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Elkins C, Ye C, Sivasami P, Mulpur R, Diaz-Saldana PP, Peng A, Xu M, Chiang YP, Moll S, Rivera-Rodriguez DE, Cervantes-Barragan L, Wu T, Au-Yeung BB, Scharer CD, Ford ML, Kissick H, Li C. Obesity reshapes regulatory T cells in the visceral adipose tissue by disrupting cellular cholesterol homeostasis. Sci Immunol 2025; 10:eadl4909. [PMID: 39792637 PMCID: PMC11786953 DOI: 10.1126/sciimmunol.adl4909] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2023] [Revised: 09/08/2024] [Accepted: 11/22/2024] [Indexed: 01/12/2025]
Abstract
Regulatory T cells (Tregs) accumulate in the visceral adipose tissue (VAT) to maintain systemic metabolic homeostasis but decline during obesity. Here, we explored the metabolic pathways controlling the homeostasis, composition, and function of VAT Tregs under normal and high-fat diet feeding conditions. We found that cholesterol metabolism was specifically up-regulated in ST2hi VAT Treg subsets. Treg-specific deletion of Srebf2, the master regulator of cholesterol homeostasis, selectively reduced ST2hi VAT Tregs, increasing VAT inflammation and insulin resistance. Single-cell RNA/T cell receptor (TCR) sequencing revealed a specific loss and reduced clonal expansion of ST2hi VAT Treg subsets after Srebf2 deletion. Srebf2-mediated cholesterol homeostasis potentiated strong TCR signaling, which preferentially promoted ST2hi VAT Treg accumulation. However, long-term high-fat diet feeding disrupted VAT Treg cholesterol homeostasis and impaired clonal expansion of the ST2hi subset. Restoring Treg cholesterol homeostasis rescued VAT Treg accumulation in obese mice, suggesting that modulation of cholesterol homeostasis could be a promising strategy for Treg-targeted therapies in obesity-associated metabolic diseases.
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Affiliation(s)
- Cody Elkins
- Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA, USA
| | - Chengyu Ye
- Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA, USA
| | - Pulavendran Sivasami
- Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA, USA
| | - Roy Mulpur
- Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA, USA
| | - Pamela P. Diaz-Saldana
- Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA, USA
| | - Amy Peng
- Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA, USA
| | - Miaoer Xu
- Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA, USA
| | - Yeun-po Chiang
- Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA, USA
| | - Samara Moll
- Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA, USA
| | - Dormarie E. Rivera-Rodriguez
- Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA, USA
- Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA, USA
| | - Luisa Cervantes-Barragan
- Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA, USA
| | - Tuoqi Wu
- Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX, USA
- Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Byron B. Au-Yeung
- Division of Immunology, Lowance Center for Human Immunology, Department of Medicine, Emory University School of Medicine, Atlanta, GA, USA
| | - Christopher D. Scharer
- Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA, USA
| | - Mandy L. Ford
- Department of Surgery, Emory University School of Medicine, Atlanta, GA, USA
- Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA, USA
- Emory Transplant Center, Emory University School of Medicine, Atlanta, GA, USA
| | - Haydn Kissick
- Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA, USA
- Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA, USA
- Department of Urology, Emory University School of Medicine, Atlanta, GA, USA
| | - Chaoran Li
- Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA, USA
- Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA, USA
- Department of Dermatology, Emory University School of Medicine, Atlanta, GA, USA
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Dong SS, Duan YY, Zhu RJ, Jia YY, Chen JX, Huang XT, Tang SH, Yu K, Shi W, Chen XF, Jiang F, Hao RH, Liu Y, Liu Z, Guo Y, Yang TL. Systematic functional characterization of non-coding regulatory SNPs associated with central obesity. Am J Hum Genet 2025; 112:116-134. [PMID: 39753113 PMCID: PMC11739881 DOI: 10.1016/j.ajhg.2024.11.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2024] [Revised: 11/03/2024] [Accepted: 11/13/2024] [Indexed: 01/20/2025] Open
Abstract
Central obesity is associated with higher risk of developing a wide range of diseases independent of overall obesity. Genome-wide association studies (GWASs) have identified more than 300 susceptibility loci associated with central obesity. However, the functional understanding of these loci is limited by the fact that most loci are in non-coding regions. To address this issue, our study first prioritized 2,034 single-nucleotide polymorphisms (SNPs) based on fine-mapping and epigenomic annotation analysis. Subsequently, we employed self-transcribing active regulatory region sequencing (STARR-seq) to systematically evaluate the enhancer activity of these prioritized SNPs. The resulting data analysis identified 141 SNPs with allelic enhancer activity. Further analysis of allelic transcription factor (TF) binding prioritized 20 key TFs mediating the central-obesity-relevant genetic regulatory network. Finally, as an example, we illustrate the molecular mechanisms of how rs8079062 acts as an allele-specific enhancer to regulate the expression of its targeted RNF157. We also evaluated the role of RNF157 in the adipogenic differentiation process. In conclusion, our results provide an important resource for understanding the genetic regulatory mechanisms underlying central obesity.
