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Sun Y, Dai X, Yang J, Chen Y, Feng J, Shi X, Li X, Liu X. Deficiency of hepatokine orosomucoid1 aggravates NAFLD progression in mice. Biochim Biophys Acta Mol Basis Dis 2025; 1871:167654. [PMID: 39756714 DOI: 10.1016/j.bbadis.2024.167654] [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: 08/09/2024] [Revised: 12/29/2024] [Accepted: 12/29/2024] [Indexed: 01/07/2025]
Abstract
Orosomucoid (ORM) is an important hepatokine that regulates metabolism. Previous report showed that isoform ORM2 but not ORM1 could downregulate lipogenic genes and ameliorate hepatic steatosis in obese mice, thereby categorizing ORM2 as a promising candidate for therapeutic intervention in nonalcoholic fatty liver disease (NAFLD). However, our previous studies found that mice lacking ORM1 gradually developed an obese phenotype with severe hepatic steatosis at the age of 24 weeks. Consequently, it remains imperative to further investigate the precise role of ORM1 in the context of NAFLD. The current study aims to assess the function and therapeutic prospects of ORM1 in NAFLD models induced by a high-fat diet (HFD) or a methionine- and choline-deficient diet (MCD), employing a series of loss- and gain-of-function experiments. The results showed that liver ORM levels elevated in fat NAFLD models but decreased in lean NAFLD models. Orm1-deficient mice fed either on HFD or MCD had significantly higher NAFLD activity score with more severe steatosis and ballooning, showing an aggravated NAFLD progression. However, liver-specific Orm1 overexpression in mice could not alleviate NAFLD when fed on HFD or MCD. These results suggest that systemic endogenous ORM1 is indispensable in protecting against the development of NAFLD; however, it may not serve as an effective localized therapeutic target for managing the disease.
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Affiliation(s)
- Yang Sun
- Department of Clinical Pharmacy, School of Pharmacy, Naval Medical University/Second Military Medical University, Shanghai 200433, China
| | - XianMin Dai
- Department of Clinical Pharmacy, School of Pharmacy, Naval Medical University/Second Military Medical University, Shanghai 200433, China
| | - JinRun Yang
- Department of Clinical Pharmacy, School of Pharmacy, Naval Medical University/Second Military Medical University, Shanghai 200433, China
| | - Yi Chen
- Department of Clinical Pharmacy, School of Pharmacy, Naval Medical University/Second Military Medical University, Shanghai 200433, China
| | - JiaYi Feng
- Department of Clinical Pharmacy, School of Pharmacy, Naval Medical University/Second Military Medical University, Shanghai 200433, China
| | - XiaoFei Shi
- Department of Clinical Pharmacy, School of Pharmacy, Naval Medical University/Second Military Medical University, Shanghai 200433, China
| | - Xiang Li
- Department of Clinical Pharmacy, School of Pharmacy, Naval Medical University/Second Military Medical University, Shanghai 200433, China.
| | - Xia Liu
- Department of Clinical Pharmacy, School of Pharmacy, Naval Medical University/Second Military Medical University, Shanghai 200433, China.
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2
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Kondratyeva LG, Rakitina OA, Pleshkan VV, Kuzmich AI, Linge IA, Kondratieva SA, Snezhkov EV, Alekseenko IV, Sverdlov ED. The Cellular and Transcriptomic Early Innate Immune Response to BCG Vaccination in Mice. Cells 2024; 13:2043. [PMID: 39768135 PMCID: PMC11674076 DOI: 10.3390/cells13242043] [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: 10/31/2024] [Revised: 12/04/2024] [Accepted: 12/09/2024] [Indexed: 01/11/2025] Open
Abstract
It is established that BCG vaccination results in the development of both a specific immune response to mycobacterial infections and a nonspecific (heterologous) immune response, designated as trained immunity (TRIM), to other pathogens. We hypothesized that local BCG immunization may induce an early immune response in bone marrow and spleen innate immunity cells. The early transcriptomic response of various populations of innate immune cells, including monocytes, neutrophils, and natural killer (NK) cells, to BCG vaccination was examined. To this end, C57Bl/6J mice were subcutaneously immunized with 106 CFU of BCG. Three days following BCG administration, the three cell populations were collected from the control and BCG-vaccinated groups using FACS. All cell populations obtained were utilized for the preparation and sequencing of RNA-seq libraries. The analysis of FACS data revealed an increase in the proportion of splenic NK cells and monocytes 3 days post-vaccination. Transcriptomic analysis revealed the deregulation of genes associated with the regulation of immune response (according to Gene Ontology terms) in NK cells, monocytes, and unsorted bone marrow cells. Two NK cell-specific immune ligands (Tnfsf14 and S100a8) and two bone marrow-specific immune receptors (C5ar1 and Csf2rb) were identified among differentially expressed genes. No alterations were identified in neutrophils in either their percentage or at the transcriptomic level. Thus, in this study, we demonstrated that BCG vaccination provides an early increase in the proportion of murine bone marrow and spleen immune cell populations, as well as transcriptomic alterations in monocytes, NK cells, and non-sorted bone marrow cells. This early innate immune response may be beneficial for enhancing TRIM.
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Affiliation(s)
- Liya G. Kondratyeva
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of Sciences, Moscow 117997, Russia; (O.A.R.); (V.V.P.); (A.I.K.); (S.A.K.); (E.V.S.); (I.V.A.)
- National Research Center “Kurchatov Institute”, Moscow 123182, Russia;
| | - Olga A. Rakitina
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of Sciences, Moscow 117997, Russia; (O.A.R.); (V.V.P.); (A.I.K.); (S.A.K.); (E.V.S.); (I.V.A.)
| | - Victor V. Pleshkan
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of Sciences, Moscow 117997, Russia; (O.A.R.); (V.V.P.); (A.I.K.); (S.A.K.); (E.V.S.); (I.V.A.)
- National Research Center “Kurchatov Institute”, Moscow 123182, Russia;
| | - Alexey I. Kuzmich
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of Sciences, Moscow 117997, Russia; (O.A.R.); (V.V.P.); (A.I.K.); (S.A.K.); (E.V.S.); (I.V.A.)
| | - Irina A. Linge
- Central Tuberculosis Research Institute, Moscow 107564, Russia;
| | - Sofia A. Kondratieva
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of Sciences, Moscow 117997, Russia; (O.A.R.); (V.V.P.); (A.I.K.); (S.A.K.); (E.V.S.); (I.V.A.)
| | - Eugene V. Snezhkov
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of Sciences, Moscow 117997, Russia; (O.A.R.); (V.V.P.); (A.I.K.); (S.A.K.); (E.V.S.); (I.V.A.)
| | - Irina V. Alekseenko
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of Sciences, Moscow 117997, Russia; (O.A.R.); (V.V.P.); (A.I.K.); (S.A.K.); (E.V.S.); (I.V.A.)
- National Research Center “Kurchatov Institute”, Moscow 123182, Russia;
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Mohammed AN, Yadav N, Kaur P, Jandarov R, Yadav JS. Immunomodulation of susceptibility to pneumococcal pneumonia infection in mouse lungs exposed to carbon nanoparticles via dysregulation of innate and adaptive immune responses. Toxicol Appl Pharmacol 2024; 483:116820. [PMID: 38218205 DOI: 10.1016/j.taap.2024.116820] [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: 10/23/2023] [Revised: 01/05/2024] [Accepted: 01/10/2024] [Indexed: 01/15/2024]
Abstract
Carbon nanotubes (CNTs) are emerging pollutants of occupational and environmental health concern. While toxicological mechanisms of CNTs are emerging, there is paucity of information on their modulatory effects on susceptibility to infections. Here, we investigated cellular and molecular events underlying the effect of multi-walled CNT (MWCNT) exposure on susceptibility to Streptococcus pneumoniae infection in our 28-day sub-chronic exposure mouse model. Data indicated reduced phagocytic function in alveolar macrophages (AMs) from MWCNT-exposed lungs evidenced by lower pathogen uptake in 1-h infection assay. At 24-h post-infection, intracellular pathogen count in exposed AMs showed 2.5 times higher net increase (2-fold in vehicle- versus 5-fold in MWCNT-treated), indicating a greater rate of intracellular multiplication and/or survival due to MWCNT exposure. AMs from MWCNT-exposed lungs exhibited downregulation of pathogen-uptake receptors CD163, Phosphatidyl-serine receptor (Ptdsr), and Macrophage scavenger receptors class A type 1 (Msr1) and type 2 (MSr2). In whole lung, MWCNT exposure shifted the macrophage polarization state towards the immunosuppressive phenotype M2b and increased the CD11c+ dendritic cell population required to activate the adaptive immune response. Notably, the MWCNT pre-exposure dysregulated T-cell immunity, evidenced by diminished CD4 and Th17 response, and exacerbated Th1 and Treg responses (skewed Th17/Treg ratio), thereby favoring the pneumococcal infection. Overall, these findings indicated that MWCNT exposure compromises both innate and adaptive immunity leading to diminished host lung defense against pneumonia infection. To our knowledge, this is the first report on an immunomodulatory role of CNT pre-exposure on pneumococcal infection susceptibility due to dysregulation of both innate and adaptive immunity targets.
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Affiliation(s)
- Afzaal Nadeem Mohammed
- Pulmonary Pathogenesis and Immunotoxicology Laboratory, Division of Environmental Genetics and Molecular Toxicology, Department of Environmental and Public Health Sciences, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA
| | - Niket Yadav
- Medical Scientist Training Program, University of Virginia School of Medicine, Charlottesville, VA 22908-0738, USA
| | - Perminder Kaur
- Pulmonary Pathogenesis and Immunotoxicology Laboratory, Division of Environmental Genetics and Molecular Toxicology, Department of Environmental and Public Health Sciences, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA
| | - Roman Jandarov
- Division of Biostatistics and Bioinformatics, Department of Environmental and Public Health Sciences, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA
| | - Jagjit Singh Yadav
- Pulmonary Pathogenesis and Immunotoxicology Laboratory, Division of Environmental Genetics and Molecular Toxicology, Department of Environmental and Public Health Sciences, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA.
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Apeku E, Tantuoyir MM, Zheng R, Tanye N. Exploring the polarization of M1 and M2 macrophages in the context of skin diseases. Mol Biol Rep 2024; 51:269. [PMID: 38302766 DOI: 10.1007/s11033-023-09014-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2023] [Accepted: 10/30/2023] [Indexed: 02/03/2024]
Abstract
Macrophages are critical components of the immune system and play vital roles in pathogen defense, immune regulation, and tissue repair. These cells exhibit different polarization states depending on environmental signals, and the M1/M2 paradigm is a useful tool for comprehending these states. This review article comprehensively presents the underlying mechanisms of M1 and M2 macrophage polarization and examines their polarization in various skin diseases. Additionally, this paper discusses therapeutic strategies that target M1 and M2 macrophage polarization in skin diseases. A more profound understanding of macrophage polarization in skin diseases could provide valuable insights for the development of innovative therapeutic strategies.
