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Zhao M, Zheng Z, Li C, Wan J, Wang M. Developmental endothelial locus-1 in cardiovascular and metabolic diseases: A promising biomarker and therapeutic target. Front Immunol 2022; 13:1053175. [PMID: 36518760 PMCID: PMC9742254 DOI: 10.3389/fimmu.2022.1053175] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2022] [Accepted: 11/11/2022] [Indexed: 11/29/2022] Open
Abstract
Cardiovascular and metabolic diseases (CVMDs) are a leading cause of death worldwide and impose a major socioeconomic burden on individuals and healthcare systems, underscoring the urgent need to develop new drug therapies. Developmental endothelial locus-1 (DEL-1) is a secreted multifunctional domain protein that can bind to integrins and play an important role in the occurrence and development of various diseases. Recently, DEL-1 has attracted increased interest for its pharmacological role in the treatment and/or management of CVMDs. In this review, we present the current knowledge on the predictive and therapeutic role of DEL-1 in a variety of CVMDs, such as atherosclerosis, hypertension, cardiac remodeling, ischemic heart disease, obesity, and insulin resistance. Collectively, DEL-1 is a promising biomarker and therapeutic target for CVMDs.
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Affiliation(s)
- Mengmeng Zhao
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China,Cardiovascular Research Institute, Wuhan University, Wuhan, China,Hubei Key Laboratory of Cardiology, Wuhan, China
| | - Zihui Zheng
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China,Cardiovascular Research Institute, Wuhan University, Wuhan, China,Hubei Key Laboratory of Cardiology, Wuhan, China
| | - Chenfei Li
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China,Cardiovascular Research Institute, Wuhan University, Wuhan, China
| | - Jun Wan
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China,Cardiovascular Research Institute, Wuhan University, Wuhan, China,Hubei Key Laboratory of Cardiology, Wuhan, China,*Correspondence: Menglong Wang, ; Jun Wan,
| | - Menglong Wang
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China,Cardiovascular Research Institute, Wuhan University, Wuhan, China,Hubei Key Laboratory of Cardiology, Wuhan, China,*Correspondence: Menglong Wang, ; Jun Wan,
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Camacho-Muñoz D, Niven J, Kucuk S, Cucchi D, Certo M, Jones SW, Fischer DP, Mauro C, Nicolaou A. Omega-3 polyunsaturated fatty acids reverse the impact of western diets on regulatory T cell responses through averting ceramide-mediated pathways. Biochem Pharmacol 2022; 204:115211. [PMID: 35985403 DOI: 10.1016/j.bcp.2022.115211] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2022] [Revised: 08/10/2022] [Accepted: 08/10/2022] [Indexed: 11/02/2022]
Abstract
Western diet (WD), high in sugar and fat, promotes obesity and associated chronic low-grade pro-inflammatory environment, leading to impaired immune function, reprogramming of innate and adaptive immune cells, and development of chronic degenerative diseases, including cardiovascular disease. Increased concentrations of circulating and tissue ceramides contribute to inflammation and cellular dysfunction common in immune metabolic and cardiometabolic disease. Therefore, ceramide-lowering interventions have been considered as strategies to improve adipose tissue health. Here, we report the ability of omega-3 polyunsaturated fatty acids (n-3PUFA) to attenuate inflammatory phenotypes promoted by WD, through ceramide-dependent pathways. Using an animal model, we show that enrichment of WD diet with n-3PUFA, reduced the expression of ceramide synthase 2 (CerS2), and lowered the concentration of long-chain ceramides (C23-C26) in plasma and adipose tissues. N-3PUFA also increased prevalence of the anti-inflammatory CD4+Foxp3+ and CD4+Foxp3+CD25+ Treg subtypes in lymphoid organs. The CerS inhibitor FTY720 mirrored the effect of n-3PUFA. Treatment of animal and human T cells with ceramide C24 in vitro, reduced CD4+Foxp3+ Treg polarisation and IL-10 production, and increased IL-17, while it decreased Erk and Akt phosphorylation downstream of T cell antigen receptors (TCR). These findings suggest that molecular mechanisms mediating the adverse effect of ceramides on regulatory T lymphocytes, progress through reduced TCR signalling. Our findings suggest that nutritional enrichment of WD with fish oil n-3PUFA can partially mitigate its detrimental effects, potentially improving the low-grade inflammation associated with immune metabolic disease. Compared to pharmacological interventions, n-3PUFA offer a simpler approach that can be accommodated as lifestyle choice.
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Affiliation(s)
- Dolores Camacho-Muñoz
- Laboratory for Lipidomics and Lipid Biology, Division of Pharmacy and Optometry, School of Health Sciences, Faculty of Biology Medicine and Health, The University of Manchester, Manchester Academic Health Science Centre, Manchester M13 9PT, UK
| | - Jennifer Niven
- Institute of Inflammation and Ageing, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2WB, UK
| | - Salih Kucuk
- Institute of Inflammation and Ageing, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2WB, UK
| | - Danilo Cucchi
- William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK
| | - Michelangelo Certo
- Institute of Inflammation and Ageing, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2WB, UK
| | - Simon W Jones
- Institute of Inflammation and Ageing, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2WB, UK
| | - Deborah P Fischer
- Laboratory for Lipidomics and Lipid Biology, Division of Pharmacy and Optometry, School of Health Sciences, Faculty of Biology Medicine and Health, The University of Manchester, Manchester Academic Health Science Centre, Manchester M13 9PT, UK
| | - Claudio Mauro
- Institute of Inflammation and Ageing, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2WB, UK; William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK.
| | - Anna Nicolaou
- Laboratory for Lipidomics and Lipid Biology, Division of Pharmacy and Optometry, School of Health Sciences, Faculty of Biology Medicine and Health, The University of Manchester, Manchester Academic Health Science Centre, Manchester M13 9PT, UK; Lydia Becker Institute of Immunology and Inflammation, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester Academic Health Science Centre, Manchester M13 9NT, UK.
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Bohm MS, Sipe LM, Pye ME, Davis MJ, Pierre JF, Makowski L. The role of obesity and bariatric surgery-induced weight loss in breast cancer. Cancer Metastasis Rev 2022; 41:673-695. [PMID: 35870055 PMCID: PMC9470652 DOI: 10.1007/s10555-022-10050-6] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/24/2022] [Accepted: 07/06/2022] [Indexed: 02/07/2023]
Abstract
Obesity is a complex metabolic condition considered a worldwide public health crisis, and a deeper mechanistic understanding of obesity-associated diseases is urgently needed. Obesity comorbidities include many associated cancers and are estimated to account for 20% of female cancer deaths in the USA. Breast cancer, in particular, is associated with obesity and is the focus of this review. The exact causal links between obesity and breast cancer remain unclear. Still, interactions have emerged between body mass index, tumor molecular subtype, genetic background, and environmental factors that strongly suggest obesity influences the risk and progression of certain breast cancers. Supportive preclinical research uses various diet-induced obesity models to demonstrate that weight loss, via dietary interventions or changes in energy expenditure, reduces the onset or progression of breast cancers. Ongoing and future studies are now aimed at elucidating the underpinning mechanisms behind weight-loss-driven observations to improve therapy and outcomes in patients with breast cancer and reduce risk. This review aims to summarize the rapidly emerging literature on obesity and weight loss strategies with a focused discussion of bariatric surgery in both clinical and preclinical studies detailing the complex interactions between metabolism, immune response, and immunotherapy in the setting of obesity and breast cancer.
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Affiliation(s)
- Margaret S Bohm
- Department of Microbiology, Immunology, and Biochemistry, College of Medicine, The University of Tennessee Health Science Center, Memphis, TN, 38163, USA
| | - Laura M Sipe
- Division of Hematology and Oncology, Department of Medicine, College of Medicine, The University of Tennessee Health Science Center, Memphis, TN, 38163, USA
| | - Madeline E Pye
- Division of Hematology and Oncology, Department of Medicine, College of Medicine, The University of Tennessee Health Science Center, Memphis, TN, 38163, USA
| | - Matthew J Davis
- Division of Bariatric Surgery, Department of Surgery, College of Medicine, The University of Tennessee Health Science Center, Memphis, TN, 38163, USA
| | - Joseph F Pierre
- Department of Microbiology, Immunology, and Biochemistry, College of Medicine, The University of Tennessee Health Science Center, Memphis, TN, 38163, USA
- Department of Nutritional Sciences, College of Agriculture and Life Science, The University of Wisconsin-Madison, Madison, WI, 53706, USA
| | - Liza Makowski
- Department of Microbiology, Immunology, and Biochemistry, College of Medicine, The University of Tennessee Health Science Center, Memphis, TN, 38163, USA.
- Division of Hematology and Oncology, Department of Medicine, College of Medicine, The University of Tennessee Health Science Center, Memphis, TN, 38163, USA.
- Department of Pharmaceutical Sciences, College of Pharmacy, The University of Tennessee Health Science Center, Memphis, TN, 38163, USA.
- College of Medicine, UTHSC Center for Cancer Research, The University of Tennessee Health Science Center, Cancer Research Building Room 322, 19 S Manassas Street, Memphis, TN, 38163, USA.
