Zhang L, Fang Z, Wei Z. The decreased expression of TIPE2 protein in the decidua of patients with missed abortion and possible significance. Reprod Biol Endocrinol 2017; 15:68. [PMID: 28851386 PMCID: PMC5576376 DOI: 10.1186/s12958-017-0285-y] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2017] [Accepted: 06/29/2017] [Indexed: 12/21/2022] Open
Abstract
BACKGROUND Missed abortion is a common occurrence for otherwise healthy women. Immunological factor is one of the most important reasons. Tumor necrosis factor-α-induced protein-8 like-2 (TIPE2) is a novel negative immune regulator related to several human diseases. However, the expression level and clinical significance of TIPE2 in missed abortion remain unclear. METHODS The expression of TIPE2 mRNA and protein in decidua and chorion from 36 missed abortion patients and 36 healthy controls was detected using quantitative real-time PCR, western blot and immunohistochemistry. In addition, serum TNF-ɑ and IL-10 levels were measured using flow cytometry. Serum estradiol and progesterone levels were measured by radioimmunoassay test. The correlations of TIPE2 protein levels with TNF-ɑ, IL-10, estradiol and progesterone were further analyzed. RESULTS TIPE2 protein levels were significantly lower in decidual tissues of missed abortion patients than those in healthy controls. The patients with missed abortion had significantly higher levels of serum TNF-ɑ, and lower levels of serum IL-10, estradiol and progesterone compared with healthy controls. The TIPE2 protein levels were positively related to serum IL-10 levels. CONCLUSION Our data indicate TIPE2 could play important roles in maintaining the maternal-fetal tolerance and decreased TIPE2 expression in the decidua may be related to the development of missed abortion.
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Affiliation(s)
- Yingshuo Sun
- 0000 0004 1761 1174grid.27255.37Department of Gynecology and Obstetrics, Clinical Medical School, Shandong University, 44# Wenhua Xi Road, Jinan, Shandong 250012 People’s Republic of China
- 0000 0004 1761 1174grid.27255.37Department of Immunology, School of Basic Medical Sciences, Shandong University, 44# Wenhua Xi Road, Jinan, Shandong People’s Republic of China
| | - Xiaoyan Wang
- 0000 0004 1761 1174grid.27255.37Department of Immunology, School of Basic Medical Sciences, Shandong University, 44# Wenhua Xi Road, Jinan, Shandong People’s Republic of China
| | - Yue Li
- 0000 0004 1761 1174grid.27255.37Department of Immunology, School of Basic Medical Sciences, Shandong University, 44# Wenhua Xi Road, Jinan, Shandong People’s Republic of China
| | - Han Sun
- 0000 0004 1761 1174grid.27255.37Department of Immunology, School of Basic Medical Sciences, Shandong University, 44# Wenhua Xi Road, Jinan, Shandong People’s Republic of China
- grid.415946.bDepartment of Clinical Laboratory Services, Linyi People’s Hospital, Linyi, Shandong People’s Republic of China
| | - Lu Wan
- 0000 0004 1761 1174grid.27255.37Department of Immunology, School of Basic Medical Sciences, Shandong University, 44# Wenhua Xi Road, Jinan, Shandong People’s Republic of China
| | - Xishuang Wang
- 0000 0004 1761 1174grid.27255.37Department of Immunology, School of Basic Medical Sciences, Shandong University, 44# Wenhua Xi Road, Jinan, Shandong People’s Republic of China
| | - Lining Zhang
- 0000 0004 1761 1174grid.27255.37Department of Immunology, School of Basic Medical Sciences, Shandong University, 44# Wenhua Xi Road, Jinan, Shandong People’s Republic of China
| | - Zhenghui Fang
- grid.452222.1Department of Gynecology and Obstetrics, Jinan Central Hospital affiliated to Shandong University, 105# Jiefang Road, Jinan, Shandong 250013 People’s Republic of China
| | - Zengtao Wei
- 0000 0004 1761 1174grid.27255.37Department of Gynecology and Obstetrics, Clinical Medical School, Shandong University, 44# Wenhua Xi Road, Jinan, Shandong 250012 People’s Republic of China
- 0000 0004 1761 1174grid.27255.37Department of Immunology, School of Basic Medical Sciences, Shandong University, 44# Wenhua Xi Road, Jinan, Shandong People’s Republic of China
- grid.452222.1Department of Gynecology and Obstetrics, Jinan Central Hospital affiliated to Shandong University, 105# Jiefang Road, Jinan, Shandong 250013 People’s Republic of China
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Sheng X, Yan J, Meng Y, Kang Y, Han Z, Tai G, Zhou Y, Cheng H. Immunomodulatory effects of Hericium erinaceus derived polysaccharides are mediated by intestinal immunology. Food Funct 2017; 8:1020-1027. [PMID: 28266682 DOI: 10.1039/c7fo00071e] [Citation(s) in RCA: 54] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
This study was aimed at investigating the immunomodulating activity of Hericium erinaceus polysaccharide (HEP) in mice, by assessing splenic lymphocyte proliferation (cell-mediated immunity), serum hemolysin levels (humoral immunity), phagocytic capacity of peritoneal cavity phagocytes (macrophage phagocytosis), and NK cell activity. ELISA of immunoglobulin A (SIgA) in the lamina propria, and western blotting of small intestinal proteins were also performed to gain insight into the mechanism by which HEP affects the intestinal immune system. Here, we report that HEP improves immune function by functionally enhancing cell-mediated and humoral immunity, macrophage phagocytosis, and NK cell activity. In addition, HEP was found to upregulate the secretion of SIgA and activate the MAPK and AKT cellular signaling pathways in the intestine. In conclusion, all these results allow us to postulate that the immunomodulatory effects of HEP are most likely attributed to the effective regulation of intestinal mucosal immune activity.