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Affiliation(s)
- Ernestina Apeku
- Department of Dermatology, The 1st Hospital of Shanxi Medical University; Graduate Department of Shanxi Medical University, Taiyuan, Shanxi, China
| | | | - Rui Zheng
- Department of Dermatology, The 1st Hospital of Shanxi Medical University, Taiyuan, Shanxi, China.
| | - Nestor Tanye
- School of Automation Science and Engineering, Xi'an Jiaotong University, Xi'an, China
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Peckert-Maier K, Wild AB, Sprißler L, Fuchs M, Beck P, Auger JP, Sinner P, Strack A, Mühl-Zürbes P, Ramadan N, Kunz M, Krönke G, Stich L, Steinkasserer A, Royzman D. Soluble CD83 modulates human-monocyte-derived macrophages toward alternative phenotype, function, and metabolism. Front Immunol 2023; 14:1293828. [PMID: 38162675 PMCID: PMC10755915 DOI: 10.3389/fimmu.2023.1293828] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2023] [Accepted: 11/24/2023] [Indexed: 01/03/2024] Open
Abstract
Alterations in macrophage (Mφ) polarization, function, and metabolic signature can foster development of chronic diseases, such as autoimmunity or fibrotic tissue remodeling. Thus, identification of novel therapeutic agents that modulate human Mφ biology is crucial for treatment of such conditions. Herein, we demonstrate that the soluble CD83 (sCD83) protein induces pro-resolving features in human monocyte-derived Mφ biology. We show that sCD83 strikingly increases the expression of inhibitory molecules including ILT-2 (immunoglobulin-like transcript 2), ILT-4, ILT-5, and CD163, whereas activation markers, such as MHC-II and MSR-1, were significantly downregulated. This goes along with a decreased capacity to stimulate alloreactive T cells in mixed lymphocyte reaction (MLR) assays. Bulk RNA sequencing and pathway analyses revealed that sCD83 downregulates pathways associated with pro-inflammatory, classically activated Mφ (CAM) differentiation including HIF-1A, IL-6, and cytokine storm, whereas pathways related to alternative Mφ activation and liver X receptor were significantly induced. By using the LXR pathway antagonist GSK2033, we show that transcription of specific genes (e.g., PPARG, ABCA1, ABCG1, CD36) induced by sCD83 is dependent on LXR activation. In summary, we herein reveal for the first time mechanistic insights into the modulation of human Mφ biology by sCD83, which is a further crucial preclinical study for the establishment of sCD83 as a new therapeutical agent to treat inflammatory conditions.
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Affiliation(s)
- Katrin Peckert-Maier
- Department of Immune Modulation, Universitätsklinikum Erlangen, Friedrich– Alexander Universität Erlangen–Nürnberg, Erlangen, Germany
| | - Andreas B. Wild
- Department of Immune Modulation, Universitätsklinikum Erlangen, Friedrich– Alexander Universität Erlangen–Nürnberg, Erlangen, Germany
| | - Laura Sprißler
- Department of Immune Modulation, Universitätsklinikum Erlangen, Friedrich– Alexander Universität Erlangen–Nürnberg, Erlangen, Germany
| | - Maximilian Fuchs
- Fraunhofer Institute for Toxicology and Experimental Medicine (ITEM), Hannover, Germany
| | - Philipp Beck
- Department of Immune Modulation, Universitätsklinikum Erlangen, Friedrich– Alexander Universität Erlangen–Nürnberg, Erlangen, Germany
| | - Jean-Philippe Auger
- Department of Internal Medicine 3 – Rheumatology and Immunology, Friedrich-Alexander University Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, Erlangen, Germany
| | - Pia Sinner
- Department of Immune Modulation, Universitätsklinikum Erlangen, Friedrich– Alexander Universität Erlangen–Nürnberg, Erlangen, Germany
| | - Astrid Strack
- Department of Immune Modulation, Universitätsklinikum Erlangen, Friedrich– Alexander Universität Erlangen–Nürnberg, Erlangen, Germany
| | - Petra Mühl-Zürbes
- Department of Immune Modulation, Universitätsklinikum Erlangen, Friedrich– Alexander Universität Erlangen–Nürnberg, Erlangen, Germany
| | - Ntilek Ramadan
- Department of Immune Modulation, Universitätsklinikum Erlangen, Friedrich– Alexander Universität Erlangen–Nürnberg, Erlangen, Germany
| | - Meik Kunz
- Fraunhofer Institute for Toxicology and Experimental Medicine (ITEM), Hannover, Germany
- Chair of Medical Informatics, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Bavaria, Germany
| | - Gerhard Krönke
- Department of Internal Medicine 3 – Rheumatology and Immunology, Friedrich-Alexander University Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, Erlangen, Germany
| | - Lena Stich
- Department of Immune Modulation, Universitätsklinikum Erlangen, Friedrich– Alexander Universität Erlangen–Nürnberg, Erlangen, Germany
| | - Alexander Steinkasserer
- Department of Immune Modulation, Universitätsklinikum Erlangen, Friedrich– Alexander Universität Erlangen–Nürnberg, Erlangen, Germany
| | - Dmytro Royzman
- Department of Immune Modulation, Universitätsklinikum Erlangen, Friedrich– Alexander Universität Erlangen–Nürnberg, Erlangen, Germany
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van Wigcheren GF, Cuenca-Escalona J, Stelloo S, Brake J, Peeters E, Horrevorts SK, Frölich S, Ramos-Tomillero I, Wesseling-Rozendaal Y, van Herpen CML, van de Stolpe A, Vermeulen M, de Vries IJM, Figdor CG, Flórez-Grau G. Myeloid-derived suppressor cells and tolerogenic dendritic cells are distinctively induced by PI3K and Wnt signaling pathways. J Biol Chem 2023; 299:105276. [PMID: 37739035 PMCID: PMC10628850 DOI: 10.1016/j.jbc.2023.105276] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2023] [Revised: 08/07/2023] [Accepted: 08/14/2023] [Indexed: 09/24/2023] Open
Abstract
Imbalanced immune responses are a prominent hallmark of cancer and autoimmunity. Myeloid cells can be overly suppressive, inhibiting protective immune responses or inactive not controlling autoreactive immune cells. Understanding the mechanisms that induce suppressive myeloid cells, such as myeloid-derived suppressor cells (MDSCs) and tolerogenic dendritic cells (TolDCs), can facilitate the development of immune-restoring therapeutic approaches. MDSCs are a major barrier for effective cancer immunotherapy by suppressing antitumor immune responses in cancer patients. TolDCs are administered to patients to promote immune tolerance with the intent to control autoimmune disease. Here, we investigated the development and suppressive/tolerogenic activity of human MDSCs and TolDCs to gain insight into signaling pathways that drive immunosuppression in these different myeloid subsets. Moreover, monocyte-derived MDSCs (M-MDSCs) generated in vitro were compared to M-MDSCs isolated from head-and-neck squamous cell carcinoma patients. PI3K-AKT signaling was identified as being crucial for the induction of human M-MDSCs. PI3K inhibition prevented the downregulation of HLA-DR and the upregulation of reactive oxygen species and MerTK. In addition, we show that the suppressive activity of dexamethasone-induced TolDCs is induced by β-catenin-dependent Wnt signaling. The identification of PI3K-AKT and Wnt signal transduction pathways as respective inducers of the immunomodulatory capacity of M-MDSCs and TolDCs provides opportunities to overcome suppressive myeloid cells in cancer patients and optimize therapeutic application of TolDCs. Lastly, the observed similarities between generated- and patient-derived M-MDSCs support the use of in vitro-generated M-MDSCs as powerful model to investigate the functionality of human MDSCs.
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Affiliation(s)
- Glenn F van Wigcheren
- Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboudumc, Nijmegen, The Netherlands; Oncode Institute, The Netherlands
| | - Jorge Cuenca-Escalona
- Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboudumc, Nijmegen, The Netherlands
| | - Suzan Stelloo
- Oncode Institute, The Netherlands; Faculty of Science, Department of Molecular Biology, Radboud Institute for Molecular Life Sciences, Radboud University Nijmegen, Nijmegen, The Netherlands
| | - Julia Brake
- Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboudumc, Nijmegen, The Netherlands
| | - Eline Peeters
- Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboudumc, Nijmegen, The Netherlands
| | - Sophie K Horrevorts
- Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboudumc, Nijmegen, The Netherlands
| | - Siebren Frölich
- Faculty of Science, Department of Molecular Biology, Radboud Institute for Molecular Life Sciences, Radboud University Nijmegen, Nijmegen, The Netherlands
| | - Iván Ramos-Tomillero
- Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboudumc, Nijmegen, The Netherlands
| | | | | | | | - Michiel Vermeulen
- Oncode Institute, The Netherlands; Faculty of Science, Department of Molecular Biology, Radboud Institute for Molecular Life Sciences, Radboud University Nijmegen, Nijmegen, The Netherlands
| | - I Jolanda M de Vries
- Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboudumc, Nijmegen, The Netherlands.
| | - Carl G Figdor
- Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboudumc, Nijmegen, The Netherlands; Oncode Institute, The Netherlands
| | - Georgina Flórez-Grau
- Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboudumc, Nijmegen, The Netherlands
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Yue L, Xu X, Dai S, Xu F, Zhao W, Gu J, Dai X, Qian X. Orosomucoid 1 promotes colorectal cancer progression and liver metastasis by affecting PI3K/AKT pathway and inducing macrophage M2 polarization. Sci Rep 2023; 13:14092. [PMID: 37640741 PMCID: PMC10462626 DOI: 10.1038/s41598-023-40404-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2023] [Accepted: 08/09/2023] [Indexed: 08/31/2023] Open
Abstract
Approximately 25-30% of those affected by colorectal cancer (CRC), the most prevalent gastrointestinal malignancy, develop metastases. The survival rate of patients with liver metastasis of CRC (CRLM) remains low owing to its unpredictability and a lack of biomarkers that can be applied to distinguish groups at higher risk for CRLM among patients with CRC. Therefore, our study aimed to find biomarkers that can predict the risk of CRLM. Screening of the Gene Expression Omnibus database, supported by an analysis of clinically obtained tissue and serum data using qPCR and ELISA, in an attempt to identify relevant biomarkers, enabled us to determine that orosomucoid 1 (ORM1) was differentially expressed in liver metastases and primary tumors of patients with CRC. Functionally, overexpression of ORM1 promoted the epithelial-mesenchymal transition and the proliferative, migratory, and invasive activities of MC38 cells and activated the PI3K/AKT signaling pathway. Moreover, MC38 cells overexpressing ORM1 enhanced the tumor immune microenvironment by promoting macrophage M2 polarization and elevating interleukin-10 (IL-10) expression. In vivo experiments further confirmed in vitro results, indicating that liver metastases elevated by ORM1 were partially attenuated by the depletion of macrophages or IL-10. Considered together, ORM1 promotes CRC progression and liver metastasis by regulating tumor cell growth and inducing macrophage M2 polarization, which mediates tumor immune tolerance, and thus acts as a potential predictive marker and therapeutic target in CRLM.