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Hippen KL, Hefazi M, Larson JH, Blazar BR. Emerging translational strategies and challenges for enhancing regulatory T cell therapy for graft-versus-host disease. Front Immunol 2022; 13:926550. [PMID: 35967386 PMCID: PMC9366169 DOI: 10.3389/fimmu.2022.926550] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2022] [Accepted: 06/27/2022] [Indexed: 02/03/2023] Open
Abstract
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a curative therapy for many types of cancer. Genetic disparities between donor and host can result in immune-mediated attack of host tissues, known as graft versus host disease (GVHD), a major cause of morbidity and mortality following HSCT. Regulatory CD4+ T cells (Tregs) are a rare cell type crucial for immune system homeostasis, limiting the activation and differentiation of effector T cells (Teff) that are self-reactive or stimulated by foreign antigen exposure. Adoptive cell therapy (ACT) with Treg has demonstrated, first in murine models and now in patients, that prophylactic Treg infusion can also suppress GVHD. While clinical trials have demonstrated Treg reduce severe GVHD occurrence, several impediments remain, including Treg variability and practical need for individualized Treg production for each patient. Additionally, there are challenges in the use of in vitro expansion techniques and in achieving in vivo Treg persistence in context of both immune suppressive drugs and in lymphoreplete patients being treated for GVHD. This review will focus on 3 main translational approaches taken to improve the efficacy of tTreg ACT in GVHD prophylaxis and development of treatment options, following HSCT: genetic modification, manipulating TCR and cytokine signaling, and Treg production protocols. In vitro expansion for Treg ACT presents a multitude of approaches for gene modification to improve efficacy, including: antigen specificity, tissue targeting, deletion of negative regulators/exhaustion markers, resistance to immunosuppressive drugs common in GVHD treatment. Such expansion is particularly important in patients without significant lymphopenia that can drive Treg expansion, enabling a favorable Treg:Teff ratio in vivo. Several potential therapeutics have also been identified that enhance tTreg stability or persistence/expansion following ACT that target specific pathways, including: DNA/histone methylation status, TCR/co-stimulation signaling, and IL-2/STAT5 signaling. Finally, this review will discuss improvements in Treg production related to tissue source, Treg subsets, therapeutic approaches to increase Treg suppression and stability during tTreg expansion, and potential for storing large numbers of Treg from a single production run to be used as an off-the-shelf infusion product capable of treating multiple recipients.
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Affiliation(s)
- Keli L. Hippen
- University of Minnesota Cancer Center and the Department of Pediatrics, Division of Blood & Marrow Transplant & Cellular Therapy, Minneapolis, MN, United States
| | - Mehrdad Hefazi
- Division of Hematology, Mayo Clinic, Rochester, MN, United States
| | - Jemma H. Larson
- University of Minnesota Cancer Center and the Department of Pediatrics, Division of Blood & Marrow Transplant & Cellular Therapy, Minneapolis, MN, United States
| | - Bruce R. Blazar
- University of Minnesota Cancer Center and the Department of Pediatrics, Division of Blood & Marrow Transplant & Cellular Therapy, Minneapolis, MN, United States
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Rahman MM, Liu FF, Eckel SP, Sankaranarayanan I, Shafiei-Jahani P, Howard E, Baronikian L, Sattler F, Lurmann FW, Allayee H, Akbari O, McConnell R. Near-roadway air pollution, immune cells and adipokines among obese young adults. Environ Health 2022; 21:36. [PMID: 35305663 PMCID: PMC8933931 DOI: 10.1186/s12940-022-00842-2] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2021] [Accepted: 02/22/2022] [Indexed: 06/14/2023]
Abstract
BACKGROUND Air pollution has been associated with metabolic disease and obesity. Adipokines are potential mediators of these effects, but studies of air pollution-adipokine relationships are inconclusive. Macrophage and T cells in adipose tissue (AT) and blood modulate inflammation; however, the role of immune cells in air pollution-induced dysregulation of adipokines has not been studied. We examined the association between air pollution exposure and circulating and AT adipokine concentrations, and whether these relationships were modified by macrophage and T cell numbers in the blood and AT. METHODS Fasting blood and abdominal subcutaneous AT biopsies were collected from 30 overweight/obese 18-26 year-old volunteers. Flow cytometry was used to quantify T effector (Teff, inflammatory) and regulatory (Treg, anti-inflammatory) lymphocytes and M1 [inflammatory] and M2 [anti-inflammatory]) macrophage cell number. Serum and AT leptin and adiponectin were measured using enzyme-linked immunosorbent assay (ELISA). Exposure to near-roadway air pollution (NRAP) from freeway and non-freeway vehicular sources and to regional particulate matter, nitrogen dioxide and ozone were estimated for the year prior to biopsy, based on participants' residential addresses. Linear regression models were used to examine the association between air pollution exposures and adipokines and to evaluate effect modification by immune cell counts. RESULTS An interquartile increase in non-freeway NRAP exposure during 1 year prior to biopsy was associated with higher leptin levels in both serum [31.7% (95% CI: 10.4, 52.9%)] and AT [19.4% (2.2, 36.6%)]. Non-freeway NRAP exposure effect estimates were greater among participants with greater than median Teff/Treg ratio and M1/M2 ratio in blood, and with greater M1 counts in AT. No adipokine associations with regional air pollutants were found. DISCUSSION Our results suggest that NRAP may increase serum leptin levels in obese young adults, and this association may be promoted in a pro-inflammatory immune cell environment in blood and AT.
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Affiliation(s)
- Md Mostafijur Rahman
- Department of Preventive Medicine, Keck School of Medicine, University of Southern California, 2001 N. Soto Street Building: SSB, Los Angeles, CA, 90032, USA
| | - Fei Fei Liu
- Department of Preventive Medicine, Keck School of Medicine, University of Southern California, 2001 N. Soto Street Building: SSB, Los Angeles, CA, 90032, USA
| | - Sandrah P Eckel
- Department of Preventive Medicine, Keck School of Medicine, University of Southern California, 2001 N. Soto Street Building: SSB, Los Angeles, CA, 90032, USA
| | - Ishwarya Sankaranarayanan
- Department of Molecular and Cellular Immunology, University of Southern California, Los Angeles, California, USA
| | - Pedram Shafiei-Jahani
- Department of Molecular and Cellular Immunology, University of Southern California, Los Angeles, California, USA
| | - Emily Howard
- Department of Molecular and Cellular Immunology, University of Southern California, Los Angeles, California, USA
| | - Lilit Baronikian
- Department of Medicine, Keck School of Medicine, University of Southern California, Keck School of Medicine, Los Angeles, CA, USA
| | - Fred Sattler
- Department of Medicine, Keck School of Medicine, University of Southern California, Keck School of Medicine, Los Angeles, CA, USA
| | | | - Hooman Allayee
- Department of Preventive Medicine, Keck School of Medicine, University of Southern California, 2001 N. Soto Street Building: SSB, Los Angeles, CA, 90032, USA
| | - Omid Akbari
- Department of Molecular and Cellular Immunology, University of Southern California, Los Angeles, California, USA
| | - Rob McConnell
- Department of Preventive Medicine, Keck School of Medicine, University of Southern California, 2001 N. Soto Street Building: SSB, Los Angeles, CA, 90032, USA.
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Laparoscopic sleeve gastrectomy for morbid obesity improves gut microbiota balance, increases colonic mucosal-associated invariant T cells and decreases circulating regulatory T cells. Surg Endosc 2022; 36:7312-7324. [PMID: 35182212 DOI: 10.1007/s00464-022-09122-z] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2021] [Accepted: 02/07/2022] [Indexed: 01/06/2023]
Abstract
BACKGROUND Laparoscopic sleeve gastrectomy (LSG) for morbid obesity may improve gut microbiota balance and decrease chronic inflammation. This study examines the changes in gut microbiota and immune environment, including mucosal-associated invariant T cells (MAIT cells) and regulatory T cells (Treg cells) caused by LSG. METHODS Ten morbidly obese patients underwent LSG at our institution between December 2018 and March 2020. Flow cytometry for Th1/Th2/Th17 cells, Treg cells and MAIT cells in peripheral blood and colonic mucosa and 16S rRNA analysis of gut microbiota were performed preoperatively and then 12 months postoperatively. RESULTS Twelve months after LSG, the median percent total weight loss was 30.3% and the median percent excess weight loss was 66.9%. According to laboratory data, adiponectin increased, leptin decreased, and chronic inflammation improved after LSG. In the gut microbiota, Bacteroidetes and Fusobacteria increased after LSG, and indices of alpha diversity increased after LSG. In colonic mucosa, the frequency of MAIT cells increased after LSG. In peripheral blood, the frequency of Th1 cells and effector Treg cells decreased after LSG. CONCLUSIONS After LSG for morbid obesity, improvement in chronic inflammation in obesity is suggested by change in the constituent bacterial species, increase in the diversity of gut microbiota, increase in MAIT cells in the colonic mucosa, and decrease in effector Treg cells in the peripheral blood.
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7
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Nicholls J, Cao B, Le Texier L, Xiong LY, Hunter CR, Llanes G, Aguliar EG, Schroder WA, Phipps S, Lynch JP, Cao H, Heazlewood SY, Williams B, Clouston AD, Nefzger CM, Polo JM, Nilsson SK, Blazar BR, MacDonald KPA. Bone Marrow Regulatory T Cells Are a Unique Population, Supported by Niche-Specific Cytokines and Plasmacytoid Dendritic Cells, and Required for Chronic Graft-Versus-Host Disease Control. Front Cell Dev Biol 2021; 9:737880. [PMID: 34631716 PMCID: PMC8493124 DOI: 10.3389/fcell.2021.737880] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2021] [Accepted: 08/16/2021] [Indexed: 11/23/2022] Open
Abstract
Regulatory T cell (Treg) reconstitution is essential for reestablishing tolerance and maintaining homeostasis following stem-cell transplantation. We previously reported that bone marrow (BM) is highly enriched in autophagy-dependent Treg and autophagy disruption leads to a significant Treg loss, particularly BM-Treg. To correct the known Treg deficiency observed in chronic graft-versus-host disease (cGVHD) patients, low dose IL-2 infusion has been administered, substantially increasing peripheral Treg (pTreg) numbers. However, as clinical responses were only seen in ∼50% of patients, we postulated that pTreg augmentation was more robust than for BM-Treg. We show that BM-Treg and pTreg have distinct characteristics, indicated by differential transcriptome expression for chemokine receptors, transcription factors, cell cycle control of replication and genes linked to Treg function. Further, BM-Treg were more quiescent, expressed lower FoxP3, were highly enriched for co-inhibitory markers and more profoundly depleted than splenic Treg in cGVHD mice. In vivo our data are consistent with the BM and not splenic microenvironment is, at least in part, driving this BM-Treg signature, as adoptively transferred splenic Treg that entered the BM niche acquired a BM-Treg phenotype. Analyses identified upregulated expression of IL-9R, IL-33R, and IL-7R in BM-Treg. Administration of the T cell produced cytokine IL-2 was required by splenic Treg expansion but had no impact on BM-Treg, whereas the converse was true for IL-9 administration. Plasmacytoid dendritic cells (pDCs) within the BM also may contribute to BM-Treg maintenance. Using pDC-specific BDCA2-DTR mice in which diptheria toxin administration results in global pDC depletion, we demonstrate that pDC depletion hampers BM, but not splenic, Treg homeostasis. Together, these data provide evidence that BM-Treg and splenic Treg are phenotypically and functionally distinct and influenced by niche-specific mediators that selectively support their respective Treg populations. The unique properties of BM-Treg should be considered for new therapies to reconstitute Treg and reestablish tolerance following SCT.