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Affiliation(s)
- Shan-Shan Dong
- Key Laboratory of Biomedical Information Engineering of Ministry of Education, Key Laboratory of Biology Multiomics and Diseases in Shaanxi Province Higher Education Institutions, Biomedical Informatics & Genomics Center, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an 710049, Shaanxi, China
| | - Yuan-Yuan Duan
- Key Laboratory of Biomedical Information Engineering of Ministry of Education, Key Laboratory of Biology Multiomics and Diseases in Shaanxi Province Higher Education Institutions, Biomedical Informatics & Genomics Center, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an 710049, Shaanxi, China; Key Laboratory of Shaanxi Province for Craniofacial Precision Medicine Research, College of Stomatology, Xi'an Jiaotong University, Xi'an 710004, Shaanxi, China
| | - Ren-Jie Zhu
- Key Laboratory of Biomedical Information Engineering of Ministry of Education, Key Laboratory of Biology Multiomics and Diseases in Shaanxi Province Higher Education Institutions, Biomedical Informatics & Genomics Center, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an 710049, Shaanxi, China
| | - Ying-Ying Jia
- Key Laboratory of Biomedical Information Engineering of Ministry of Education, Key Laboratory of Biology Multiomics and Diseases in Shaanxi Province Higher Education Institutions, Biomedical Informatics & Genomics Center, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an 710049, Shaanxi, China
| | - Jia-Xin Chen
- Key Laboratory of Biomedical Information Engineering of Ministry of Education, Key Laboratory of Biology Multiomics and Diseases in Shaanxi Province Higher Education Institutions, Biomedical Informatics & Genomics Center, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an 710049, Shaanxi, China
| | - Xiao-Ting Huang
- Key Laboratory of Biomedical Information Engineering of Ministry of Education, Key Laboratory of Biology Multiomics and Diseases in Shaanxi Province Higher Education Institutions, Biomedical Informatics & Genomics Center, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an 710049, Shaanxi, China
| | - Shi-Hao Tang
- Key Laboratory of Biomedical Information Engineering of Ministry of Education, Key Laboratory of Biology Multiomics and Diseases in Shaanxi Province Higher Education Institutions, Biomedical Informatics & Genomics Center, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an 710049, Shaanxi, China
| | - Ke Yu
- Key Laboratory of Biomedical Information Engineering of Ministry of Education, Key Laboratory of Biology Multiomics and Diseases in Shaanxi Province Higher Education Institutions, Biomedical Informatics & Genomics Center, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an 710049, Shaanxi, China
| | - Wei Shi
- Key Laboratory of Biomedical Information Engineering of Ministry of Education, Key Laboratory of Biology Multiomics and Diseases in Shaanxi Province Higher Education Institutions, Biomedical Informatics & Genomics Center, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an 710049, Shaanxi, China
| | - Xiao-Feng Chen
- Key Laboratory of Biomedical Information Engineering of Ministry of Education, Key Laboratory of Biology Multiomics and Diseases in Shaanxi Province Higher Education Institutions, Biomedical Informatics & Genomics Center, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an 710049, Shaanxi, China
| | - Feng Jiang