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Affiliation(s)
- Lei Yue
- Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, 310022, Zhejiang, China
| | - Xiaozhang Xu
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, Jiangsu Province, China
- Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, Nanjing, 210029, Jiangsu Province, China
- NHC Key Laboratory of Living Donor Liver Transplantation, Nanjing Medical University, Nanjing, 210029, Jiangsu Province, China
| | - Shipeng Dai
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, Jiangsu Province, China
- Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, Nanjing, 210029, Jiangsu Province, China
- NHC Key Laboratory of Living Donor Liver Transplantation, Nanjing Medical University, Nanjing, 210029, Jiangsu Province, China
| | - Fan Xu
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, Jiangsu Province, China
- Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, Nanjing, 210029, Jiangsu Province, China
- NHC Key Laboratory of Living Donor Liver Transplantation, Nanjing Medical University, Nanjing, 210029, Jiangsu Province, China
| | - Wenhu Zhao
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, Jiangsu Province, China
- Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, Nanjing, 210029, Jiangsu Province, China
- NHC Key Laboratory of Living Donor Liver Transplantation, Nanjing Medical University, Nanjing, 210029, Jiangsu Province, China
| | - Jian Gu
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, Jiangsu Province, China
- Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, Nanjing, 210029, Jiangsu Province, China
- NHC Key Laboratory of Living Donor Liver Transplantation, Nanjing Medical University, Nanjing, 210029, Jiangsu Province, China
| | - Xinzheng Dai
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, Jiangsu Province, China.
- Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, Nanjing, 210029, Jiangsu Province, China.
- NHC Key Laboratory of Living Donor Liver Transplantation, Nanjing Medical University, Nanjing, 210029, Jiangsu Province, China.
| | - Xiaofeng Qian
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, Jiangsu Province, China.
- Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, Nanjing, 210029, Jiangsu Province, China.
- NHC Key Laboratory of Living Donor Liver Transplantation, Nanjing Medical University, Nanjing, 210029, Jiangsu Province, China.
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Chaintreuil P, Kerreneur E, Bourgoin M, Savy C, Favreau C, Robert G, Jacquel A, Auberger P. The generation, activation, and polarization of monocyte-derived macrophages in human malignancies. Front Immunol 2023; 14:1178337. [PMID: 37143666 PMCID: PMC10151765 DOI: 10.3389/fimmu.2023.1178337] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2023] [Accepted: 04/04/2023] [Indexed: 05/06/2023] Open
Abstract
Macrophages are immune cells that originate from embryogenesis or from the differentiation of monocytes. They can adopt numerous phenotypes depending on their origin, tissue distribution and in response to different stimuli and tissue environment. Thus, in vivo, macrophages are endowed with a continuum of phenotypes that are rarely strictly pro-inflammatory or anti-inflammatory and exhibit a broad expression profile that sweeps over the whole polarization spectrum. Schematically, three main macrophage subpopulations coexist in human tissues: naïve macrophages also called M0, pro-inflammatory macrophages referred as M1 macrophages, and anti-inflammatory macrophages also known as M2 macrophages. Naïve macrophages display phagocytic functions, recognize pathogenic agents, and rapidly undergo polarization towards pro or anti-inflammatory macrophages to acquire their full panel of functions. Pro-inflammatory macrophages are widely involved in inflammatory response, during which they exert anti-microbial and anti-tumoral functions. By contrast, anti-inflammatory macrophages are implicated in the resolution of inflammation, the phagocytosis of cell debris and tissue reparation following injuries. Macrophages also play important deleterious or beneficial roles in the initiation and progression of different pathophysiological settings including solid and hematopoietic cancers. A better understanding of the molecular mechanisms involved in the generation, activation and polarization of macrophages is a prerequisite for the development of new therapeutic strategies to modulate macrophages functions in pathological situations.
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Affiliation(s)
- Paul Chaintreuil
- Université Côte d’Azur, Institut National de la Santé et de la Recherche Médicale, Nice, France
- Inserm U1065, Centre Méditerranéen de Médecine Moléculaire (C3M), Nice, France
| | - Emeline Kerreneur
- Université Côte d’Azur, Institut National de la Santé et de la Recherche Médicale, Nice, France
- Inserm U1065, Centre Méditerranéen de Médecine Moléculaire (C3M), Nice, France
| | - Maxence Bourgoin
- Université Côte d’Azur, Institut National de la Santé et de la Recherche Médicale, Nice, France
- Inserm U1065, Centre Méditerranéen de Médecine Moléculaire (C3M), Nice, France
| | - Coline Savy
- Université Côte d’Azur, Institut National de la Santé et de la Recherche Médicale, Nice, France
- Inserm U1065, Centre Méditerranéen de Médecine Moléculaire (C3M), Nice, France
| | - Cécile Favreau
- Université Côte d’Azur, Institut National de la Santé et de la Recherche Médicale, Nice, France
- Inserm U1065, Centre Méditerranéen de Médecine Moléculaire (C3M), Nice, France
| | - Guillaume Robert
- Université Côte d’Azur, Institut National de la Santé et de la Recherche Médicale, Nice, France
- Inserm U1065, Centre Méditerranéen de Médecine Moléculaire (C3M), Nice, France
| | - Arnaud Jacquel
- Université Côte d’Azur, Institut National de la Santé et de la Recherche Médicale, Nice, France
- Inserm U1065, Centre Méditerranéen de Médecine Moléculaire (C3M), Nice, France
- *Correspondence: Arnaud Jacquel, ; Patrick Auberger,
| | - Patrick Auberger
- Université Côte d’Azur, Institut National de la Santé et de la Recherche Médicale, Nice, France
- Inserm U1065, Centre Méditerranéen de Médecine Moléculaire (C3M), Nice, France
- *Correspondence: Arnaud Jacquel, ; Patrick Auberger,
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9
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Asai A, Tsuchimoto Y, Ohama H, Nishikawa H, Chopra A, Higuchi K. CD34+CD10+CD19− Cells in Patients with Unhealthy Alcohol Use Stimulate the M2b Monocyte Polarization. Cells 2022; 11:cells11172703. [PMID: 36078108 PMCID: PMC9454773 DOI: 10.3390/cells11172703] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2022] [Revised: 08/15/2022] [Accepted: 08/27/2022] [Indexed: 11/26/2022] Open
Abstract
M2b monocytes commonly isolated from patients with unhealthy alcohol use (Alc) have been described as cells that make the host susceptible to opportunistic infections. CD34+CD10+CD19− cells are multilineage progenitors of CD19+ cells, and we show that the effect of these cells from the peripheral blood on M2b monocyte polarization differed between healthy donors and Alc in this study. In healthy donors, these cells consistently differentiated into high-mobility group box-1 (HMGB1)-nonproducing cells (CD19+ cells) in response to retinoic acid (RA). However, owing to the lack of expression of RA receptor (RAR), these cells from Alc failed to differentiate into CD19+ cells under the same RA stimulation. Conditioned medium (CM) of these cells from Alc induced the polarization of M2b monocytes, which increases the susceptibility of hosts to opportunistic infections in Alc. When the alcoholic individuals were subjected to 2 weeks of abstinence from alcohol, these cells from Alc recovered their RAR expression and differentiated into CD19+ cells. Moreover, the CM of these cells from Alc after abstinence lost its ability to induce M2b monocyte polarization. These results indicate that these cells from Alc have different properties from those of healthy donors. In Alc, these cells without RAR stimulate M2b monocyte polarization through the production of HMGB1.
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Affiliation(s)
- Akira Asai
- 2nd Department of Internal Medicine, Osaka Medical and Pharmaceutical University, Takatsuki 569-8686, Japan
- Correspondence: ; Tel.: +81-(726)-83-1221
| | - Yusuke Tsuchimoto
- 2nd Department of Internal Medicine, Osaka Medical and Pharmaceutical University, Takatsuki 569-8686, Japan
| | - Hideko Ohama
- 2nd Department of Internal Medicine, Osaka Medical and Pharmaceutical University, Takatsuki 569-8686, Japan
| | - Hiroki Nishikawa
- 2nd Department of Internal Medicine, Osaka Medical and Pharmaceutical University, Takatsuki 569-8686, Japan
| | - Ashok Chopra
- Department of Microbiology and Immunology, The University of Texas Medical Branch, Galveston, TX 77555, USA
| | - Kazuhide Higuchi
- 2nd Department of Internal Medicine, Osaka Medical and Pharmaceutical University, Takatsuki 569-8686, Japan
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10
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Singer SN, Ndumnego OC, Kim RS, Ndung'u T, Anastos K, French A, Churchyard G, Paramithiothis E, Kasprowicz VO, Achkar JM. Plasma host protein biomarkers correlating with increasing Mycobacterium tuberculosis infection activity prior to tuberculosis diagnosis in people living with HIV. EBioMedicine 2022; 75:103787. [PMID: 34968761 PMCID: PMC8718743 DOI: 10.1016/j.ebiom.2021.103787] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Revised: 11/30/2021] [Accepted: 12/14/2021] [Indexed: 02/03/2023] Open
Abstract
BACKGROUND Biomarkers correlating with Mycobacterium tuberculosis infection activity/burden in asymptomatic individuals are urgently needed to identify and treat those at highest risk for developing active tuberculosis (TB). Our main objective was to identify plasma host protein biomarkers that change over time prior to developing TB in people living with HIV (PLHIV). METHODS Using multiplex MRM-MS, we investigated host protein expressions from 2 years before until time of TB diagnosis in longitudinally collected (every 3-6 months) and stored plasma from PLHIV with incident TB, identified within a South African (SA) and US cohort. We performed temporal trend and discriminant analyses for proteins, and, to assure clinical relevance, we further compared protein levels at TB diagnosis to interferon-gamma release assay (IGRA; SA) or tuberculin-skin test (TST; US) positive and negative cohort subjects without TB. SA and US exploratory data were analyzed separately. FINDINGS We identified 15 proteins in the SA (n=30) and 10 in the US (n=24) incident TB subjects which both changed from 2 years prior until time of TB diagnosis after controlling for 10% false discovery rate, and were significantly different at time of TB diagnosis compared to non-TB subjects (p<0.01). Five proteins, CD14, A2GL, NID1, SCTM1, and A1AG1, overlapped between both cohorts. Furthermore, after cross-validation, panels of 5 - 12 proteins were able to predict TB up to two years before diagnosis. INTERPRETATION Host proteins can be biomarkers for increasing Mycobacterium tuberculosis infection activity/burden, incipient TB, and predict TB development in PLHIV. FUNDING NIH/NIAID AI117927, AI146329, and AI127173 to JMA.