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Affiliation(s)
- Jemma Nicholls
- Division of Blood and Marrow Transplant and Cellular Therapies, Department of Pediatrics, Masonic Cancer Center, University of Minnesota, Minneapolis, MN, United States
| | - Benjamin Cao
- Biomedical Manufacturing Commonwealth Scientific and Industrial Research Organization, Melbourne, VIC, Australia
- Australian Regenerative Medicine Institute, Monash University, Melbourne, VIC, Australia
| | - Laetitia Le Texier
- Immunology Department, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
| | - Laura Yan Xiong
- Immunology Department, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
| | - Christopher R. Hunter
- Immunology Department, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
| | - Genesis Llanes
- Immunology Department, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
| | - Ethan G. Aguliar
- Division of Blood and Marrow Transplant and Cellular Therapies, Department of Pediatrics, Masonic Cancer Center, University of Minnesota, Minneapolis, MN, United States
| | - Wayne A. Schroder
- Immunology Department, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
| | - Simon Phipps
- Immunology Department, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
| | - Jason P. Lynch
- Immunology Department, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
| | - Huimin Cao
- Biomedical Manufacturing Commonwealth Scientific and Industrial Research Organization, Melbourne, VIC, Australia
- Australian Regenerative Medicine Institute, Monash University, Melbourne, VIC, Australia
| | - Shen Y. Heazlewood
- Biomedical Manufacturing Commonwealth Scientific and Industrial Research Organization, Melbourne, VIC, Australia
- Australian Regenerative Medicine Institute, Monash University, Melbourne, VIC, Australia
| | - Brenda Williams
- Biomedical Manufacturing Commonwealth Scientific and Industrial Research Organization, Melbourne, VIC, Australia
- Australian Regenerative Medicine Institute, Monash University, Melbourne, VIC, Australia
| | | | - Christian M. Nefzger
- Australian Regenerative Medicine Institute, Monash University, Melbourne, VIC, Australia
- Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD, Australia
- Monash Biomedicine Discovery Institute, Monash University, Melbourne, VIC, Australia
| | - Jose M. Polo
- Australian Regenerative Medicine Institute, Monash University, Melbourne, VIC, Australia
- Monash Biomedicine Discovery Institute, Monash University, Melbourne, VIC, Australia
- Department of Anatomy and Developmental Biology, Monash University, Melbourne, VIC, Australia
| | - Susan K. Nilsson
- Biomedical Manufacturing Commonwealth Scientific and Industrial Research Organization, Melbourne, VIC, Australia
- Australian Regenerative Medicine Institute, Monash University, Melbourne, VIC, Australia
| | - Bruce R. Blazar
- Division of Blood and Marrow Transplant and Cellular Therapies, Department of Pediatrics, Masonic Cancer Center, University of Minnesota, Minneapolis, MN, United States
| | - Kelli P. A. MacDonald
- Immunology Department, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
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Wei YX, Zheng KY, Wang YG. Gut microbiota-derived metabolites as key mucosal barrier modulators in obesity. World J Gastroenterol 2021; 27:5555-5565. [PMID: 34588751 PMCID: PMC8433617 DOI: 10.3748/wjg.v27.i33.5555] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Revised: 04/24/2021] [Accepted: 07/23/2021] [Indexed: 02/06/2023] Open
Abstract
A significant breakthrough in the field of obesity research was the demonstration that an obese phenotype could be manipulated by modulating the gut microbiota. An important next step is to elucidate a human-relevant “map’’ of microbiota-host interactions that regulate the metabolic health of the host. An improved understanding of this crosstalk is a prerequisite for optimizing therapeutic strategies to combat obesity. Intestinal mucosal barrier dysfunction is an important contributor to metabolic diseases and has also been found to be involved in a variety of other chronic inflammatory conditions, including cancer, neurodegeneration, and aging. The mechanistic basis for intestinal barrier dysfunction accompanying metabolic disorders remains poorly understood. Understanding the molecular and cellular modulators of intestinal barrier function will help devise improved strategies to counteract the detrimental systemic consequences of gut barrier breakage. Changes in the composition and function of the gut microbiota, i.e., dysbiosis, are thought to drive obesity-related pathogenesis and may be one of the most important drivers of mucosal barrier dysfunction. Many effects of the microbiota on the host are mediated by microbiota-derived metabolites. In this review, we focus on several relatively well-studied microbial metabolites that can influence intestinal mucosal homeostasis and discuss how they might affect metabolic diseases. The design and use of microbes and their metabolites that are locally active in the gut without systemic side effects are promising novel and safe therapeutic modalities for metabolic diseases.
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Affiliation(s)
- Yan-Xia Wei
- Laboratory of Infection and Immunity, Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou 221004, Jiangsu Province, China
| | - Kui-Yang Zheng
- Laboratory of Infection and Immunity, Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou 221004, Jiangsu Province, China
| | - Yu-Gang Wang
- Laboratory of Infection and Immunity, Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou 221004, Jiangsu Province, China
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9
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Rizk NM, Fadel A, AlShammari W, Younes N, Bashah M. The Immunophenotyping Changes of Peripheral CD4+ T Lymphocytes and Inflammatory Markers of Class III Obesity Subjects After Laparoscopic Gastric Sleeve Surgery - A Follow-Up Study. J Inflamm Res 2021; 14:1743-1757. [PMID: 33981153 PMCID: PMC8108539 DOI: 10.2147/jir.s282189] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2020] [Accepted: 03/18/2021] [Indexed: 12/12/2022] Open
Abstract
Purpose Obesity is a chronic disorder characterized by a low-grade inflammatory state and immune cell irregularities. The study aimed to follow up on the changes in the peripheral CD4+ T lymphocytes and the pro-inflammatory cytokines; IL-6, TNF-alpha, MCP-1, and IL-10 at baseline and 12 weeks post-surgical intervention by the laparoscopic gastric sleeve (LGS) in morbidly obese patients (class III obesity subjects). Materials and Methods A prospective longitudinal research included 24 class III obesity subjects with a BMI > 40 kg/m2. The subjects were enrolled from the Metabolic/Surgical Department at Hamad Medical Corporation (HMC)-Qatar. Fasting blood samples were collected at admission to LGS for weight loss and after 12 weeks of LGS. The immunophenotype of CD4+ T-cell populations; naïve (CD45RA+and CD27+), central memory T cells (CD45RO+ and CD27+), and effector memory (CD45RO+and CD27-) and T-regulatory cell (CD4+CD25+ FoxP3+) were identified using flow cytometry. Plasma pro-inflammatory cytokines and adipokines were evaluated. A control group of lean subjects was used to compare changes of T-regulatory and inflammatory biomarkers with postoperative changes in obese patients. Results The means (SD) of age and BMI of class III obesity subjects was 32.32 (8.36) years and 49.02 (6.28) kg/m2, respectively. LGS caused a significant reduction in BMI by 32%, p<0.0001. LGS intervention significantly decreased CD4+ T-lymphocytes and effector memory (TEM) cells but increased T-regulatory (Treg), naïve, and central memory (TCM) cells, with all p values < 0.05. The increase of Treg cells postoperative is significantly lower compared to lean subjects, p < 0.05. A significant reduction of plasma IL-6, TNF-α, and MCP-1, but IL-10 significantly increased after LGS, with all p<0.05. Adiponectin/leptin ratio improved after LGS by 2.9 folds, p<0.0001. Conclusion Weight loss by LGS accomplished a substantial rise of Treg and decreased EM T-lymphocytes with a shift from pro-inflammatory to the anti-inflammatory pattern.
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Affiliation(s)
- Nasser M Rizk
- Biomedical Sciences Department-College of Health Sciences, QU Health-Qatar University.,Biomedical Research Center, Qatar University.,Biomedical and Pharmaceutical Research Unit, QU Health-Qatar University
| | - Amina Fadel
- Biomedical Sciences Department-College of Health Sciences, QU Health-Qatar University
| | - Wasaif AlShammari
- Biomedical Sciences Department-College of Health Sciences, QU Health-Qatar University
| | - Noura Younes
- Clinical Chemistry Lab, Hamad Medical Corporation, Doha, Qatar
| | - Moataz Bashah
- Metabolic Unit, Surgery Department, Hammed Medical Corporation (HMC), Doha, Qatar
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10
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Wang L, Sun P, Wu Y, Wang L. Metabolic tissue-resident CD8 + T cells: A key player in obesity-related diseases. Obes Rev 2021; 22:e13133. [PMID: 32935464 DOI: 10.1111/obr.13133] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/25/2020] [Revised: 07/15/2020] [Accepted: 08/06/2020] [Indexed: 02/06/2023]
Abstract
Obesity-induced low-grade chronic inflammation in the metabolic tissues, such as adipose tissue (AT) and liver tissue, in individuals with obesity is a major etiological factor for several diseases, such as insulin resistance, type 2 diabetes, fatty liver disease, atherosclerosis and cardiovascular problems, as well as cancer and autoimmune diseases. Previous studies have revealed that tissue-resident macrophages play a crucial role in this process. However, the mechanisms responsible for recruiting and activating macrophages and initiating chronic inflammation in the metabolic tissues have not yet been clearly elucidated. In the most recent decade, there has been a growing emphasis on the critical role of the adaptive CD8+ T cells in obesity-induced chronic inflammation and related metabolic diseases. In this review, we will summarize the relevant studies in both mice and human regarding the role of metabolic tissue-resident CD8+ T cells in obesity-related inflammation and diseases, as well as the possible mechanisms underlying the regulation of CD8+ T cell recruitment, activation and function in the metabolic tissues, and discuss their potential as therapeutic targets for obesity-related diseases.