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Affiliation(s)
- Xiaotong Sheng
- Jilin Province Key Laboratory on Chemistry and Biology of Changbai Mountain Natural Drugs, School of Life Sciences, Northeast Normal University, Changchun 130024, PR China.
| | - Jingmin Yan
- Jilin Province Key Laboratory on Chemistry and Biology of Changbai Mountain Natural Drugs, School of Life Sciences, Northeast Normal University, Changchun 130024, PR China.
| | - Yue Meng
- Jilin Province Key Laboratory on Chemistry and Biology of Changbai Mountain Natural Drugs, School of Life Sciences, Northeast Normal University, Changchun 130024, PR China.
| | - Yuying Kang
- Jilin Province Key Laboratory on Chemistry and Biology of Changbai Mountain Natural Drugs, School of Life Sciences, Northeast Normal University, Changchun 130024, PR China.
| | - Zhen Han
- Jilin Province Key Laboratory on Chemistry and Biology of Changbai Mountain Natural Drugs, School of Life Sciences, Northeast Normal University, Changchun 130024, PR China.
| | - Guihua Tai
- Jilin Province Key Laboratory on Chemistry and Biology of Changbai Mountain Natural Drugs, School of Life Sciences, Northeast Normal University, Changchun 130024, PR China.
| | - Yifa Zhou
- Jilin Province Key Laboratory on Chemistry and Biology of Changbai Mountain Natural Drugs, School of Life Sciences, Northeast Normal University, Changchun 130024, PR China.
| | - Hairong Cheng
- Jilin Province Key Laboratory on Chemistry and Biology of Changbai Mountain Natural Drugs, School of Life Sciences, Northeast Normal University, Changchun 130024, PR China.
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Yao Y, Wang ZC, Liu JX, Ma J, Chen CL, Deng YK, Liao B, Wang N, Wang H, Ning Q, Liu Z. Increased expression of TIPE2 in alternatively activated macrophages is associated with eosinophilic inflammation and disease severity in chronic rhinosinusitis with nasal polyps. Int Forum Allergy Rhinol 2017; 7:963-972. [PMID: 28665518 DOI: 10.1002/alr.21984] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2017] [Revised: 05/23/2017] [Accepted: 06/08/2017] [Indexed: 12/20/2022]
Abstract
BACKGROUND Chronic rhinosinusitis with nasal polyps (CRSwNP) is a multifactorial disorder characterized by exaggerated local immune responses. Tumor necrosis factor-α-induced protein 8-like 2 (TIPE2) is a novel protein with potential immune modulating function. The expression and function of TIPE2 in human airway diseases are unclear. METHODS The expression of TIPE2 in sinonasal mucosal samples was assessed by means of quantitative reverse transcript-polymerse chain reaction, immunohistochemistry, and Western blotting. The human monocytic/macrophage cell line, THP-1 cells, was stimulated with various cytokines. Computed tomography (CT) scan images, endoscopic findings, and symptoms were scored. RESULTS Compared with non-eosinophilic polyps and control mucosa, the mRNA and protein expression of TIPE2 was significantly upregulated in eosinophilic polyps, with a further increase in those with asthma. The number of CD68+ CD163+ alternatively activated (M2) macrophages was increased in eosinophilic polyps. TIPE2 was mainly expressed by M2 macrophages in sinonasal mucosa and its expression was upregulated in M2 macrophages in eosinophilic polyps. Interleukin (IL)-4 and IL-13, but not interferon (IFN)-γ or IL-17A, induced TIPE2 expression in differentiated THP-1 cells. The mRNA levels of IL-4 and IL-13 correlated with the mRNA levels of TIPE2 and M2 macrophage markers in sinonasal mucosa. Importantly, the number of TIPE2+ cells, particularly TIPE2+ CD163+ CD68+ M2 macrophages, correlated positively with the number of eosinophils and total inflammatory cells in sinonasal mucosa, as well as disease duration, CT scores, hyposmia scores, and polyp size in CRSwNP. CONCLUSION The T-helper 2 milieu is able to induce TIPE2 expression in macrophages. TIPE2-positive M2 macrophages potentially contribute to eosinophilic inflammation and disease progression in CRSwNP.
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Affiliation(s)
- Yin Yao
- Department of Otolaryngology-Head and Neck Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, PR China
| | - Zhi-Chao Wang
- Department of Otolaryngology-Head and Neck Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, PR China
| | - Jin-Xin Liu
- Department of Otolaryngology-Head and Neck Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, PR China
| | - Jin Ma
- Department of Otolaryngology-Head and Neck Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, PR China
| | - Cai-Ling Chen
- Department of Otolaryngology-Head and Neck Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, PR China
| | - Yi-Ke Deng
- Department of Otolaryngology-Head and Neck Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, PR China
| | - Bo Liao
- Department of Otolaryngology-Head and Neck Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, PR China
| | - Nan Wang
- Department of Otolaryngology-Head and Neck Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, PR China
| | - Heng Wang
- Department of Otolaryngology-Head and Neck Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, PR China
| | - Qin Ning
- Department of Infectious Disease, Institute of Infectious Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, PR China
| | - Zheng Liu
- Department of Otolaryngology-Head and Neck Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, PR China
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