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Affiliation(s)
- Sarah N Singer
- Departments of Medicine, Albert Einstein College of Medicine, Bronx, NY 10461, USA
| | | | - Ryung S Kim
- Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY 10461, USA
| | - Thumbi Ndung'u
- Africa Health Research Institute, Durban 4013, South Africa; HIV Pathogenesis Programme, Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa; Ragon Institute of MGH, MIT and Harvard University, Cambridge, MA, USA; Max Planck Institute of Infection Biology, Berlin, Germany; Division of Infection and Immunity, University College London, London, UK
| | - Kathryn Anastos
- Departments of Medicine, Albert Einstein College of Medicine, Bronx, NY 10461, USA; Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY 10461, USA
| | - Audrey French
- Department of Medicine, Stroger Hospital of Cook County, Chicago, IL, USA
| | - Gavin Churchyard
- Aurum Institute, Johannesburg, South Africa; School of Public Health, University of Witwatersrand, Johannesburg, South Africa; Department of Medicine, Vanderbilt University, Nashville, TN, USA
| | - Eustache Paramithiothis
- CellCarta Biosciences Inc, 201 President-Kennedy Ave., Suite 3900 Montreal, H2×3Y7, Quebec, Canada
| | - Victoria O Kasprowicz
- Africa Health Research Institute, Durban 4013, South Africa; HIV Pathogenesis Programme, Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa; Ragon Institute of MGH, MIT and Harvard University, Cambridge, MA, USA
| | - Jacqueline M Achkar
- Departments of Medicine, Albert Einstein College of Medicine, Bronx, NY 10461, USA; Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
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11
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Zheng H, Rao AM, Dermadi D, Toh J, Murphy Jones L, Donato M, Liu Y, Su Y, Dai CL, Kornilov SA, Karagiannis M, Marantos T, Hasin-Brumshtein Y, He YD, Giamarellos-Bourboulis EJ, Heath JR, Khatri P. Multi-cohort analysis of host immune response identifies conserved protective and detrimental modules associated with severity across viruses. Immunity 2021; 54:753-768.e5. [PMID: 33765435 PMCID: PMC7988739 DOI: 10.1016/j.immuni.2021.03.002] [Citation(s) in RCA: 44] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2020] [Revised: 12/03/2020] [Accepted: 03/01/2021] [Indexed: 02/08/2023]
Abstract
Viral infections induce a conserved host response distinct from bacterial infections. We hypothesized that the conserved response is associated with disease severity and is distinct between patients with different outcomes. To test this, we integrated 4,780 blood transcriptome profiles from patients aged 0 to 90 years infected with one of 16 viruses, including SARS-CoV-2, Ebola, chikungunya, and influenza, across 34 cohorts from 18 countries, and single-cell RNA sequencing profiles of 702,970 immune cells from 289 samples across three cohorts. Severe viral infection was associated with increased hematopoiesis, myelopoiesis, and myeloid-derived suppressor cells. We identified protective and detrimental gene modules that defined distinct trajectories associated with mild versus severe outcomes. The interferon response was decoupled from the protective host response in patients with severe outcomes. These findings were consistent, irrespective of age and virus, and provide insights to accelerate the development of diagnostics and host-directed therapies to improve global pandemic preparedness.
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Affiliation(s)
- Hong Zheng
- Institute for Immunity, Transplantation and Infection, School of Medicine, Stanford University, CA 94305, USA; Center for Biomedical Informatics Research, Department of Medicine, School of Medicine, Stanford University, CA 94305, USA
| | - Aditya M Rao
- Institute for Immunity, Transplantation and Infection, School of Medicine, Stanford University, CA 94305, USA; Immunology program, Stanford University, CA 94305, USA
| | - Denis Dermadi
- Institute for Immunity, Transplantation and Infection, School of Medicine, Stanford University, CA 94305, USA; Center for Biomedical Informatics Research, Department of Medicine, School of Medicine, Stanford University, CA 94305, USA
| | - Jiaying Toh
- Institute for Immunity, Transplantation and Infection, School of Medicine, Stanford University, CA 94305, USA; Immunology program, Stanford University, CA 94305, USA
| | - Lara Murphy Jones
- Institute for Immunity, Transplantation and Infection, School of Medicine, Stanford University, CA 94305, USA; Center for Biomedical Informatics Research, Department of Medicine, School of Medicine, Stanford University, CA 94305, USA; Division of Critical Care Medicine, Department of Pediatrics, School of Medicine, Stanford University, CA 94305, USA
| | - Michele Donato
- Institute for Immunity, Transplantation and Infection, School of Medicine, Stanford University, CA 94305, USA; Center for Biomedical Informatics Research, Department of Medicine, School of Medicine, Stanford University, CA 94305, USA
| | - Yiran Liu
- Institute for Immunity, Transplantation and Infection, School of Medicine, Stanford University, CA 94305, USA; Cancer Biology program, Stanford University, CA 94305, USA
| | - Yapeng Su
- Institute for Systems Biology, Seattle, WA, USA
| | - Cheng L Dai
- Institute for Systems Biology, Seattle, WA, USA
| | | | - Minas Karagiannis
- 4(th) Department of Internal Medicine, National and Kapodistrian University of Athens, Medical School, 124 62 Athens, Greece
| | - Theodoros Marantos
- 4(th) Department of Internal Medicine, National and Kapodistrian University of Athens, Medical School, 124 62 Athens, Greece
| | | | | | | | - James R Heath
- Institute for Systems Biology, Seattle, WA, USA; Department of Bioengineering, University of Washington, Seattle, WA 98195
| | - Purvesh Khatri
- Institute for Immunity, Transplantation and Infection, School of Medicine, Stanford University, CA 94305, USA; Center for Biomedical Informatics Research, Department of Medicine, School of Medicine, Stanford University, CA 94305, USA.
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12
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Bailey TW, Dos Santos AP, do Nascimento NC, Xie S, Thimmapuram J, Sivasankar MP, Cox A. RNA sequencing identifies transcriptional changes in the rabbit larynx in response to low humidity challenge. BMC Genomics 2020; 21:888. [PMID: 33308144 PMCID: PMC7733274 DOI: 10.1186/s12864-020-07301-7] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2020] [Accepted: 12/04/2020] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND Voice disorders are a worldwide problem impacting human health, particularly for occupational voice users. Avoidance of surface dehydration is commonly prescribed as a protective factor against the development of dysphonia. The available literature inconclusively supports this practice and a biological mechanism for how surface dehydration of the laryngeal tissue affects voice has not been described. In this study, we used an in vivo male New Zealand white rabbit model to elucidate biological changes based on gene expression within the vocal folds from surface dehydration. Surface dehydration was induced by exposure to low humidity air (18.6% + 4.3%) for 8 h. Exposure to moderate humidity (43.0% + 4.3%) served as the control condition. Ilumina-based RNA sequencing was performed and used for transcriptome analysis with validation by RT-qPCR. RESULTS There were 103 statistically significant differentially expressed genes identified through Cuffdiff with 61 genes meeting significance by both false discovery rate and fold change. Functional annotation enrichment and predicted protein interaction mapping showed enrichment of various loci, including cellular stress and inflammatory response, ciliary function, and keratinocyte development. Eight genes were selected for RT-qPCR validation. Matrix metalloproteinase 12 (MMP12) and macrophage cationic peptide 1 (MCP1) were significantly upregulated and an epithelial chloride channel protein (ECCP) was significantly downregulated after surface dehydration by RNA-Seq and RT-qPCR. Suprabasin (SPBN) and zinc activated cationic channel (ZACN) were marginally, but non-significantly down- and upregulated as evidenced by RT-qPCR, respectively. CONCLUSIONS The data together support the notion that surface dehydration induces physiological changes in the vocal folds and justifies targeted analysis to further explore the underlying biology of compensatory fluid/ion flux and inflammatory mediators in response to airway surface dehydration.
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Affiliation(s)
- Taylor W Bailey
- Department of Comparative Pathobiology, Purdue University, West Lafayette, IN, 47907, USA.,Department of Public Health, Purdue University, West Lafayette, IN, 47907, USA
| | | | | | - Shaojun Xie
- Bioinformatics Core, Purdue University, West Lafayette, Indiana, 47907, USA
| | - Jyothi Thimmapuram
- Bioinformatics Core, Purdue University, West Lafayette, Indiana, 47907, USA
| | - M Preeti Sivasankar
- Department of Speech, Language, and Hearing Sciences, Purdue University, West Lafayette, IN, 47907, USA
| | - Abigail Cox
- Department of Comparative Pathobiology, Purdue University, West Lafayette, IN, 47907, USA.
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13
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Sumanth MS, Jacob SP, Abhilasha KV, Manne BK, Basrur V, Lehoux S, Campbell RA, Yost CC, McIntyre TM, Cummings RD, Weyrich AS, Rondina MT, Marathe GK. Different glycoforms of alpha-1-acid glycoprotein contribute to its functional alterations in platelets and neutrophils. J Leukoc Biol 2020; 109:915-930. [PMID: 33070381 DOI: 10.1002/jlb.3a0720-422r] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2020] [Revised: 09/18/2020] [Accepted: 09/30/2020] [Indexed: 12/23/2022] Open
Abstract
Alpha-1-acid glycoprotein (AGP-1) is a positive acute phase glycoprotein with uncertain functions. Serum AGP-1 (sAGP-1) is primarily derived from hepatocytes and circulates as 12-20 different glycoforms. We isolated a glycoform secreted from platelet-activating factor (PAF)-stimulated human neutrophils (nAGP-1). Its peptide sequence was identical to hepatocyte-derived sAGP-1, but nAGP-1 differed from sAGP-1 in its chromatographic behavior, electrophoretic mobility, and pattern of glycosylation. The function of these 2 glycoforms also differed. sAGP-1 activated neutrophil adhesion, migration, and neutrophil extracellular traps (NETosis) involving myeloperoxidase, peptidylarginine deiminase 4, and phosphorylation of ERK in a dose-dependent fashion, whereas nAGP-1 was ineffective as an agonist for these events. Furthermore, sAGP-1, but not nAGP-1, inhibited LPS-stimulated NETosis. Interestingly, nAGP-1 inhibited sAGP-1-stimulated neutrophil NETosis. The discordant effect of the differentially glycosylated AGP-1 glycoforms was also observed in platelets where neither of the AGP-1 glycoforms alone stimulated aggregation of washed human platelets, but sAGP-1, and not nAGP-1, inhibited aggregation induced by PAF or ADP, but not by thrombin. These functional effects of sAGP-1 correlated with intracellular cAMP accumulation and phosphorylation of the protein kinase A substrate vasodilator-stimulated phosphoprotein and reduction of Akt, ERK, and p38 phosphorylation. Thus, the sAGP-1 glycoform limits platelet reactivity, whereas nAGP-1 glycoform also limits proinflammatory actions of sAGP-1. These studies identify new functions for this acute phase glycoprotein and demonstrate that the glycosylation of AGP-1 controls its effects on 2 critical cells of acute inflammation.