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Affiliation(s)
- Lina Wang
- Institute of Immunology PLA, Army Medical University (Third Military Medical University), Chongqing, China.,Department of Immunology, Weifang Medical University, Weifang, China
| | - Ping Sun
- Department of Immunology, Weifang Medical University, Weifang, China
| | - Yuzhang Wu
- Institute of Immunology PLA, Army Medical University (Third Military Medical University), Chongqing, China
| | - Li Wang
- Institute of Immunology PLA, Army Medical University (Third Military Medical University), Chongqing, China
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11
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Effects of Vitamin D Supplementation on CD4 + T Cell Subsets and mTOR Signaling Pathway in High-Fat-Diet-Induced Obese Mice. Nutrients 2021; 13:nu13030796. [PMID: 33670988 PMCID: PMC7997284 DOI: 10.3390/nu13030796] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2020] [Revised: 02/25/2021] [Accepted: 02/25/2021] [Indexed: 12/18/2022] Open
Abstract
Obesity is associated with an impaired balance of CD4+ T cell subsets. Both vitamin D and obesity have been reported to affect the mTOR pathway. In this study, we investigated the effects of vitamin D on CD4+ T cell subsets and the mTOR pathway. Ten-week-old male C57BL/6 mice were divided into four groups and fed diets with different fat (control or high-fat diets: CON or HFD) and vitamin D contents (vitamin D control or supplemented diets: vDC or vDS) for 12 weeks. T cells purified by negative selection were stimulated with anti-CD3/anti-CD28 mAbs and cultured for 48 h. The percentage of CD4+IL-17+ T cells was higher in the vDS than vDC groups. The CD4+CD25+Foxp3+ T cells percentage was higher in HFD than CON groups. The phospho-p70S6K/total-p70S6K ratio was lower in vDS than vDC, but the phospho-AKT/total-AKT ratio was higher in vDS than vDC groups. Hif1α mRNA levels were lower in vDS than vDC groups. These findings suggest HIF1α plays an important role in vitamin-D-mediated regulation of glucose metabolism in T cells, and dietary vitamin D supplementation may contribute to the maintenance of immune homeostasis by regulating the mTOR pathway in T cells.
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12
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The omentum harbors unique conditions in the peritoneal cavity to promote healing and regeneration for diaphragm muscle repair in mdx mice. Cell Tissue Res 2020; 382:447-455. [PMID: 32661578 DOI: 10.1007/s00441-020-03238-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2020] [Accepted: 06/05/2020] [Indexed: 10/23/2022]
Abstract
Although the primary cause of Duchenne muscular dystrophy (DMD) is a genetic mutation, the inflammatory response contributes directly to severity and exacerbation of the diaphragm muscle pathology. The omentum is a lymphoid organ with unique structural and immune functions serving as a sanctuary of hematopoietic and mesenchymal progenitors that coordinate immune responses in the peritoneal cavity. Upon activation, these progenitors expand and the organ produces large amounts of growth factors orchestrating tissue regeneration. The omentum of mdx mouse, a DMD murine model, is rich in milky spots and produces growth factors that promote diaphragm muscle regeneration. The present review summarizes the current knowledge of the omentum as an important immunologic structure and highlights its contribution to resolution of dystrophic muscle injury by providing an adequate environment for muscle regeneration, thus being a potential site for therapeutic interventions in DMD.
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13
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Putilin DA, Evchenko SY, Fedoniuk LY, Tokarskyy OS, Kamyshny OM, Migenko LM, Andreychyn SM, Hanberher II, Bezruk TO. The Influence of Metformin to the Transcriptional Activity of the mTOR and FOX3 Genes in Parapancreatic Adipose Tissue of Streptozotocin-Induced Diabetic Rats. J Med Life 2020; 13:50-55. [PMID: 32341701 PMCID: PMC7175427 DOI: 10.25122/jml-2020-0029] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
The mammalian target of rapamycin is not only a central regulator of lipid metabolism that controls the processes of adipogenesis and lipolysis but also a regulator of the immunometabolism of immune cells that infiltrate adipose tissue. In turn, the level of progression of diabetes is significantly influenced by the Treg subpopulation, the complexity and heterogeneity of which is confirmed by the detection of numerous tissue-specific Tregs, including the so-called VAT Tregs (visceral adipose tissue CD4+Foxp3+ regulatory T cells). Therefore, the purpose of the study was to determine the mRNA expression levels of mTOR, Foxp3, IL1β, and IL17A genes in rat parapancreatic adipose tissue with experimental streptozotocin-induced diabetes mellitus, with or without metformin administration. The experiments were performed on male Wistar rats with induced diabetes as a result of streptozotocin administration. Molecular genetic studies were performed using real-time reverse transcription-polymerase chain reaction. The development of diabetes caused transcriptional activation of the mammalian target of rapamycin protein kinase gene, as well as increased mRNA expression of the pro-inflammatory cytokines IL1β and IL17A, but did not affect Foxp3 mRNA expression. The intervention with metformin in diabetic rats inhibited the mammalian target of rapamycin mRNA expression and caused an increase in the transcriptional activity of the Foxp3 gene in parapancreatic adipose tissue.
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Affiliation(s)
| | - Sergey Yuryevich Evchenko
- Department of Microbiology, Virology and Immunology, Zaporizhzhia State Medical University, Zaporizhzhia, Ukraine
| | | | | | - Oleksandr Mikhailovich Kamyshny
- Department of Microbiology, Virology and Immunology, Molecular Genetics Laboratory, Zaporizhzhia State Medical University, Zaporizhzhia, Ukraine
| | | | - Serhiy Mikhailovich Andreychyn
- Department of Propedeutics of Internal Medicine and Phthisiology, I. Horbachevsky Ternopil National Medical University, Ternopil, Ukraine
| | - Iryna Ihorivna Hanberher
- Department of Propedeutics of Internal Medicine and Phthisiology, I. Horbachevsky Ternopil National Medical University, Ternopil, Ukraine
| | - Tetyana Oleksandrivna Bezruk
- Department of Internal Medicine and Infectious Diseases, Bukovinian State Medical University, Chernivtsi, Ukraine
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14
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Salminen A. Activation of immunosuppressive network in the aging process. Ageing Res Rev 2020; 57:100998. [PMID: 31838128 DOI: 10.1016/j.arr.2019.100998] [Citation(s) in RCA: 103] [Impact Index Per Article: 20.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2019] [Revised: 11/29/2019] [Accepted: 12/09/2019] [Indexed: 12/19/2022]
Abstract
Chronic low-grade inflammation has a key role in the aging process, a state called inflammaging. It is known that the chronic inflammatory condition generates counteracting immunosuppressive state in many diseases. Inflammaging is also associated with an immune deficiency; generally termed as immunosenescence, although it is not known whether it represents the senescence of immune cells or the active remodeling of immune system. Evidence has accumulated since the 1970's indicating that immunosenescence might be caused by an increased activity of immunosuppressive cells rather than cellular senescence. Immune cells display remarkable plasticity; many of these cells can express both proinflammatory and immunosuppressive phenotypes in a context-dependent manner. The immunosuppressive network involves the regulatory subtypes of T (Treg) and B (Breg) cells as well as regulatory phenotypes of macrophages (Mreg), dendritic (DCreg), natural killer (NKreg), and type II natural killer T (NKT) cells. The immunosuppressive network also includes monocytic (M-MDSC) and polymorphonuclear (PMN-MDSC) myeloid-derived suppressor cells which are immature myeloid cells induced by inflammatory mediators. This co-operative network is stimulated in chronic inflammatory conditions preventing excessive inflammatory responses but at the same time they exert harmful effects on the immune system and tissue homeostasis. Recent studies have revealed that the aging process is associated with the activation of immunosuppressive network, especially the functions of MDSCs, Tregs, and Mregs are increased. I will briefly review the properties of the regulatory phenotypes of immune cells and examine in detail the evidences for an activation of immunosuppressive network with aging.
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15
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Ozeki Y, Masaki T, Yoshida Y, Okamoto M, Anai M, Gotoh K, Endo Y, Ohta M, Inomata M, Shibata H. Relationships between computed tomography-assessed density, abdominal fat volume, and glucose metabolism after sleeve gastrectomy in Japanese patients with obesity. Endocr J 2019; 66:605-613. [PMID: 31019152 DOI: 10.1507/endocrj.ej18-0543] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
In this study, we investigated the relationships between body weight (BW), computed tomography (CT)-assessed abdominal adipose tissue, and the glycemic metabolic profile in obese Japanese patients following laparoscopic sleeve gastrectomy (LSG). This study analyzed adipose tissue compartments using CT methods before and 1 year after LSG. Thirty obese patients were studied, and variables measured included visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT), density of VAT (VAT-D), and density of SAT (SAT-D). We also examined the parameters in patients according to whether they had type-2 diabetes (T2DM). LSG induced significant losses in BW, SAT, and VAT after LSG. Additionally, SAT-D and VAT-D both increased and fasting plasma glucose (FPG) and HbA1c, but not C-peptide, decreased after surgery. ΔSAT and ΔVAT were positively related, and ΔSAT-D and ΔVAT-D were negatively related to ΔBW and/or FPG. Furthermore, a multivariate regression model showed that total BW loss (TBWL) was closely related to ΔSAT (β = 0.84; p < 0.001) and ΔVAT-D (β = -0.45; p < 0.05) and improvement of FPG was related to ΔVAT (β = 0.61; p < 0.05) after LSG. Finally, ΔFPG was correlated with ΔVAT in 16 T2DM patients (r = 0.58; p < 0.05) but not in non-T2DM patients. TBWL was related to ΔSAT and ΔVAT-D, and improvement of FPG was related to ΔVAT in obese Japanese patients after LSG.