- Key Laboratory of Biomedical Information Engineering of Ministry of Education, Key Laboratory of Biology Multiomics and Diseases in Shaanxi Province Higher Education Institutions, Biomedical Informatics & Genomics Center, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an 710049, Shaanxi, China
| | - Ruo-Han Hao
- Key Laboratory of Biomedical Information Engineering of Ministry of Education, Key Laboratory of Biology Multiomics and Diseases in Shaanxi Province Higher Education Institutions, Biomedical Informatics & Genomics Center, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an 710049, Shaanxi, China
| | - Yunlong Liu
- Department of Medical and Molecular Genetics, School of Medicine, Indiana University, Indianapolis, IN 46202, USA
| | - Zhongbo Liu
- Key Laboratory of Shaanxi Province for Craniofacial Precision Medicine Research, College of Stomatology, Xi'an Jiaotong University, Xi'an 710004, Shaanxi, China
| | - Yan Guo
- Key Laboratory of Biomedical Information Engineering of Ministry of Education, Key Laboratory of Biology Multiomics and Diseases in Shaanxi Province Higher Education Institutions, Biomedical Informatics & Genomics Center, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an 710049, Shaanxi, China.
| | - Tie-Lin Yang
- Key Laboratory of Biomedical Information Engineering of Ministry of Education, Key Laboratory of Biology Multiomics and Diseases in Shaanxi Province Higher Education Institutions, Biomedical Informatics & Genomics Center, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an 710049, Shaanxi, China.
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Zhang P, Watari K, Karin M. Innate immune cells link dietary cues to normal and abnormal metabolic regulation. Nat Immunol 2025; 26:29-41. [PMID: 39747429 PMCID: PMC12040443 DOI: 10.1038/s41590-024-02037-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2024] [Accepted: 10/24/2024] [Indexed: 01/04/2025]
Abstract
A slew of common metabolic disorders, including type 2 diabetes, metabolic dysfunction-associated steatotic liver disease and steatohepatitis, are exponentially increasing in our sedentary and overfed society. While macronutrients directly impact metabolism and bioenergetics, new evidence implicates immune cells as critical sensors of nutritional cues and important regulators of metabolic homeostasis. A deeper interrogation of the intricate and multipartite interactions between dietary components, immune cells and metabolically active tissues is needed for a better understanding of metabolic regulation and development of new treatments for common metabolic diseases. Responding to macronutrients and micronutrients, immune cells play pivotal roles in interorgan communication between the microbiota, small intestine, metabolically active cells including hepatocytes and adipocytes, and the brain, which controls feeding behavior and energy expenditure. This Review focuses on the response of myeloid cells and innate lymphocytes to dietary cues, their cross-regulatory interactions and roles in normal and aberrant metabolic control.
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Affiliation(s)
- Peng Zhang
- Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, School of Medicine, University of California, San Diego, La Jolla, CA, USA
| | - Kosuke Watari
- Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, School of Medicine, University of California, San Diego, La Jolla, CA, USA
| | - Michael Karin
- Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, School of Medicine, University of California, San Diego, La Jolla, CA, USA.