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Affiliation(s)
- Mosale Seetharam Sumanth
- Department of Studies in Biochemistry, University of Mysore, Manasagangothri, Mysuru, Karnataka, India
| | - Shancy P Jacob
- Department of Pediatrics, Division of Allergy and Immunology, University of Utah, Salt Lake City, Utah, USA
| | | | - Bhanu Kanth Manne
- Molecular Medicine Program, and Department of Internal Medicine and Pathology, University of Utah, Salt Lake City, Utah, USA
| | - Venkatesha Basrur
- Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan, USA
| | - Sylvain Lehoux
- Beth Israel Deaconess Medical Center, Department of Surgery, Harvard Medical School, Boston, Massachusetts, USA
| | - Robert A Campbell
- Molecular Medicine Program, and Department of Internal Medicine and Pathology, University of Utah, Salt Lake City, Utah, USA
| | - Christian C Yost
- Molecular Medicine Program, and Department of Internal Medicine and Pathology, University of Utah, Salt Lake City, Utah, USA.,Department of Pediatrics, University of Utah, Salt Lake City, Utah, USA
| | - Thomas M McIntyre
- Department of Cardiovascular & Metabolic Sciences, Cleveland Clinic Lerner Research Institute, Cleveland, Ohio, USA
| | - Richard D Cummings
- Beth Israel Deaconess Medical Center, Department of Surgery, Harvard Medical School, Boston, Massachusetts, USA
| | - Andrew S Weyrich
- Molecular Medicine Program, and Department of Internal Medicine and Pathology, University of Utah, Salt Lake City, Utah, USA
| | - Matthew T Rondina
- Molecular Medicine Program, and Department of Internal Medicine and Pathology, University of Utah, Salt Lake City, Utah, USA.,The Geriatric Research Education and Clinical Center, Salt Lake City, Utah, USA.,Department of Internal Medicine, George E. Wahlen VAMC, Salt Lake City, Utah, USA
| | - Gopal K Marathe
- Department of Studies in Biochemistry, University of Mysore, Manasagangothri, Mysuru, Karnataka, India.,Department of Studies in Molecular Biology, University of Mysore, Manasagangothri, Mysuru, Karnataka, India
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14
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Asai A, Yasuoka H, Matsui M, Tsuchimoto Y, Fukunishi S, Higuchi K. Programmed Death 1 Ligand Expression in the Monocytes of Patients with Hepatocellular Carcinoma Depends on Tumor Progression. Cancers (Basel) 2020; 12:E2286. [PMID: 32824016 PMCID: PMC7465257 DOI: 10.3390/cancers12082286] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2020] [Revised: 08/05/2020] [Accepted: 08/08/2020] [Indexed: 12/13/2022] Open
Abstract
Monocytes (CD14+ cells) from advanced-stage hepatocellular carcinoma (HCC) patients express programmed death 1 ligand (PD-L)/PD-1 and suppress the host antitumor immune response. However, it is unclear whether cancer progression is associated with CD14+ cells. We compared CD14+ cell properties before and after cancer progression in the same HCC patients and examined their role in antitumor immunity. CD14+ cells were isolated from 15 naïve early-stage HCC patients before treatment initiation and after cancer progression to advanced stages. Although CD14+ cells from patients at early HCC stages exhibited antitumor activity in humanized murine chimera, CD14+ cells from the same patients after progression to advanced stages lacked this activity. Moreover, CD14+ cells from early HCC stages scantly expressed PD-L1 and PD-L2 and produced few cytokines, while CD14+ cells from advanced stages showed increased PD-L expression and produced IL-10 and CCL1. CD14+ cells were also isolated from five naïve advanced-stage HCC patients before treatment as well as after treatment-induced tumor regression. The CD14+ cells from patients with advanced-stage HCC expressed PD-L expressions, produced IL-10 and CCL1, and exhibited minimal tumoricidal activity. After treatment-induced tumor regression, CD14+ cells from the same patients did not express PD-Ls, failed to produce cytokines, and recovered tumoricidal activity. These results indicate that PD-L expression as well as CD14+ cell phenotype depend on the tumor stage in HCC patients. PD-L expressions of monocytes may be used as a new marker in the classification of cancer progression in HCC.
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Affiliation(s)
- Akira Asai
- The Second Department of Internal Medicine, Osaka Medical College, Takatsuki 5698686, Japan; (H.Y.); (M.M.); (Y.T.); (S.F.); (K.H.)
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15
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Watanabe H, Bi J, Murata R, Fujimura R, Nishida K, Imafuku T, Nakamura Y, Maeda H, Mukunoki A, Takeo T, Nakagata N, Kurauchi Y, Katsuki H, Tanaka M, Matsushita K, Fukagawa M, Maruyama T. A synthetic retinoic acid receptor agonist Am80 ameliorates renal fibrosis via inducing the production of alpha-1-acid glycoprotein. Sci Rep 2020; 10:11424. [PMID: 32651445 PMCID: PMC7351735 DOI: 10.1038/s41598-020-68337-z] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2019] [Accepted: 06/09/2020] [Indexed: 01/30/2023] Open
Abstract
Renal fibrosis is a major factor in the progression of chronic kidney disease and the final common pathway of kidney injury. Therefore, the effective therapies against renal fibrosis are urgently needed. The objective of this study was to investigate the effect of Am80, a synthetic retinoic acid receptor (RAR) agonist, in the treatment of renal interstitial fibrosis using unilateral ureteral obstruction (UUO) mice. The findings indicate that Am80 treatment suppressed renal fibrosis and inflammation to the same degree as the naturally-occuring retinoic acid, all-trans retinoic acid (atRA). But the adverse effect of body weight loss in Am80-treated mice was lower compared to the atRA treatment. The hepatic mRNA levels of alpha-1-acid glycoprotein (AGP), a downstream molecule of RAR agonist, was increased following administration of Am80 to healthy mice. In addition, increased AGP mRNA expression was also observed in HepG2 cells and THP-1-derived macrophages that had been treated with Am80. AGP-knockout mice exacerbated renal fibrosis, inflammation and macrophage infiltration in UUO mice, indicating endogenous AGP played an anti-fibrotic and anti-inflammatory role during the development of renal fibrosis. We also found that no anti-fibrotic effect of Am80 was observed in UUO-treated AGP-knockout mice whereas atRA treatment tended to show a partial anti-fibrotic effect. These collective findings suggest that Am80 protects against renal fibrosis via being involved in AGP function.
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Affiliation(s)
- Hiroshi Watanabe
- Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto, 862-0973, Japan.
| | - Jing Bi
- Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto, 862-0973, Japan
- Program for Leading Graduate Schools "HIGO (Health Life Science: Interdisciplinary and Global Oriented) Program", Kumamoto University, Kumamoto, Japan
| | - Ryota Murata
- Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto, 862-0973, Japan
| | - Rui Fujimura
- Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto, 862-0973, Japan
- Program for Leading Graduate Schools "HIGO (Health Life Science: Interdisciplinary and Global Oriented) Program", Kumamoto University, Kumamoto, Japan
| | - Kento Nishida
- Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto, 862-0973, Japan
| | - Tadashi Imafuku
- Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto, 862-0973, Japan
- Program for Leading Graduate Schools "HIGO (Health Life Science: Interdisciplinary and Global Oriented) Program", Kumamoto University, Kumamoto, Japan
| | - Yuka Nakamura
- Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto, 862-0973, Japan
| | - Hitoshi Maeda
- Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto, 862-0973, Japan
| | - Ayumi Mukunoki
- Division of Reproductive Engineering, Center for Animal Resources and Development (CARD), Kumamoto University, Kumamoto, Japan
| | - Toru Takeo
- Division of Reproductive Engineering, Center for Animal Resources and Development (CARD), Kumamoto University, Kumamoto, Japan
| | - Naomi Nakagata
- Division of Reproductive Engineering, Center for Animal Resources and Development (CARD), Kumamoto University, Kumamoto, Japan
| | - Yuki Kurauchi
- Department of Chemico-Pharmacological Sciences, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan
| | - Hiroshi Katsuki
- Department of Chemico-Pharmacological Sciences, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan
| | - Motoko Tanaka
- Department of Nephrology, Akebono Clinic, Kumamoto, Japan
| | | | - Masafumi Fukagawa
- Division of Nephrology, Endocrinology and Metabolism, Tokai University School of Medicine, Kanagawa, Japan
| | - Toru Maruyama
- Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto, 862-0973, Japan.
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16
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Fujimura R, Watanabe H, Nishida K, Fujiwara Y, Koga T, Bi J, Imafuku T, Kobayashi K, Komori H, Miyahisa M, Maeda H, Tanaka M, Matsushita K, Wada T, Fukagawa M, Maruyama T. α 1-Acid Glycoprotein Attenuates Adriamycin-Induced Nephropathy via CD163 Expressing Macrophage Induction. KIDNEY360 2020; 1:343-353. [PMID: 35369369 PMCID: PMC8809281 DOI: 10.34067/kid.0000782019] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/26/2019] [Accepted: 03/12/2020] [Indexed: 06/14/2023]
Abstract
BACKGROUND Recent clinical studies have shown that proteinuria is a critical factor in the progression of CKD and onset of cardiovascular disease. Inflammation and infiltration of macrophages into renal tissue are implicated as causes of proteinuria. α1-Acid glycoprotein (AGP), an acute-phase plasma protein, is leaked into the urine in patients with proteinuria. However, the relationship between urinary leakage of AGP, renal inflammation, and proteinuria remains unclear. METHODS Human AGP (hAGP) was exogenously administrated for 5 consecutive days to adriamycin-induced nephropathy model mice. RESULTS Adriamycin treatment increased urinary AGP, accompanied by decreased plasma AGP in mice. Exogenous hAGP administration to adriamycin-treated mice suppressed proteinuria, renal histologic injury, and inflammation. hAGP administration increased renal CD163 expression, a marker of anti-inflammatory macrophages. Similar changes were observed in PMA-differentiated THP-1 cells treated with hAGP. Even in the presence of LPS, hAGP treatment increased CD163/IL-10 expression in differentiated THP-1 cells. CONCLUSIONS AGP alleviates proteinuria and renal injury in mice with proteinuric kidney disease via induction of CD163-expressing macrophages with anti-inflammatory function. The results demonstrate that endogenous AGP could work to protect against glomerular disease. Thus, AGP supplementation could be a possible new therapeutic intervention for patients with glomerular disease.
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Affiliation(s)
- Rui Fujimura
- Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan
- Program for Leading Graduate Schools “HIGO (Health life science: Interdisciplinary and Global Oriented) Program,” Kumamoto University, Kumamoto, Japan
| | - Hiroshi Watanabe
- Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan
| | - Kento Nishida
- Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan
| | - Yukio Fujiwara
- Department of Cell Pathology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Tomoaki Koga
- Department of Medical Cell Biology, Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto, Japan
| | - Jing Bi
- Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan
- Program for Leading Graduate Schools “HIGO (Health life science: Interdisciplinary and Global Oriented) Program,” Kumamoto University, Kumamoto, Japan
| | - Tadashi Imafuku
- Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan
- Program for Leading Graduate Schools “HIGO (Health life science: Interdisciplinary and Global Oriented) Program,” Kumamoto University, Kumamoto, Japan
| | - Kazuki Kobayashi
- Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan
| | - Hisakazu Komori
- Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan
| | - Masako Miyahisa
- Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan
| | - Hitoshi Maeda
- Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan
| | - Motoko Tanaka
- Department of Nephrology, Akebono Clinic, Kumamoto, Japan
| | | | - Takashi Wada
- Department of Nephrology and Laboratory Medicine, Faculty of Medicine, Institute of Medical, Pharmaceutical and Health Sciences, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan
| | - Masafumi Fukagawa
- Division of Nephrology, Endocrinology and Metabolism, Tokai University School of Medicine, Kanagawa, Japan
| | - Toru Maruyama
- Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan
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Vitko D, Cho PS, Kostel SA, DiMartino SE, Cabour LD, Migliozzi MA, Logvinenko T, Warren PG, Froehlich JW, Lee RS. Characterizing Patients with Recurrent Urinary Tract Infections in Vesicoureteral Reflux: A Pilot Study of the Urinary Proteome. Mol Cell Proteomics 2020; 19:456-466. [PMID: 31896675 PMCID: PMC7050111 DOI: 10.1074/mcp.ra119.001873] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2019] [Revised: 12/25/2019] [Indexed: 01/23/2023] Open
Abstract
Recurrent urinary tract infections (UTIs) pose a significant burden on the health care system. Underlying mechanisms predisposing children to UTIs and associated changes in the urinary proteome are not well understood. We aimed to investigate the urinary proteome of a subset of children who have vesicoureteral reflux (VUR) and recurrent UTIs because of their risk of developing infection-related renal damage. Improving diagnostic modalities to identify UTI risk factors would significantly alter the clinical management of children with VUR. We profiled the urinary proteomes of 22 VUR patients with low grade VUR (1-3 out of 5), a history of recurrent UTIs, and renal scarring, comparing them to those obtained from 22 age-matched controls. Urinary proteins were analyzed by mass spectrometry followed by protein quantitation based on spectral counting. Of the 2,551 proteins identified across both cohorts, 964 were robustly quantified, as defined by meeting criteria with spectral count (SC) ≥2 in at least 7 patients in either VUR or control cohort. Eighty proteins had differential expression between the two cohorts, with 44 proteins significantly up-regulated and 36 downregulated (q <0.075, FC ≥1.2). Urinary proteins involved in inflammation, acute phase response (APR), modulation of extracellular matrix (ECM), and carbohydrate metabolism were altered among the study cohort.