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Affiliation(s)
- Yoshinori Ozeki
- Department of Endocrinology, Metabolism, Rheumatology and Nephrology, Faculty of Medicine, Yufu, Oita 879-5593, Japan
| | - Takayuki Masaki
- Department of Endocrinology, Metabolism, Rheumatology and Nephrology, Faculty of Medicine, Yufu, Oita 879-5593, Japan
| | - Yuichi Yoshida
- Department of Endocrinology, Metabolism, Rheumatology and Nephrology, Faculty of Medicine, Yufu, Oita 879-5593, Japan
| | - Mitsuhiro Okamoto
- Department of Endocrinology, Metabolism, Rheumatology and Nephrology, Faculty of Medicine, Yufu, Oita 879-5593, Japan
| | - Manabu Anai
- Department of Endocrinology, Metabolism, Rheumatology and Nephrology, Faculty of Medicine, Yufu, Oita 879-5593, Japan
| | - Koro Gotoh
- Department of Endocrinology, Metabolism, Rheumatology and Nephrology, Faculty of Medicine, Yufu, Oita 879-5593, Japan
| | - Yuichi Endo
- Department of Gastroenterological and Pediatric Surgery, Oita University, Yufu, Oita 879-5593, Japan
| | - Masayuki Ohta
- Department of Gastroenterological and Pediatric Surgery, Oita University, Yufu, Oita 879-5593, Japan
| | - Masafumi Inomata
- Department of Gastroenterological and Pediatric Surgery, Oita University, Yufu, Oita 879-5593, Japan
| | - Hirotaka Shibata
- Department of Endocrinology, Metabolism, Rheumatology and Nephrology, Faculty of Medicine, Yufu, Oita 879-5593, Japan
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16
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Zhao Y, Lin L, Li J, Xiao Z, Chen B, Wan L, Li M, Wu X, Hin Cho C, Shen J. CD4+ T cells in obesity and obesity-associated diseases. Cell Immunol 2018; 332:1-6. [DOI: 10.1016/j.cellimm.2018.08.013] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2018] [Revised: 07/29/2018] [Accepted: 08/20/2018] [Indexed: 02/08/2023]
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Agabiti-Rosei C, Trapletti V, Piantoni S, Airò P, Tincani A, De Ciuceis C, Rossini C, Mittempergher F, Titi A, Portolani N, Caletti S, Coschignano MA, Porteri E, Tiberio GAM, Pileri P, Solaini L, Kumar R, Ministrini S, Agabiti Rosei E, Rizzoni D. Decreased circulating T regulatory lymphocytes in obese patients undergoing bariatric surgery. PLoS One 2018; 13:e0197178. [PMID: 29758052 PMCID: PMC5951588 DOI: 10.1371/journal.pone.0197178] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2017] [Accepted: 04/27/2018] [Indexed: 12/18/2022] Open
Abstract
OBJECTIVE It has been previously demonstrated that T lymphocytes may be involved in the development of hypertension and microvascular remodeling, and that circulating T effector lymphocytes may be increased in hypertension. In particular, Th1 and Th 17 lymphocytes may contribute to the progression of hypertension and microvascular damage while T-regulatory (Treg) lymphocytes seem to be protective in this regard. However, no data is available about patients with severe obesity, in which pronounced microvascular alterations were observed. DESIGN AND METHODS We have investigated 32 severely obese patients undergoing bariatric surgery, as well as 24 normotensive lean subjects and 12 hypertensive lean subjects undergoing an elective surgical intervention. A peripheral blood sample was obtained before surgery for assessment of CD4+ T lymphocyte subpopulations. Lymphocyte phenotype was evaluated by flow cytometry in order to assess T-effector and Treg lymphocytes. RESULTS A marked reduction of several Treg subpopulations was observed in obese patients compared with controls, together with an increased in CD4+ effector memory T-effector cells. CONCLUSION In severely obese patients, Treg lymphocytes are clearly reduced and CD4+ effector memory cells are increased. It may be hypothesized that they might contribute to the development of marked microvascular alterations previously observed in these patients.
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Affiliation(s)
- Claudia Agabiti-Rosei
- Clinica Medica, Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy
| | - Valentina Trapletti
- Clinica Medica, Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy
| | - Silvia Piantoni
- Chair of Rheumatology, Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy
| | - Paolo Airò
- Chair of Rheumatology, Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy
| | - Angela Tincani
- Chair of Rheumatology, Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy
| | - Carolina De Ciuceis
- Clinica Medica, Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy
| | - Claudia Rossini
- Clinica Medica, Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy
| | - Francesco Mittempergher
- Clinica Chirurgica, Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy
| | - Amin Titi
- Clinica Chirurgica, Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy
| | - Nazario Portolani
- Clinica Chirurgica, Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy
| | - Stefano Caletti
- Clinica Medica, Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy
| | | | - Enzo Porteri
- Clinica Medica, Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy
| | - Guido A. M. Tiberio
- Clinica Chirurgica, Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy
| | - Paola Pileri
- Clinica Medica, Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy
| | - Leonardo Solaini
- Clinica Chirurgica, Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy
| | - Rajesh Kumar
- Chair of Rheumatology, Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy
| | - Silvia Ministrini
- Clinica Chirurgica, Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy
| | - Enrico Agabiti Rosei
- Clinica Medica, Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy
| | - Damiano Rizzoni
- Clinica Medica, Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy
- Istituto Clinico Città di Brescia, Division of Medicine, Brescia, Italy
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18
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Villarroya F, Cereijo R, Villarroya J, Gavaldà-Navarro A, Giralt M. Toward an Understanding of How Immune Cells Control Brown and Beige Adipobiology. Cell Metab 2018; 27:954-961. [PMID: 29719233 DOI: 10.1016/j.cmet.2018.04.006] [Citation(s) in RCA: 141] [Impact Index Per Article: 20.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/17/2018] [Revised: 03/13/2018] [Accepted: 04/03/2018] [Indexed: 12/19/2022]
Abstract
Immune cells were recently found to have an unexpected involvement in controlling the thermogenic activity of brown and beige adipose tissue. Here, we review how macrophages, eosinophils, type 2 innate lymphoid cells, and T lymphocytes are linked to this process. In particular, the recruitment of alternatively activated macrophages and eosinophils is associated with brown fat activation and white fat browning. Conversely, pro-inflammatory immune cell recruitment represses the thermogenic activity of brown and beige adipose tissues via cytokines that inhibit noradrenergic signaling. Macrophages also influence the noradrenergic tone by degrading norepinephrine locally and by inhibiting sympathetic innervation over time.
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Affiliation(s)
- Francesc Villarroya
- Departament de Bioquímica i Biomedicina Molecular, Universitat de Barcelona, Barcelona, Catalonia, Spain; CIBER Fisiopatología de la Obesidad y Nutrición, Barcelona, Catalonia, Spain.
| | - Rubén Cereijo
- Departament de Bioquímica i Biomedicina Molecular, Universitat de Barcelona, Barcelona, Catalonia, Spain; CIBER Fisiopatología de la Obesidad y Nutrición, Barcelona, Catalonia, Spain
| | - Joan Villarroya
- Departament de Bioquímica i Biomedicina Molecular, Universitat de Barcelona, Barcelona, Catalonia, Spain; Hospital de la Santa Creu i Sant Pau, Barcelona, Catalonia, Spain
| | - Aleix Gavaldà-Navarro
- Departament de Bioquímica i Biomedicina Molecular, Universitat de Barcelona, Barcelona, Catalonia, Spain; CIBER Fisiopatología de la Obesidad y Nutrición, Barcelona, Catalonia, Spain
| | - Marta Giralt
- Departament de Bioquímica i Biomedicina Molecular, Universitat de Barcelona, Barcelona, Catalonia, Spain; CIBER Fisiopatología de la Obesidad y Nutrición, Barcelona, Catalonia, Spain
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19
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Chen X, Zhang D, Chen X, Meng G, Zheng Q, Mai W, Wu Y, Ye L, Wang L. Oral administration of visceral adipose tissue antigens ameliorates metabolic disorders in mice and elevates visceral adipose tissue-resident CD4 +CD25 +Foxp3 + regulatory T cells. Vaccine 2017; 35:4612-4620. [PMID: 28736203 DOI: 10.1016/j.vaccine.2017.07.014] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2017] [Revised: 06/09/2017] [Accepted: 07/03/2017] [Indexed: 01/12/2023]
Abstract
Obesity and type 2 diabetes are linked with chronic, low-grade inflammation in visceral adipose tissue (VAT). A unique population of VAT-resident CD4+Foxp3+ Tregs plays a crucial role in regulating VAT inflammation and metabolic homeostasis. VAT-resident Tregs display a highly restricted TCR repertoire, suggesting they recognize certain autoantigen(s) in VAT. A dramatic reduction of VAT-resident Tregs has been shown to closely correlate with obesity-related VAT chronic inflammation and metabolic disorders. Oral tolerance strategy may modulate inflammatory response to autoantigens by several mechanisms including induction of autoantigen-specific Tregs. Here, we explored the effects and cellular mechanism of oral administration of VAT pooled antigens on high-fat diet (HFD)-induced metabolic disorders in mice. Indeed, we found that oral treatment of VAT mixture antigens effectively inhibited gain in body weight and fat mass, ameliorated serum lipid parameters, and improved insulin sensitivity in HFD mice. This strategy was shown to significantly restore HFD-induced decrease of VAT-resident Tregs, accompanied by a hampered M2-type to M1-type macrophages phenotypic switch as well as decreased CD8+ T cells infiltration in VAT. Thus, oral administration of VAT antigens may be a novel and safe strategy against obesity and its related metabolic disorders.