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Kowitt C, Zhang Q. Interleukin-33 and Obesity-Related Inflammation and Cancer. ENCYCLOPEDIA 2024; 4:1770-1789. [PMID: 40236667 PMCID: PMC11999627 DOI: 10.3390/encyclopedia4040117] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Indexed: 04/17/2025]
Abstract
Interleukin-33 (IL-33) is a cytokine belonging to the IL-1 family. It is primarily associated with type 2 immune responses. It interacts with a receptor complex on immune cells in reaction to tissue damage or cellular injury. IL-33 is crucial in immune responses and is involved in various autoimmune and inflammatory diseases. Obesity is marked by chronic inflammation and is a known risk factor for several types of cancer. Recent studies have shown that IL-33 and its receptor complex are expressed in adipose (fat) tissue, suggesting they may play a role in obesity. While inflammation connects obesity and cancer, it is not yet clear whether IL-33 contributes to cancer associated with obesity. Depending on the cellular context, inflammatory environment, expression levels, and bioactivity, IL-33 can exhibit both protumorigenic and antitumorigenic effects. This review will explore the various functions of IL-33 in the inflammation linked to obesity and its relationship with cancer.
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Affiliation(s)
- Cameron Kowitt
- Department of Structural & Cellular Biology, Tulane University School of Medicine, New Orleans, LA 70112, USA
- School of Public Health and Tropical Medicine, Tulane University, New Orleans, LA 70112, USA
| | - Qiuyang Zhang
- Department of Structural & Cellular Biology, Tulane University School of Medicine, New Orleans, LA 70112, USA
- Tulane Center for Aging, Tulane University School of Medicine, New Orleans, LA 70112, USA
- Tulane Cancer Center, Tulane University School of Medicine, New Orleans, LA 70112, USA
- Louisiana Cancer Research Center, New Orleans, LA 70112, USA
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Liao J, Zhu Y, Zhang A, Wu D, Yan X, He Q, Song F, Chen J, Li Y, Li L, Chen Z, Li W, Yang Q, Fang Z, Wu M. Association Apo B/Apo a-1 Ratio and Prognostic Nutritional Index with 90-Day Outcomes of Acute Ischemic Stroke. Diabetes Metab Syndr Obes 2024; 17:3009-3018. [PMID: 39155912 PMCID: PMC11330243 DOI: 10.2147/dmso.s473385] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/11/2024] [Accepted: 08/08/2024] [Indexed: 08/20/2024] Open
Abstract
Background The relationship between insulin resistance-related indices and the outcomes of acute ischemic stroke (AIS) is still unclear. This study aimed to explore the association between the Apo B/Apo A-1 ratio and the Prognostic Nutritional Index (PNI) with the 90-day outcomes of AIS. Methods A total of 2011 AIS patients with a 3-month follow-up were enrolled in the present study from January 2017 to July 2021. Multivariate logistic regression modeling was performed to analyze the relationship between Apo B/Apo A-1 ratio, PNI, and AIS poor outcomes. The mediating effect between the three was analyzed using the Bootstrap method with PNI as the mediating variable. Results Among the 2011 included AIS patients, 20.3% had a poor outcome. Patients were categorized according to quartiles of Apo B/Apo A-1 ratio and PNI. Multivariate logistic regression revealed that the fourth Apo B/Apo A-1 ratio quartile had poorer outcomes than the first quartile (OR 1.75,95%CL 1.21-2.53, P=0.003), and the fourth PNI quartile exhibited a lower risk of poor outcomes than the first quartile (OR 0.40, 95%CL 0.27-0.61, P<0.001). PNI displayed a significant partially mediating effect (21.4%) between the Apo B/Apo A-1 ratio and poor AIS outcomes. Conclusion The Apo B/Apo A-1 ratio is a risk factor for poor AIS outcomes, whereas PNI acts as a protective factor. The association between the ApoB/ApoA-1 ratio and poor AIS outcomes was partially mediated by PNI.