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Affiliation(s)
- Dijana Vitko
- Department of Urology, Boston Children's Hospital, Boston, Massachusetts
| | - Patricia S Cho
- Department of Urology, Boston Children's Hospital, Boston, Massachusetts; Department of Urology, University of Massachusetts Medical School, Worcester, Massachusetts
| | - Stephen A Kostel
- Department of Urology, Boston Children's Hospital, Boston, Massachusetts
| | | | - Lily D Cabour
- Department of Urology, Boston Children's Hospital, Boston, Massachusetts
| | | | - Tanya Logvinenko
- Department of Urology, Boston Children's Hospital, Boston, Massachusetts
| | - Peter G Warren
- Department of Urology, Boston Children's Hospital, Boston, Massachusetts
| | - John W Froehlich
- Department of Urology, Boston Children's Hospital, Boston, Massachusetts
| | - Richard S Lee
- Department of Urology, Boston Children's Hospital, Boston, Massachusetts.
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Zhu HZ, Zhou WJ, Wan YF, Ge K, Lu J, Jia CK. Downregulation of orosomucoid 2 acts as a prognostic factor associated with cancer-promoting pathways in liver cancer. World J Gastroenterol 2020; 26:804-817. [PMID: 32148378 PMCID: PMC7052533 DOI: 10.3748/wjg.v26.i8.804] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/26/2019] [Revised: 01/04/2020] [Accepted: 01/11/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Liver cancer has a high mortality and morbidity rate throughout the world. In clinical practice, the prognosis of liver cancer patients is poor, and the complex reasons contribute to treatment failures, including fibrosis, hepatitis viral infection, drug resistance and metastasis. Thus, screening novel prognostic biomarkers is of great importance for guiding liver cancer therapy. Orosomucoid genes (ORMs) encode acute phase plasma proteins, including orosomucoid 1 (ORM1) and ORM2. Previous studies showed their upregulation upon inflammation, but the specific function of ORMs has not yet been determined, especially in the development of liver cancer. AIM To determine the expression of ORMs and their potential function in liver cancer. METHODS Analysis of the expression of ORMs in different human tissues was performed on data from the HPA RNA-seq normal tissues project. The expression ratio of ORMs was determined using the HCCDB database, including the ratio between liver cancer and other cancers, normal liver and other normal tissues, liver cancer and adjacent normal liver tissues. Analysis of ORM expression in different cancer types was performed using The Cancer Genome Atlas and TIMER database. The expression of ORMs in liver tumor tissues and adjacent normal tissues were further confirmed using Gene Expression Omnibus data, including GSE36376 and GSE14520. The 10-year overall survival (OS), progression-free survival (PFS) and relapse-free survival (RFS) rates between high and low ORM expression groups in liver cancer patients were determined using the Kaplan-Meier plotter tool. Gene Set Enrichment Analysis (GSEA) was employed to explore the ORM2-associated signaling network. Correlations between ORM2 expression and tumor purity or the infiltration level of macrophages in liver tumor tissues were determined using the TIMER database. The correlation between ORM2 gene levels, tumor-associated macrophage (TAM) markers (including CD68 and TGFβ1) and T cell immunosuppression (including CTLA4 and PD-1) in liver tumor tissues and liver GTEx was determined using the GEPIA database. RESULTS ORM1 and ORM2 were highly expressed in normal liver and liver tumor tissues. ORM1 and ORM2 expression was significantly decreased in liver tumor tissues compared with adjacent normal tissues, and similar results were also noted in cholangiocarcinoma, esophageal carcinoma, and lung squamous cell carcinoma. Further analysis of the Gene Expression Omnibus Database also confirmed the downregulation of ORM1 and ORM2 in liver tumors. Survival analysis showed that the high ORM2 group had better survival rates in OS, PFS and RFS. ORM1 only represented better performance in PFS, but not in OS or RFS. GSEA analysis of ORM2 from The Cancer Genome Atlas liver cancer data identified that ORM2 positively associated with the G2/M checkpoint, E2F target signaling, as well as Wnt/β-catenin and Hedgehog signaling. Moreover, apoptosis, IFN-α responses, IFN-γ responses and humoral immune responses were upregulated in the ORM2 high group. ORM2 expression was negatively correlated with the macrophage infiltration level, CD68, TGFβ1, CTLA4 and PD-1 levels. CONCLUSION The results showed that ORM1 and ORM2 were highly expressed specifically in liver tissues, whereas ORM1 and ORM2 were downregulated in liver tumor tissues. ORM2 is a better prognostic factor for liver cancer. Furthermore, ORM2 is closely associated with cancer-promoting pathways.
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Affiliation(s)
- Han-Zhang Zhu
- Department of Hepatopancreatobiliary Surgery, Hangzhou First People’s Hospital, The Affiliated Hospital of Medical School of Zhejiang University. Hangzhou 310006, Zhejiang Province, China
| | - Wei-Jiang Zhou
- Department of Hepatopancreatobiliary Surgery, Hangzhou First People’s Hospital, The Affiliated Hospital of Medical School of Zhejiang University. Hangzhou 310006, Zhejiang Province, China
| | - Ya-Feng Wan
- Department of Hepatopancreatobiliary Surgery, Hangzhou First People’s Hospital, The Affiliated Hospital of Medical School of Zhejiang University. Hangzhou 310006, Zhejiang Province, China
| | - Ke Ge
- Department of Hepatopancreatobiliary Surgery, Hangzhou First People’s Hospital, The Affiliated Hospital of Medical School of Zhejiang University. Hangzhou 310006, Zhejiang Province, China
| | - Jun Lu
- Department of Hepatopancreatobiliary Surgery, Hangzhou First People’s Hospital, The Affiliated Hospital of Medical School of Zhejiang University. Hangzhou 310006, Zhejiang Province, China
| | - Chang-Ku Jia
- Department of Hepatopancreatobiliary Surgery, Hangzhou First People’s Hospital, The Affiliated Hospital of Medical School of Zhejiang University. Hangzhou 310006, Zhejiang Province, China
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Astrup LB, Skovgaard K, Rasmussen RS, Iburg TM, Agerholm JS, Aalbæk B, Jensen HE, Nielsen OL, Johansen FF, Heegaard PMH, Leifsson PS. Staphylococcus aureus infected embolic stroke upregulates Orm1 and Cxcl2 in a rat model of septic stroke pathology. Neurol Res 2019; 41:399-412. [DOI: 10.1080/01616412.2019.1573455] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Affiliation(s)
- Lærke Boye Astrup
- Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Frederiksberg, Denmark
| | - Kerstin Skovgaard
- Division of Immunology and Vaccinology, National Veterinary Institute, Technical University of Denmark, Kgs. Lyngby, Denmark
| | - Rune Skovgaard Rasmussen
- Biotech Research and Innovation Centre, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Tine Moesgaard Iburg
- Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Frederiksberg, Denmark
| | - Jørgen Steen Agerholm
- Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Frederiksberg, Denmark
| | - Bent Aalbæk
- Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Frederiksberg, Denmark
| | - Henrik Elvang Jensen
- Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Frederiksberg, Denmark
| | - Ole Lerberg Nielsen
- Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Frederiksberg, Denmark
| | - Flemming Fryd Johansen
- Biotech Research and Innovation Centre, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Peter Mikael Helweg Heegaard
- Division of Immunology and Vaccinology, National Veterinary Institute, Technical University of Denmark, Kgs. Lyngby, Denmark
| | - Páll Skúli Leifsson
- Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Frederiksberg, Denmark
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Ee Uli J, Yong CSY, Yeap SK, Alitheen NB, Rovie-Ryan JJ, Mat Isa N, Tan SG. RNA sequencing of kidney and liver transcriptome obtained from wild cynomolgus macaque (Macaca fascicularis) originating from Peninsular Malaysia. BMC Res Notes 2018; 11:923. [PMID: 30577850 PMCID: PMC6303865 DOI: 10.1186/s13104-018-4014-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2018] [Accepted: 12/12/2018] [Indexed: 01/22/2023] Open
Abstract
Objective Using high-throughput RNA sequencing technology, this study aimed to sequence the transcriptome of kidney and liver tissues harvested from Peninsular Malaysia cynomolgus macaque (Macaca fascicularis). M. fascicularis are significant nonhuman primate models in the biomedical field, owing to the macaque’s biological similarities with humans. The additional transcriptomic dataset will supplement the previously described Peninsular Malaysia M. fascicularis transcriptomes obtained in a past endeavour. Results A total of 75,350,240 sequence reads were obtained via Hi-seq 2500 sequencing technology. A total of 5473 significant differentially expressed genes were called. Gene ontology functional categorisation showed that cellular process, catalytic activity, and cell part categories had the highest number of expressed genes, while the metabolic pathways category possessed the highest number of expressed genes in the KEGG pathway analysis. The additional sequence dataset will further enrich existing M. fascicularis transcriptome assemblies, and provide a dataset for further downstream studies. Electronic supplementary material The online version of this article (10.1186/s13104-018-4014-1) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Joey Ee Uli
- Department of Cell and Molecular Biology, Faculty of Biotechnology and Biomolecular Sciences, Universiti Putra Malaysia, Serdang, Selangor, Malaysia
| | - Christina Seok-Yien Yong
- Department of Biology, Faculty of Science, Universiti Putra Malaysia, 43400, Serdang, Selangor, Malaysia.
| | - Swee Keong Yeap
- China-ASEAN College of Marine Sciences, Xiamen University, Sepang, Selangor, Malaysia
| | - Noorjahan Banu Alitheen
- Department of Cell and Molecular Biology, Faculty of Biotechnology and Biomolecular Sciences, Universiti Putra Malaysia, Serdang, Selangor, Malaysia
| | - Jeffrine J Rovie-Ryan
- National Wildlife Forensic Laboratory, Ex-Situ Conservation Division, Department of Wildlife and National Parks, Kuala Lumpur, Malaysia
| | - Nurulfiza Mat Isa
- Department of Cell and Molecular Biology, Faculty of Biotechnology and Biomolecular Sciences, Universiti Putra Malaysia, Serdang, Selangor, Malaysia
| | - Soon Guan Tan
- Department of Cell and Molecular Biology, Faculty of Biotechnology and Biomolecular Sciences, Universiti Putra Malaysia, Serdang, Selangor, Malaysia
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Wang LX, Zhang SX, Wu HJ, Rong XL, Guo J. M2b macrophage polarization and its roles in diseases. J Leukoc Biol 2018; 106:345-358. [PMID: 30576000 PMCID: PMC7379745 DOI: 10.1002/jlb.3ru1018-378rr] [Citation(s) in RCA: 555] [Impact Index Per Article: 79.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2018] [Revised: 12/07/2018] [Accepted: 12/09/2018] [Indexed: 12/14/2022] Open
Abstract
Macrophages play an important role in a wide variety of physiologic and pathologic processes. Plasticity and functional polarization are hallmarks of macrophages. Macrophages commonly exist in two distinct subsets: classically activated macrophages (M1) and alternatively activated macrophages (M2). M2b, a subtype of M2 macrophages, has attracted increasing attention over the past decade due to its strong immune‐regulated and anti‐inflammatory effects. A wide variety of stimuli and multiple factors modulate M2b macrophage polarization in vitro and in vivo. M2b macrophages possess both protective and pathogenic roles in various diseases. Understanding the mechanisms of M2b macrophage activation and the modulation of their polarization might provide a great perspective for the design of novel therapeutic strategies. The purpose of this review is to discuss current knowledge of M2b macrophage polarization, the roles of M2b macrophages in a variety of diseases and the stimuli to modulate M2b macrophage polarization.