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Affiliation(s)
- Xiangyu Chen
- Institute of Immunology PLA & Department of Immunology, Third Military Medical University, Chongqing 400038, China
| | - Dali Zhang
- Institute of Immunology PLA & Department of Immunology, Third Military Medical University, Chongqing 400038, China; Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing 400038, China
| | - Xiaoling Chen
- Institute of Immunology PLA & Department of Immunology, Third Military Medical University, Chongqing 400038, China
| | - Gang Meng
- Department of Pathology, Southwest Hospital, Third Military Medical University, Chongqing 400038, China
| | - Qian Zheng
- Function Center, North Sichuan Medical College, Nanchong 637100, Sichuan, China
| | - Wenli Mai
- Function Center, North Sichuan Medical College, Nanchong 637100, Sichuan, China
| | - Yuzhang Wu
- Institute of Immunology PLA & Department of Immunology, Third Military Medical University, Chongqing 400038, China.
| | - Lilin Ye
- Institute of Immunology PLA & Department of Immunology, Third Military Medical University, Chongqing 400038, China.
| | - Li Wang
- Institute of Immunology PLA & Department of Immunology, Third Military Medical University, Chongqing 400038, China.
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20
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Abstract
Foxp3+ regulatory T cells (Tregs) play an indispensable role in controlling tolerance and immunity against self- and foreign antigens. The failure of Tregs to properly function is the direct cause of systemic and chronic inflammation as well as immune suppression. It is now evident that Tregs are highly heterogeneous populations depending on the surface phenotypes, cytokine profiles, and anatomical locations. Yet, our understanding of the cellular and molecular pathways underlying such heterogeneity is very limited. Furthermore, some Tregs lose the phenotype (and suppressive functions) and instead acquire pathogenicity. Since utilizing Tregs as a tool for immunotherapy is being implemented in many clinical settings, it is of utmost importance to understand the precise mechanisms by which the loss of Treg phenotype (and function) is prevented. In this review, both cellular and molecular factors involved in Treg heterogeneity and stability are discussed.
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Affiliation(s)
- Booki Min
- Department of Immunology/NB30, Lerner Research Institute , Cleveland Clinic Foundation, Cleveland, Ohio
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21
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Abstract
Body weight regain often causes failure of obesity therapies while the underlying mechanism remains largely unknown. In this study, we report that immune cells, especially CD4+ T cells, mediate the ‘memory’ of previous obese status. In a weight gain-loss-regain model, we found that C57BL/6J mice with an obesity history showed a much faster rate of body weight regain. This obesity memory could last for at least 2 months after previously obese mice were kept at the same body weight as non-obese mice. Surprisingly, such obesity memory was abrogated by dexamethasone treatment, whereas immunodeficient Rag1−/− and H2A−/− mice failed to establish such memory. Rag1−/− mice repossessed the obesity memory when immune cells or CD4+ T cells isolated from previously obese mice were transferred. Furthermore, depletion of CD4+ T cells led to obesity memory ablation. Taken together, we conclude that CD4+ T cells mediate obesity memory and promote weight regain.
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22
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Luo A, Leach ST, Barres R, Hesson LB, Grimm MC, Simar D. The Microbiota and Epigenetic Regulation of T Helper 17/Regulatory T Cells: In Search of a Balanced Immune System. Front Immunol 2017; 8:417. [PMID: 28443096 PMCID: PMC5385369 DOI: 10.3389/fimmu.2017.00417] [Citation(s) in RCA: 108] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2016] [Accepted: 03/23/2017] [Indexed: 12/14/2022] Open
Abstract
Immune cells not only affect tissue homeostasis at the site of inflammation but also exert systemic effects contributing to multiple chronic conditions. Recent evidence clearly supports an altered T helper 17/regulatory T cell (Th17/Treg) balance leading to the development and progression of inflammatory diseases that not only affect the gastrointestinal tract but also have whole-body manifestations, including insulin resistance. Epigenetic mechanisms are amenable to both environmental and circulating factors and contribute to determining the T cell landscape. The recently identified participation of the gut microbiota in the remodeling of the epigenome of immune cells has triggered a paradigm shift in our understanding of the etiology of various inflammatory diseases and opened new paths toward therapeutic strategies. In this review, we provide an overview of the contribution of the Th17/Treg balance in the development and progression of inflammatory bowel diseases and metabolic diseases. We discuss the involvement of epigenetic mechanisms in the regulation of T cell function in the particular context of dysbiosis. Finally, we examine the potential for nutritional interventions affecting the gut microbiota to reshape the T cell epigenome and address the inflammatory component of various diseases.
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Affiliation(s)
- Annie Luo
- St George and Sutherland Clinical School, University of New South Wales, Sydney, NSW, Australia
| | - Steven T Leach
- School of Women and Children's Health, University of New South Wales, Sydney, NSW, Australia
| | - Romain Barres
- The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Luke B Hesson
- Adult Cancer Program, Lowy Cancer Research Centre, Prince of Wales Clinical School, University of New South Wales, Sydney, NSW, Australia
| | - Michael C Grimm
- St George and Sutherland Clinical School, University of New South Wales, Sydney, NSW, Australia
| | - David Simar
- The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.,Mechanisms of Disease and Translational Research, School of Medical Sciences, University of New South Wales, Sydney, NSW, Australia
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23
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Zhu F, Wang A, Li Y, Liang R, Li D, Li B. Adipose Tissue-Resident Regulatory T Cells. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2017; 1011:153-162. [DOI: 10.1007/978-94-024-1170-6_4] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
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Donma M, Karasu E, Ozdilek B, Turgut B, Topcu B, Nalbantoglu B, Donma O. CD4(+), CD25(+), FOXP3 (+) T Regulatory Cell Levels in Obese, Asthmatic, Asthmatic Obese, and Healthy Children. Inflammation 2016; 38:1473-8. [PMID: 25655390 DOI: 10.1007/s10753-015-0122-4] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
The aim of this prospective case control study is to determine CD4(+), CD25(+), and FoxP3(+) T regulatory cells (Tregs) and T helper cells (Ths) in obese, asthmatic, asthmatic obese, and healthy children. Obese (n = 40), asthmatic (n = 40), asthmatic obese (n = 40), and healthy children (n = 40) were included in this study. Blood samples collected from children were marked with CD4, CD25, ve Foxp3 in order to detect Tregs and Ths by flow cytometric method. Statistical analyses were performed. p ≤ 0.05 was chosen as meaningful threshold. Tregs exhibiting anti-inflammatory nature were significantly lower in obese (0.16 %; p ≤ 0.001), asthmatic (0.25 %; p ≤ 0.01), and asthmatic obese (0.29 %; p ≤ 0.05) groups than control group (0.38 %). Ths were counted higher in asthma group than control (p ≤ 0.01) and obese (p ≤ 0.001) groups. T cell immunity plays important roles in chronic inflammatory diseases such as obesity and asthma pathogeneses. Decreased numbers of Tregs found in obese, asthmatic, and asthmatic obese children might represent a challenge of these cells.
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Affiliation(s)
- Metin Donma
- Medical Faculty, Department of Pediatrics, Namik Kemal University, Tekirdag, Turkey,
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Diminished levels of regulatory T cell subsets (CD8+Foxp3, CD4+Foxp3 and CD4+CD39+Foxp3) but increased Foxp3 expression in adipose tissue from overweight subjects. Nutrition 2016; 32:943-54. [PMID: 27160497 DOI: 10.1016/j.nut.2016.02.006] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2015] [Revised: 02/04/2016] [Accepted: 02/09/2016] [Indexed: 01/17/2023]
Abstract
OBJECTIVES The aim of this study was to identify regulatory T cell (Treg) subsets residing in adipose tissue, demonstrate their immunosuppressive functions, and assess the possible role of Sirt1 in their function in overweight subjects. METHODS Fat samples were obtained by lipoaspiration from healthy overweight (n = 15) and normoweight (n = 11) subjects. We obtained the stromal vascular fraction and then isolated the mononuclear cells by Ficoll-Hypaque sedimentation. The Treg subsets were analyzed by flow cytometry, the expression of Sirt1 and Foxp3 was detected by western blot, and peroxisome proliferator-activated receptor gamma (PPAR-γ) expression was evaluated by qPCR. RESULTS We detected low numbers of Treg cell subsets displaying the phenotypes CD4+CD25-Foxp3+, CD8+CD25-Foxp3+, and CD4+CD39+Foxp3+ associated with increased body mass index in overweight subjects. We found lower levels of mRNA SIRT1 expression in adipocytes from overweight subjects than in those from normoweight subjects. In contrast, increased amounts of the Sirt1 and Foxp3 proteins in adipose tissue mononuclear cells from overweight subjects were observed. The immunosuppressive function of CD4+CD25+ Treg cells is higher in cells from obese subject than in those from normoweight subject. CONCLUSIONS Low levels of Treg subsets in overweight subjects with a high percentage of inhibition of proliferation could be related to high levels of the Foxp3 protein. Likewise, the low expression of SIRT1 and PPAR-γ mRNA levels and increased concentration of Sirt1 proteins allows adipose tissue mononuclear cells to respond to stimuli dependent on adenosine receptors and sirtuin pathways.