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Affiliation(s)
- Junqi Liao
- Department of Neurology, Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinese Medicine, Nanjing, 210029, People’s Republic of China
| | - Yuan Zhu
- Department of Neurology, Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinese Medicine, Nanjing, 210029, People’s Republic of China
- Department of Medicine, Physiology and Biophysics, UC Irvine Diabetes Center, University of California Irvine (UCI), Irvine, CA, USA
| | - Aimei Zhang
- Department of Neurology, Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinese Medicine, Nanjing, 210029, People’s Republic of China
| | - Dan Wu
- Department of Neurology, Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinese Medicine, Nanjing, 210029, People’s Republic of China
| | - Xiaohui Yan
- Department of Neurology, Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinese Medicine, Nanjing, 210029, People’s Republic of China
| | - Qiuhua He
- Department of Neurology, Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinese Medicine, Nanjing, 210029, People’s Republic of China
| | - Fantao Song
- Department of Neurology, Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinese Medicine, Nanjing, 210029, People’s Republic of China
| | - Jingyi Chen
- Department of Neurology, Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinese Medicine, Nanjing, 210029, People’s Republic of China
| | - Yunze Li
- Department of Neurology, Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinese Medicine, Nanjing, 210029, People’s Republic of China
| | - Li Li
- Department of Neurology, Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinese Medicine, Nanjing, 210029, People’s Republic of China
| | - Zhaoyao Chen
- Department of Neurology, Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinese Medicine, Nanjing, 210029, People’s Republic of China
| | - Wenlei Li
- Department of Neurology, Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinese Medicine, Nanjing, 210029, People’s Republic of China
| | - Qin Yang
- Department of Medicine, Physiology and Biophysics, UC Irvine Diabetes Center, University of California Irvine (UCI), Irvine, CA, USA
| | - Zhuyuan Fang
- Department of Cardiology, Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinese Medicine, Nanjing, 210029, People’s Republic of China
| | - Minghua Wu
- Department of Neurology, Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinese Medicine, Nanjing, 210029, People’s Republic of China
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Staller DW, Bennett RG, Mahato RI. Therapeutic perspectives on PDE4B inhibition in adipose tissue dysfunction and chronic liver injury. Expert Opin Ther Targets 2024; 28:545-573. [PMID: 38878273 PMCID: PMC11305103 DOI: 10.1080/14728222.2024.2369590] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2024] [Accepted: 06/14/2024] [Indexed: 06/20/2024]
Abstract
INTRODUCTION Chronic liver disease (CLD) is a complex disease associated with profound dysfunction. Despite an incredible burden, the first and only pharmacotherapy for metabolic-associated steatohepatitis was only approved in March of this year, indicating a gap in the translation of preclinical studies. There is a body of preclinical work on the application of phosphodiesterase 4 inhibitors in CLD, none of these molecules have been successfully translated into clinical use. AREAS COVERED To design therapies to combat CLD, it is essential to consider the dysregulation of other tissues that contribute to its development and progression. As such, proper therapies must combat this throughout the body rather than focusing only on the liver. To detail this, literature characterizing the pathogenesis of CLD was pulled from PubMed, with a particular focus placed on the role of PDE4 in inflammation and metabolism. Then, the focus is shifted to detailing the available information on existing PDE4 inhibitors. EXPERT OPINION This review gives a brief overview of some of the pathologies of organ systems that are distinct from the liver but contribute to disease progression. The demonstrated efficacy of PDE4 inhibitors in other human inflammatory diseases should earn them further examination for the treatment of CLD.