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Affiliation(s)
- Le-Xun Wang
- Guangdong Metabolic Disease Research Center of Integrated Chinese and Western Medicine, Joint Laboratory of Guangdong, Hong Kong and Macao on Glycolipid Metabolic Diseases, Guangdong Key Laboratory of Metabolic Disease Prevention and Treatment of Traditional Chinese Medicine, Institute of Chinese Medicine Sciences, Guangdong Pharmaceutical University, Guangzhou, China
| | - Sheng-Xi Zhang
- Guangdong Metabolic Disease Research Center of Integrated Chinese and Western Medicine, Joint Laboratory of Guangdong, Hong Kong and Macao on Glycolipid Metabolic Diseases, Guangdong Key Laboratory of Metabolic Disease Prevention and Treatment of Traditional Chinese Medicine, Institute of Chinese Medicine Sciences, Guangdong Pharmaceutical University, Guangzhou, China
| | - Hui-Juan Wu
- Guangdong Metabolic Disease Research Center of Integrated Chinese and Western Medicine, Joint Laboratory of Guangdong, Hong Kong and Macao on Glycolipid Metabolic Diseases, Guangdong Key Laboratory of Metabolic Disease Prevention and Treatment of Traditional Chinese Medicine, Institute of Chinese Medicine Sciences, Guangdong Pharmaceutical University, Guangzhou, China
| | - Xiang-Lu Rong
- Guangdong Metabolic Disease Research Center of Integrated Chinese and Western Medicine, Joint Laboratory of Guangdong, Hong Kong and Macao on Glycolipid Metabolic Diseases, Guangdong Key Laboratory of Metabolic Disease Prevention and Treatment of Traditional Chinese Medicine, Institute of Chinese Medicine Sciences, Guangdong Pharmaceutical University, Guangzhou, China
| | - Jiao Guo
- Guangdong Metabolic Disease Research Center of Integrated Chinese and Western Medicine, Joint Laboratory of Guangdong, Hong Kong and Macao on Glycolipid Metabolic Diseases, Guangdong Key Laboratory of Metabolic Disease Prevention and Treatment of Traditional Chinese Medicine, Institute of Chinese Medicine Sciences, Guangdong Pharmaceutical University, Guangzhou, China
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Plasma proteome changes in cord blood samples from preterm infants. J Perinatol 2018; 38:1182-1189. [PMID: 29910464 DOI: 10.1038/s41372-018-0150-7] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/22/2017] [Revised: 05/22/2018] [Accepted: 05/23/2018] [Indexed: 01/23/2023]
Abstract
OBJECTIVE In the presented study, we aimed to systematically analyze plasma proteomes in cord blood samples from preterm infants stratified by their gestational age to identify proteins and related malfunctioning pathways at birth, possibly contributing to the complications observed among preterm infants. STUDY DESIGN Preterm newborns were enrolled of three subgroups with different gestation age: newborns born ≤26 (group 1), between 27 and 28 (group 2) and between 29 and 30 (group 3) weeks of gestation, respectively, and compared to the control group of healthy, full-term newborns in respect to their plasma proteome composition. RESULT Preterm delivery is associated with multiple protein abundance changes in plasma related to a plethora of processes, including inflammation and immunomodulation, coagulation, and complement activation as some key features. CONCLUSION Plasma proteome analysis revealed numerous gestation-age-dependent protein abundance differences between term and preterm infants, which highlight key dysregulated pathways and potential new protein treatment targets.
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Prospective plasma proteome changes in preterm infants with different gestational ages. Pediatr Res 2018; 84:104-111. [PMID: 29795197 DOI: 10.1038/s41390-018-0003-2] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/27/2017] [Revised: 02/12/2018] [Accepted: 03/10/2018] [Indexed: 12/27/2022]
Abstract
BACKGROUND In this study, we aimed to analyze time-resolved plasma proteome changes in preterm neonates stratified by their gestational age to detect malfunctioning pathways that derive from the systemic immaturity of the neonate and to highlight those that are differentially regulated during the early development. METHODS Preterm newborns were enrolled in three subgroups with different gestational ages: before 26 weeks of gestation (group 1), between 27 and 28 weeks of gestation (group 2), and between 29 and 30 (group 3) weeks of gestation. Plasma protein abundances were assessed at two time points (at preterm delivery and at the 36th week of post-menstrual age) by quantitative proteomics. RESULT The quantitative analysis of plasma proteome in preterm infants revealed a multitude of time-related differences in protein abundances between the studied groups. We report protein changes in several functional domains, including inflammatory domains, immunomodulatory factors, and coagulation regulators as key features, with important gestational age-dependent hemopexin induction. CONCLUSION The global trend emerging from our data, which can collectively be interpreted as a progression toward recovery from the perinatal perturbations, highlights the profound impact of gestation duration on the ability to bridge the gap in systemic homeostasis after preterm labor.
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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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Candidate Genes as Biomarkers in Lipopolysaccharide-Induced Acute Respiratory Distress Syndrome Based on mRNA Expression Profile by Next-Generation RNA-Seq Analysis. BIOMED RESEARCH INTERNATIONAL 2018; 2018:4384797. [PMID: 29850515 PMCID: PMC5911337 DOI: 10.1155/2018/4384797] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/18/2017] [Revised: 01/09/2018] [Accepted: 01/22/2018] [Indexed: 01/04/2023]
Abstract
Up until now, the regulation mechanism at the level of gene during lipopolysaccharide- (LPS-) induced acute respiratory distress syndrome (ARDS) remains unclear. The discovery of differentially expressed genes (DEGs) between LPS-induced ARDS rats and normal rats by next-generation RNA sequencing analysis is of particular interest for the current study. These DEGs may help clinical diagnosis of ARDS and facilitate the selection of the optimal treatment strategy. Randomly, 20 rats were equally divided into 2 groups, the control group and the LPS group. Three rats from each group were selected at random for RNA sequencing analysis. Sequence reads were obtained from Illumina HiSeq4000 and mapped onto the rat reference genome RN6 using Hisat2. We identified 5244 DEGs (Fold_Change > 1.5, and P < 0.05) in the lung tissues from LPS-treated rats compared with normal rats, including 1413 upregulated and 3831 downregulated expressed genes. Lots of chemokine family members were among the most upregulated genes in LPS group. Gene ontology (GO) analysis revealed that almost all of the most enriched and meaningful biological process terms were mainly involved in the functions like immune-inflammation response and the pathways like cytokine-cytokine receptor interaction. We also found that, as for GO molecular function terms, the enriched terms were mainly related to chemokines and cytokines. DEGs with fold change over 100 were verified by quantitative real-time polymerase chain reaction and reanalyzed by gene-gene coexpression network, and the results elucidated central roles of chemokines in LPS-induced ARDS. Our results revealed some new biomarkers for uncovering mechanisms and processes of ARDS.
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High-density lipoprotein immunomodulates the functional activities of macrophage and cytokines produced during ex vivo macrophage-CD4 + T cell crosstalk at the recent-onset human type 1 diabetes. Cytokine 2017; 96:59-70. [DOI: 10.1016/j.cyto.2017.03.001] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2016] [Revised: 02/08/2017] [Accepted: 03/01/2017] [Indexed: 12/31/2022]
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Xiao X, Liu Y, Guo Z, Liu X, Sun H, Li Q, Sun W. Comparative proteomic analysis of the influence of gender and acid stimulation on normal human saliva using LC/MS/MS. Proteomics Clin Appl 2017; 11. [PMID: 28198151 DOI: 10.1002/prca.201600142] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2016] [Revised: 12/23/2016] [Accepted: 02/10/2017] [Indexed: 12/14/2022]
Abstract
PURPOSE Human saliva is an important source for disease biomarker discovery. This study is to investigate the influence of gender and acid stimulation on the normal human salivary proteome. EXPERIMENTAL DESIGN Unstimulated and acid-stimulated saliva samples from 5 males and 5 females were labeled with 4-plex iTRAQ and analyzed by 2-DLC MS/MS. By bioinformatics analysis the gender and acid stimulation related proteins were defined. According to protein annotation the important proteins were validated by multiple reaction monitor analysis. RESULTS A total of 1770 proteins were identified, and 82 proteins in unstimulated saliva were found to be gender-specific, mainly associated with immune function, metabolism and inflammation. However, no gender-specific proteins were found in acid-stimulated saliva. In addition, 182 and 307 differential proteins were found to be acid stimulation-specific in male samples and female samples, respectively, mainly participated in the process of cellular movement, immune function and inflammatory response. Besides, it was found that acid stimulation caused more significant alteration and played a more important role in the human salivary proteome than gender. Gender-specific (IGHG2 and TIMP1) and acid stimulation (PERL, ENOA, ACTB, B4E022 and CALL3) related proteins were validated by MRM analysis. CONCLUSIONS AND CLINICAL RELEVANCE The results indicate that gender differences exist in the unstimulated salivary proteome, and the influence of acid stimulation on the salivary proteome was more significant than that of gender. The above results may be helpful for salivary proteome research in the future.