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Abstract
BACKGROUND To determine if Type 2 diabetes mellitus (DM) is protective against giant cell arteritis (GCA) and to estimate the incidence of GCA diagnosis from Medicare claims. METHODS Medicare 5% claims files from 1991 to 2011 were used to identify beneficiaries diagnosed with DM, but not GCA, within a 3-year ascertainment period. Propensity score matching was used to define a control group of nondiabetics with comparable demographic covariates. Competing risk regression was then used to assess the impact of DM diagnosis on GCA diagnosis. To allow for a 3-year ascertainment period, the analysis sample was limited to beneficiaries older than 68 years at baseline. RESULTS A total of 151,041 beneficiaries diagnosed with DM were matched to an equal number of controls. Mean study follow-up was 67.75 months. GCA was diagnosed among 1116 beneficiaries with DM (0.73%) vs 465 (0.30%) controls. The risk of receiving a GCA diagnosis among patients with DM was increased by 100% (subhazard ratio, 2.00; 95% confidence interval, 1.78-2.25). The annual incidence of GCA diagnosis among claims for US Medicare beneficiaries older than 68 years old was 93 in 100,000. CONCLUSIONS A DM diagnosis is not protective against a GCA diagnosis in the Medicare population. Our data suggest that a DM diagnosis increases the risk of GCA diagnosis within 5.7 years for Medicare beneficiaries older than 68 years.
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Abstract
Low-grade inflammation in the obese AT (AT) and the liver is a critical player in the development of obesity-related metabolic dysregulation, including insulin resistance, type 2 diabetes and non-alcoholic steatohepatitis (NASH). Myeloid as well as lymphoid cells infiltrate the AT and the liver and expand within these metabolic organs as a result of excessive nutrient intake, thereby exacerbating tissue inflammation. Macrophages are the paramount cell population in the field of metabolism-related inflammation; as obesity progresses, a switch takes place within the AT environment from an M2-alternatively activated macrophage state to an M1-inflammatory macrophage-dominated milieu. M1-polarized macrophages secrete inflammatory cytokines like TNF in the obese AT; such cytokines contribute to insulin resistance in adipocytes. Besides macrophages, also CD8+ T cells promote inflammation in the AT and the liver and thereby the deterioration of the metabolic balance in adipocytes and hepatocytes. Other cells of the innate immunity, such as neutrophils or mast cells, interfere with metabolic homeostasis as well. On the other hand, eosinophils or T-regulatory cells, the number of which in the AT decreases in the course of obesity, function to maintain metabolic balance by ameliorating inflammatory processes. In addition, eosinophils and M2-polarized macrophages may contribute to "beige" adipogenesis under lean conditions; beige adipocytes are located predominantly in the subcutaneous AT and have thermogenic and optimal energy-dispensing properties like brown adipocytes. This chapter will summarize the different aspects of the regulation of homeostasis of metabolic tissues by immune cells.
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Affiliation(s)
- Antonios Chatzigeorgiou
- Department of Clinical Pathobiochemistry, Technische Universität Dresden, Fetscherstrasse 74, 01307, Dresden, Germany.
- Institute for Clinical Chemistry and Laboratory Medicine, Technische Universität Dresden, Dresden, Germany.
- Paul Langerhans Institute Dresden, German Center for Diabetes Research, Dresden, Germany.
| | - Triantafyllos Chavakis
- Department of Clinical Pathobiochemistry, Technische Universität Dresden, Fetscherstrasse 74, 01307, Dresden, Germany
- Institute for Clinical Chemistry and Laboratory Medicine, Technische Universität Dresden, Dresden, Germany
- Paul Langerhans Institute Dresden, German Center for Diabetes Research, Dresden, Germany
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Xie Z, Hao H, Tong C, Cheng Y, Liu J, Pang Y, Si Y, Guo Y, Zang L, Mu Y, Han W. Human umbilical cord-derived mesenchymal stem cells elicit macrophages into an anti-inflammatory phenotype to alleviate insulin resistance in type 2 diabetic rats. Stem Cells 2015; 34:627-39. [PMID: 26523620 DOI: 10.1002/stem.2238] [Citation(s) in RCA: 104] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2015] [Accepted: 10/11/2015] [Indexed: 12/30/2022]
Affiliation(s)
- Zongyan Xie
- Department of Endocrinology; Chinese PLA General Hospital; Beijing China
- School of Medicine; Nankai University; Tianjin China
| | - Haojie Hao
- Institute of Basic Medicine Science, College of Life Science; Chinese PLA General Hospital; Beijing China
| | - Chuan Tong
- Institute of Basic Medicine Science, College of Life Science; Chinese PLA General Hospital; Beijing China
| | - Yu Cheng
- Department of Endocrinology; Chinese PLA General Hospital; Beijing China
| | - Jiejie Liu
- Institute of Basic Medicine Science, College of Life Science; Chinese PLA General Hospital; Beijing China
| | - Yaping Pang
- Department of Endocrinology; Chinese PLA 309 Hospital; Beijing China
| | - Yiling Si
- Institute of Basic Medicine Science, College of Life Science; Chinese PLA General Hospital; Beijing China
| | - Yulin Guo
- Department of General surgery; Chinese PLA General Hospital; Beijing China
| | - Li Zang
- Department of Endocrinology; Chinese PLA General Hospital; Beijing China
| | - Yiming Mu
- Department of Endocrinology; Chinese PLA General Hospital; Beijing China
| | - Weidong Han
- Institute of Basic Medicine Science, College of Life Science; Chinese PLA General Hospital; Beijing China
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Interleukin-1 Family Cytokines in Liver Diseases. Mediators Inflamm 2015; 2015:630265. [PMID: 26549942 PMCID: PMC4624893 DOI: 10.1155/2015/630265] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2015] [Accepted: 09/27/2015] [Indexed: 02/06/2023] Open
Abstract
The gene encoding IL-1 was sequenced more than 30 years ago, and many related cytokines, such as IL-18, IL-33, IL-36, IL-37, IL-38, IL-1 receptor antagonist (IL-1Ra), and IL-36Ra, have since been identified. IL-1 is a potent proinflammatory cytokine and is involved in various inflammatory diseases. Other IL-1 family ligands are critical for the development of diverse diseases, including inflammatory and allergic diseases. Only IL-1Ra possesses the leader peptide required for secretion from cells, and many ligands require posttranslational processing for activation. Some require inflammasome-mediated processing for activation and release, whereas others serve as alarmins and are released following cell membrane rupture, for example, by pyroptosis or necroptosis. Thus, each ligand has the proper molecular process to exert its own biological functions. In this review, we will give a brief introduction to the IL-1 family cytokines and discuss their pivotal roles in the development of various liver diseases in association with immune responses. For example, an excess of IL-33 causes liver fibrosis in mice via activation and expansion of group 2 innate lymphoid cells to produce type 2 cytokines, resulting in cell conversion into pro-fibrotic M2 macrophages. Finally, we will discuss the importance of IL-1 family cytokine-mediated molecular and cellular networks in the development of acute and chronic liver diseases.
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Tissue resident regulatory T cells: novel therapeutic targets for human disease. Cell Mol Immunol 2015; 12:543-52. [PMID: 25891216 PMCID: PMC4579654 DOI: 10.1038/cmi.2015.23] [Citation(s) in RCA: 45] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2014] [Revised: 02/25/2015] [Accepted: 02/25/2015] [Indexed: 02/07/2023] Open
Abstract
Over the past decade, the ability of regulatory T cells (Tregs) to suppress multiple types of immune cells has received tremendous attention. Mounting evidence has revealed that tissue resident Tregs control non-immunological processes of their target tissues and contribute to a plethora of human diseases. The identification of novel tissue-specific Tregs has highlighted their heterogeneity and complexity. This review summarizes the recent findings for visceral adipose tissue CD4+Foxp3+ regulatory T cells (VAT Tregs), muscle Tregs, bone Tregs and skin memory Tregs, with a focus on their unique functions in local tissues. This interpretation of the roles of tissue-specific Tregs and of their involvement in disease progression provides new insight into the discovery of potential therapeutic targets of human diseases.
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Zhang Y, Yang P, Cui R, Zhang M, Li H, Qian C, Sheng C, Qu S, Bu L. Eosinophils Reduce Chronic Inflammation in Adipose Tissue by Secreting Th2 Cytokines and Promoting M2 Macrophages Polarization. Int J Endocrinol 2015; 2015:565760. [PMID: 26688684 PMCID: PMC4673347 DOI: 10.1155/2015/565760] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/24/2015] [Accepted: 11/04/2015] [Indexed: 11/17/2022] Open
Abstract
Obesity is now recognized as a low-grade, chronic inflammatory disease that is linked to a myriad of disorders including cardiovascular diseases, type 2 diabetes, and liver diseases. Recently it is found that eosinophils accelerate alternative activation macrophage (AAM) polarization by secreting Th2 type cytokines such as interleukin-4 and interleukin-13, thereby reducing metainflammation in adipose tissue. In this review, we focused on the role of eosinophils in regulating metabolic homeostasis and obesity.
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Affiliation(s)
- Yi Zhang
- Shanghai Tenth People's Hospital, Tongji University, Shanghai 200072, China
| | - Peng Yang
- Shanghai Tenth People's Hospital, Tongji University, Shanghai 200072, China
| | - Ran Cui
- Shanghai Tenth People's Hospital, Tongji University, Shanghai 200072, China
| | - Manna Zhang
- Shanghai Tenth People's Hospital, Tongji University, Shanghai 200072, China
| | - Hong Li
- Shanghai Tenth People's Hospital, Tongji University, Shanghai 200072, China
| | - Chunhua Qian
- Shanghai Tenth People's Hospital, Tongji University, Shanghai 200072, China
| | - Chunjun Sheng
- Shanghai Tenth People's Hospital, Tongji University, Shanghai 200072, China
| | - Shen Qu
- Shanghai Tenth People's Hospital, Tongji University, Shanghai 200072, China
| | - Le Bu
- Shanghai Tenth People's Hospital, Tongji University, Shanghai 200072, China
- *Le Bu:
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32
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Kucharska AM, Pyrżak B, Demkow U. Regulatory T Cells in Obesity. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2015; 866:35-40. [PMID: 26022902 DOI: 10.1007/5584_2015_147] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
The current concept of the pathogenesis of obesity relates to the inflammation caused by excess of adipose tissue. Regulatory T cells accumulated in visceral adipose tissue (VAT-resident Tregs) are also involved in this pathogenesis. In the present paper the mechanisms responsible for alterations in the number and function of VAT-resident Tregs T in obesity are described. The role of Tregs in inflammation, insulin resistance, atherogenesis, and also the influence on VAT-resident Tregs of adipocytokines and insulin are reviewed.
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Affiliation(s)
- Anna M Kucharska
- Department of Pediatrics and Endocrinology, Medical University of Warsaw, 24 Marszalkowska St., 00-576, Warsaw, Poland,
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Abstract
Obesity and its comorbidities are closely related to the inflammatory environment created by expanded adipose tissue. Several mechanisms trigger inflammation in adipose tissue, including excess fatty acids, hypoxia, and activation of the inflammasome. Inflammation is characterized by the abundance of immune cells, particularly M1 macrophages and T lymphocytes, which have increased secretion of proinflammatory cytokines that act to perpetuate systemic inflammation and induce insulin resistance. The gut microbiota is also involved in obesity-induced inflammation via LPS-related endotoxemia that induces cytokine secretion and insulin resistance. Innate lymphoid type 2 cells, regulatory T cells, and interleukine (IL)-10 counteract the inflammation and insulin resistance, establishing classical or metabolically healthy obesity.
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Affiliation(s)
- Solange S Pereira
- Department Biochemistry and Immunology, Universidade Federal de Minas Gerais, Caixa Postal 486, 30161-970, Belo Horizonte, Brazil
| | - Jacqueline I Alvarez-Leite
- Department Biochemistry and Immunology, Universidade Federal de Minas Gerais, Caixa Postal 486, 30161-970, Belo Horizonte, Brazil.
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Makki K, Taront S, Molendi-Coste O, Bouchaert E, Neve B, Eury E, Lobbens S, Labalette M, Duez H, Staels B, Dombrowicz D, Froguel P, Wolowczuk I. Beneficial metabolic effects of rapamycin are associated with enhanced regulatory cells in diet-induced obese mice. PLoS One 2014; 9:e92684. [PMID: 24710396 PMCID: PMC3977858 DOI: 10.1371/journal.pone.0092684] [Citation(s) in RCA: 55] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2013] [Accepted: 02/25/2014] [Indexed: 12/20/2022] Open
Abstract
The “mechanistic target of rapamycin” (mTOR) is a central controller of growth, proliferation and/or motility of various cell-types ranging from adipocytes to immune cells, thereby linking metabolism and immunity. mTOR signaling is overactivated in obesity, promoting inflammation and insulin resistance. Therefore, great interest exists in the development of mTOR inhibitors as therapeutic drugs for obesity or diabetes. However, despite a plethora of studies characterizing the metabolic consequences of mTOR inhibition in rodent models, its impact on immune changes associated with the obese condition has never been questioned so far. To address this, we used a mouse model of high-fat diet (HFD)-fed mice with and without pharmacologic mTOR inhibition by rapamycin. Rapamycin was weekly administrated to HFD-fed C57BL/6 mice for 22 weeks. Metabolic effects were determined by glucose and insulin tolerance tests and by indirect calorimetry measures of energy expenditure. Inflammatory response and immune cell populations were characterized in blood, adipose tissue and liver. In parallel, the activities of both mTOR complexes (e. g. mTORC1 and mTORC2) were determined in adipose tissue, muscle and liver. We show that rapamycin-treated mice are leaner, have enhanced energy expenditure and are protected against insulin resistance. These beneficial metabolic effects of rapamycin were associated to significant changes of the inflammatory profiles of both adipose tissue and liver. Importantly, immune cells with regulatory functions such as regulatory T-cells (Tregs) and myeloid-derived suppressor cells (MDSCs) were increased in adipose tissue. These rapamycin-triggered metabolic and immune effects resulted from mTORC1 inhibition whilst mTORC2 activity was intact. Taken together, our results reinforce the notion that controlling immune regulatory cells in metabolic tissues is crucial to maintain a proper metabolic status and, more generally, comfort the need to search for novel pharmacological inhibitors of the mTOR signaling pathway to prevent and/or treat metabolic diseases.
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Affiliation(s)
- Kassem Makki
- Centre National de la Recherche Scientifique (CNRS), Unité Mixte de Recherche (UMR)8199, Lille Pasteur Institute, Lille, France
- Lille 2 University, Lille, France
- European Genomic Institute for Diabetes (EGID), Lille, France
| | - Solenne Taront
- Centre National de la Recherche Scientifique (CNRS), Unité Mixte de Recherche (UMR)8199, Lille Pasteur Institute, Lille, France
- Lille 2 University, Lille, France
- European Genomic Institute for Diabetes (EGID), Lille, France
| | - Olivier Molendi-Coste
- Lille 2 University, Lille, France
- European Genomic Institute for Diabetes (EGID), Lille, France
- Institut National de la Santé et de la Recherche Médicale (Inserm), UMR1011, Lille Pasteur Institute, Lille, France
| | - Emmanuel Bouchaert
- Lille 2 University, Lille, France
- European Genomic Institute for Diabetes (EGID), Lille, France
- Institut National de la Santé et de la Recherche Médicale (Inserm), UMR1011, Lille Pasteur Institute, Lille, France
| | - Bernadette Neve
- Centre National de la Recherche Scientifique (CNRS), Unité Mixte de Recherche (UMR)8199, Lille Pasteur Institute, Lille, France
- Lille 2 University, Lille, France
- European Genomic Institute for Diabetes (EGID), Lille, France
| | - Elodie Eury
- Centre National de la Recherche Scientifique (CNRS), Unité Mixte de Recherche (UMR)8199, Lille Pasteur Institute, Lille, France
- Lille 2 University, Lille, France
- European Genomic Institute for Diabetes (EGID), Lille, France
| | - Stéphane Lobbens
- Centre National de la Recherche Scientifique (CNRS), Unité Mixte de Recherche (UMR)8199, Lille Pasteur Institute, Lille, France
- Lille 2 University, Lille, France
- European Genomic Institute for Diabetes (EGID), Lille, France
| | - Myriam Labalette
- Lille 2 University, Lille, France
- Immunology Institute, Centre Hospitalier Régional Universitaire (CHRU) Lille and Equipe d'Accueil (EA)2686, Lille 2 University, Lille, France
| | - Hélène Duez
- Lille 2 University, Lille, France
- European Genomic Institute for Diabetes (EGID), Lille, France
- Institut National de la Santé et de la Recherche Médicale (Inserm), UMR1011, Lille Pasteur Institute, Lille, France
| | - Bart Staels
- Lille 2 University, Lille, France
- European Genomic Institute for Diabetes (EGID), Lille, France
- Institut National de la Santé et de la Recherche Médicale (Inserm), UMR1011, Lille Pasteur Institute, Lille, France
| | - David Dombrowicz
- Lille 2 University, Lille, France
- European Genomic Institute for Diabetes (EGID), Lille, France
- Institut National de la Santé et de la Recherche Médicale (Inserm), UMR1011, Lille Pasteur Institute, Lille, France
| | - Philippe Froguel
- Centre National de la Recherche Scientifique (CNRS), Unité Mixte de Recherche (UMR)8199, Lille Pasteur Institute, Lille, France
- Lille 2 University, Lille, France
- European Genomic Institute for Diabetes (EGID), Lille, France
- Department of Genomics of Common Disease, School of Public Health, Imperial College London, London, United Kingdom
- * E-mail: (PF); (IW)
| | - Isabelle Wolowczuk
- Centre National de la Recherche Scientifique (CNRS), Unité Mixte de Recherche (UMR)8199, Lille Pasteur Institute, Lille, France
- Lille 2 University, Lille, France
- European Genomic Institute for Diabetes (EGID), Lille, France
- * E-mail: (PF); (IW)
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Pecht T, Gutman-Tirosh A, Bashan N, Rudich A. Peripheral blood leucocyte subclasses as potential biomarkers of adipose tissue inflammation and obesity subphenotypes in humans. Obes Rev 2014; 15:322-37. [PMID: 24251825 DOI: 10.1111/obr.12133] [Citation(s) in RCA: 57] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/18/2013] [Revised: 10/01/2013] [Accepted: 10/18/2013] [Indexed: 12/14/2022]
Abstract
While obesity is clearly accepted as a major risk factor for cardio-metabolic morbidity, it is also apparent that some obese patients largely escape this association, forming a unique obese subphenotype(s). Current approaches to define such subphenotypes include clinical biomarkers that largely reflect already manifested comorbidities, such as markers of dyslipidaemia, hyperglycaemia and impaired regulation of vascular tone, and anthropometric or imaging-based assessment of adipose tissue distribution. Low-grade inflammation, evident both systemically and within adipose tissue (particularly intra-abdominal fat depots), seems to characterize the more cardio-metabolically morbid forms of obesity. Indeed, several systemic inflammatory markers (C-reactive protein), adipokines (retinol-binding protein 4, adiponectin) and cytokines have been shown to correlate in humans with adipose tissue inflammation and with obesity-associated health risks. Circulating leucocytes constitute a diverse group of cells that form a major arm of the immune system. They are both major sources of cytokines and likely also of infiltrating adipose tissue immune cells in obesity. In the present review, we summarize currently available literature on 'classical' blood white cell classes and on more specific leucocyte subclasses present in the circulation in human obesity. We critically raise the possibility that leucocytes may constitute clinically available markers for the more morbidity-associated obesity subphenotype(s), and when available, for intra-abdominal adipose tissue inflammation.
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Affiliation(s)
- T Pecht
- Department of Clinical Biochemistry and Pharmacology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel; The National Institute of Biotechnology (NIBN) in the Negev, Ben-Gurion University of the Negev, Beer-Sheva, Israel
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