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Affiliation(s)
- Xiaoping Xiao
- Core Facility of Instrument, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Beijing, China
| | - Yaoran Liu
- Department of stomatology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China
| | - Zhengguang Guo
- Core Facility of Instrument, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Beijing, China
| | - Xiaoyan Liu
- Core Facility of Instrument, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Beijing, China
| | - Haidan Sun
- Core Facility of Instrument, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Beijing, China
| | - Qian Li
- Department of stomatology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China
| | - Wei Sun
- Core Facility of Instrument, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Beijing, China
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Ito I, Bhopale KK, Nishiguchi T, Lee JO, Herndon DN, Suzuki S, Sowers LC, Suzuki F, Kobayashi M. The Polarization of M2b Monocytes in Cultures of Burn Patient Peripheral CD14 + Cells Treated with a Selected Human CCL1 Antisense Oligodeoxynucleotide. Nucleic Acid Ther 2016; 26:269-276. [PMID: 27548631 DOI: 10.1089/nat.2016.0617] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
M2b macrophages (Mφ) play a major role in the increased susceptibility of subacutely burned patients, to sepsis stemming from enterococcal translocation. Certain opportunistic infections in severely burned mice have been controlled by murine CCL1 antisense oligodeoxynucleotide (ODN), a specific polarizer of mouse M2bMφ. In the present study, we have screened CCL1 antisense ODN, which is active against human M2bMφ. Among the 20 CCL1 antisense ODNs synthesized in our laboratory, HCA-11 was shown to be the most active polarizer for human CCL1+CD163+CD14+ cells. Burn patient CCL1+CD163+CD14+ cells (3 × 105 cells/mL) switched to quiescent CCL1-CD163-CD14+ cells within 48 h in cultures supplemented with 100 μg/mL of HCA-11. After treatment with a 25 μg/chimera dose of HCA-11, the bacterial growth was not observed in various organs of patient chimeras (γNSG mice inoculated with burn patient WBCs) infected with a lethal dose of Methicillin-resistant Staphylococcus aureus. The host antibacterial defenses against certain opportunistic pathogens should be improved in severely burned patients treated with a human CCL1 antisense ODN, HCA-11.
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Affiliation(s)
- Ichiaki Ito
- 1 Department of Internal Medicine, The University of Texas Medical Branch , Galveston, Texas
| | - Kamlesh K Bhopale
- 1 Department of Internal Medicine, The University of Texas Medical Branch , Galveston, Texas
| | - Tomoki Nishiguchi
- 1 Department of Internal Medicine, The University of Texas Medical Branch , Galveston, Texas
| | - Jong O Lee
- 2 Shriners Hospitals for Children , Galveston, Texas
| | | | - Sumihiro Suzuki
- 3 University of North Texas Health Science Center , Fort Worth, Texas
| | - Lawrence C Sowers
- 4 Department of Pharmacology and Toxicology, The University of Texas Medical Branch , Galveston, Texas
| | - Fujio Suzuki
- 1 Department of Internal Medicine, The University of Texas Medical Branch , Galveston, Texas.,2 Shriners Hospitals for Children , Galveston, Texas
| | - Makiko Kobayashi
- 1 Department of Internal Medicine, The University of Texas Medical Branch , Galveston, Texas.,2 Shriners Hospitals for Children , Galveston, Texas
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Whibley N, Tritto E, Traggiai E, Kolbinger F, Moulin P, Brees D, Coleman BM, Mamo AJ, Garg AV, Jaycox JR, Siebenlist U, Kammüller M, Gaffen SL. Antibody blockade of IL-17 family cytokines in immunity to acute murine oral mucosal candidiasis. J Leukoc Biol 2016; 99:1153-64. [PMID: 26729813 PMCID: PMC4952011 DOI: 10.1189/jlb.4a0915-428r] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2015] [Revised: 11/16/2015] [Accepted: 12/14/2015] [Indexed: 12/13/2022] Open
Abstract
Antibodies targeting IL-17A or its receptor, IL-17RA, are approved to treat psoriasis and are being evaluated for other autoimmune conditions. Conversely, IL-17 signaling is critical for immunity to opportunistic mucosal infections caused by the commensal fungus Candida albicans, as mice and humans lacking the IL-17R experience chronic mucosal candidiasis. IL-17A, IL-17F, and IL-17AF bind the IL-17RA-IL-17RC heterodimeric complex and deliver qualitatively similar signals through the adaptor Act1. Here, we used a mouse model of acute oropharyngeal candidiasis to assess the impact of blocking IL-17 family cytokines compared with specific IL-17 cytokine gene knockout mice. Anti-IL-17A antibodies, which neutralize IL-17A and IL-17AF, caused elevated oral fungal loads, whereas anti-IL-17AF and anti-IL-17F antibodies did not. Notably, there was a cooperative effect of blocking IL-17A, IL-17AF, and IL-17F together. Termination of anti-IL-17A treatment was associated with rapid C. albicans clearance. IL-17F-deficient mice were fully resistant to oropharyngeal candidiasis, consistent with antibody blockade. However, IL-17A-deficient mice had lower fungal burdens than anti-IL-17A-treated mice. Act1-deficient mice were much more susceptible to oropharyngeal candidiasis than anti-IL-17A antibody-treated mice, yet anti-IL-17A and anti-IL-17RA treatment caused equivalent susceptibilities. Based on microarray analyses of the oral mucosa during infection, only a limited number of genes were associated with oropharyngeal candidiasis susceptibility. In sum, we conclude that IL-17A is the main cytokine mediator of immunity in murine oropharyngeal candidiasis, but a cooperative relationship among IL-17A, IL-17AF, and IL-17F exists in vivo. Susceptibility displays the following hierarchy: IL-17RA- or Act1-deficiency > anti-IL-17A + anti-IL-17F antibodies > anti-IL-17A or anti-IL-17RA antibodies > IL-17A deficiency.
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Affiliation(s)
- Natasha Whibley
- Department of Medicine, Division of Rheumatology & Clinical Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Elaine Tritto
- Novartis Institutes for Biomedical Research, Basel, Switzerland; and
| | | | - Frank Kolbinger
- Novartis Institutes for Biomedical Research, Basel, Switzerland; and
| | - Pierre Moulin
- Novartis Institutes for Biomedical Research, Basel, Switzerland; and
| | - Dominique Brees
- Novartis Institutes for Biomedical Research, Basel, Switzerland; and
| | - Bianca M Coleman
- Department of Medicine, Division of Rheumatology & Clinical Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Anna J Mamo
- Department of Medicine, Division of Rheumatology & Clinical Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Abhishek V Garg
- Department of Medicine, Division of Rheumatology & Clinical Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Jillian R Jaycox
- Department of Medicine, Division of Rheumatology & Clinical Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Ulrich Siebenlist
- National Institute of Allergy and Infectious Disease, Laboratory of Molecular Immunology, National Institutes of Health, Bethesda, Maryland, USA
| | - Michael Kammüller
- Novartis Institutes for Biomedical Research, Basel, Switzerland; and
| | - Sarah L Gaffen
- Department of Medicine, Division of Rheumatology & Clinical Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA;
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30
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di Masi A, Trezza V, Leboffe L, Ascenzi P. Human plasma lipocalins and serum albumin: Plasma alternative carriers? J Control Release 2016; 228:191-205. [PMID: 26951925 DOI: 10.1016/j.jconrel.2016.02.049] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2015] [Revised: 02/23/2016] [Accepted: 02/24/2016] [Indexed: 01/14/2023]
Abstract
Lipocalins are an evolutionarily conserved family of proteins that bind and transport a variety of exogenous and endogenous ligands. Lipocalins share a conserved eight anti-parallel β-sheet structure. Among the different lipocalins identified in humans, α-1-acid glycoprotein (AGP), apolipoprotein D (apoD), apolipoprotein M (apoM), α1-microglobulin (α1-m) and retinol-binding protein (RBP) are plasma proteins. In particular, AGP is the most important transporter for basic and neutral drugs, apoD, apoM, and RBP mainly bind endogenous molecules such as progesterone, pregnenolone, bilirubin, sphingosine-1-phosphate, and retinol, while α1-m binds the heme. Human serum albumin (HSA) is a monomeric all-α protein that binds endogenous and exogenous molecules like fatty acids, heme, and acidic drugs. Changes in the plasmatic levels of lipocalins and HSA are responsible for the onset of pathological conditions associated with an altered drug transport and delivery. This, however, does not necessary result in potential adverse effects in patients because many drugs can bind both HSA and lipocalins, and therefore mutual compensatory binding mechanisms can be hypothesized. Here, molecular and clinical aspects of ligand transport by plasma lipocalins and HSA are reviewed, with special attention to their role as alterative carriers in health and disease.
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Affiliation(s)
- Alessandra di Masi
- Dipartimento di Scienze, Università Roma Tre, Viale Marconi 446, I-00146 Roma, Italy; Istituto Nazionale di Biostrutture e Biosistemi, Via delle Medaglie d'Oro 305, I-00136 Roma, Italy.
| | - Viviana Trezza
- Dipartimento di Scienze, Università Roma Tre, Viale Marconi 446, I-00146 Roma, Italy
| | - Loris Leboffe
- Dipartimento di Scienze, Università Roma Tre, Viale Marconi 446, I-00146 Roma, Italy; Istituto Nazionale di Biostrutture e Biosistemi, Via delle Medaglie d'Oro 305, I-00136 Roma, Italy
| | - Paolo Ascenzi
- Istituto Nazionale di Biostrutture e Biosistemi, Via delle Medaglie d'Oro 305, I-00136 Roma, Italy; Laboratorio Interdipartimentale di Microscopia Elettronica, Università Roma Tre, Via della Vasca Navale 79, I-00146 Roma, Italy
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31
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Graham A. Mitochondrial regulation of macrophage cholesterol homeostasis. Free Radic Biol Med 2015; 89:982-92. [PMID: 26416507 DOI: 10.1016/j.freeradbiomed.2015.08.010] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/08/2015] [Revised: 07/28/2015] [Accepted: 08/11/2015] [Indexed: 12/19/2022]
Abstract
This review explores the relationship between mitochondrial structure and function in the regulation of macrophage cholesterol metabolism and proposes that mitochondrial dysfunction contributes to loss of the elegant homeostatic mechanisms which normally maintain cellular sterol levels within defined limits. Mitochondrial sterol 27-hydroxylase (CYP27A1) can generate oxysterol activators of liver X receptors which heterodimerise with retinoid X receptors, enhancing the transcription of ATP binding cassette transporters (ABCA1, ABCG1, and ABCG4), that can remove excess cholesterol via efflux to apolipoproteins A-1, E, and high density lipoprotein, and inhibit inflammation. The activity of CYP27A1 is regulated by the rate of supply of cholesterol substrate to the inner mitochondrial membrane, mediated by a complex of proteins. The precise identity of this dynamic complex remains controversial, even in steroidogenic tissues, but may include steroidogenic acute regulatory protein and the 18 kDa translocator protein, together with voltage-dependent anion channels, ATPase AAA domain containing protein 3A, and optic atrophy type 1 proteins. Certainly, overexpression of StAR and TSPO proteins can enhance macrophage cholesterol efflux to apoA-I and/or HDL, while perturbations in mitochondrial function, or changes in the expression of mitochondrial fusion proteins, alter the efficiency of cholesterol efflux. Molecules which can sustain or improve mitochondrial function or increase the activity of the protein complex involved in cholesterol transfer may have utility in resolving the problem of dysregulated macrophage cholesterol homeostasis, a condition which may contribute to inflammation, atherosclerosis, nonalcoholic steatohepatitis, osteoblastic bone resorption, and some disorders of the central nervous system.
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Affiliation(s)
- Annette Graham
- Department of Life Sciences, School of Health and Life Sciences, and Institute for Applied Health Research, Glasgow Caledonian University, 70 Cowcaddens Road, Glasgow G4 0BA, United Kingdom.
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