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Affiliation(s)
- Dalton W. Staller
- Department of Cellular & Integrative Physiology, University of Nebraska Medical Center, Omaha, NE, USA
| | - Robert G. Bennett
- Department of Internal Medicine, Division of Diabetes Endocrinology and Metabolism, University of Nebraska Medical Center, Omaha, NE, USA
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA
- VA Nebraska-Western Iowa Health Care System, Omaha, NE, USA
| | - Ram I. Mahato
- Department of Cellular & Integrative Physiology, University of Nebraska Medical Center, Omaha, NE, USA
- Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE, USA
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Elkins C, Li C. Deciphering visceral adipose tissue regulatory T cells: Key contributors to metabolic health. Immunol Rev 2024; 324:52-67. [PMID: 38666618 PMCID: PMC11262988 DOI: 10.1111/imr.13336] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/23/2024]
Abstract
Regulatory T cells (Tregs) within the visceral adipose tissue (VAT) play a crucial role in controlling tissue inflammation and maintaining metabolic health. VAT Tregs display a unique transcriptional profile and T cell receptor (TCR) repertoire, and closely interact with adipocytes, stromal cells, and other immune components within the local VAT microenvironment. However, in the context of obesity, there is a notable decline in VAT Tregs, resulting in heightened VAT inflammation and insulin resistance. A comprehensive understanding of the biology of VAT Tregs is essential for the development of Treg-based therapies for mitigating obesity-associated metabolic diseases. Recent advancements in lineage tracing tools, genetic mouse models, and various single cell "omics" techniques have significantly progressed our understandings of the origin, differentiation, and regulation of this unique VAT Treg population at steady state and during obesity. The identification of VAT-Treg precursor cells in the secondary lymphoid organs has also provided important insights into the timing, location, and mechanisms through which VAT Tregs acquire their distinctive phenotype that enables them to function within a lipid-rich microenvironment. In this review, we highlight key recent breakthroughs in the VAT-Treg field while discussing pivotal questions that remain unanswered.
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Affiliation(s)
- Cody Elkins
- Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA, USA
| | - Chaoran Li
- Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA, USA
- Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA, USA
- Department of Dermatology, Emory University School of Medicine, Atlanta, GA, USA
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Wang G, Muñoz-Rojas AR, Spallanzani RG, Franklin RA, Benoist C, Mathis D. Adipose-tissue Treg cells restrain differentiation of stromal adipocyte precursors to promote insulin sensitivity and metabolic homeostasis. Immunity 2024; 57:1345-1359.e5. [PMID: 38692280 PMCID: PMC11188921 DOI: 10.1016/j.immuni.2024.04.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2023] [Revised: 02/08/2024] [Accepted: 04/04/2024] [Indexed: 05/03/2024]
Abstract
Regulatory T (Treg) cells in epidydimal visceral adipose tissue (eVAT) of lean mice and humans regulate metabolic homeostasis. We found that constitutive or punctual depletion of eVAT-Treg cells reined in the differentiation of stromal adipocyte precursors. Co-culture of these precursors with conditional medium from eVAT-Treg cells limited their differentiation in vitro, suggesting a direct effect. Transcriptional comparison of adipocyte precursors, matured in the presence or absence of the eVAT-Treg-conditioned medium, identified the oncostatin-M (OSM) signaling pathway as a key distinction. Addition of OSM to in vitro cultures blocked the differentiation of adipocyte precursors, while co-addition of anti-OSM antibodies reversed the ability of the eVAT-Treg-conditioned medium to inhibit in vitro adipogenesis. Genetic depletion of OSM (specifically in Treg) cells or of the OSM receptor (specifically on stromal cells) strongly impaired insulin sensitivity and related metabolic indices. Thus, Treg-cell-mediated control of local progenitor cells maintains adipose tissue and metabolic homeostasis, a regulatory axis seemingly conserved in humans.
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Affiliation(s)
- Gang Wang
- Department of Immunology, Harvard Medical School, Boston, MA, USA
| | | | | | - Ruth A Franklin
- Department of Immunology, Harvard Medical School, Boston, MA, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA
| | | | - Diane Mathis
- Department of Immunology, Harvard Medical School, Boston, MA, USA.
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Xu D, Zhuang S, Chen H, Jiang M, Jiang P, Wang Q, Wang X, Chen R, Tang H, Tang L. IL-33 regulates adipogenesis via Wnt/β-catenin/PPAR-γ signaling pathway in preadipocytes. J Transl Med 2024; 22:363. [PMID: 38632591 PMCID: PMC11022325 DOI: 10.1186/s12967-024-05180-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2023] [Accepted: 04/05/2024] [Indexed: 04/19/2024] Open
Abstract
Interleukin-33 (IL-33), an emerging cytokine within the IL-1 family, assumes a pivotal function in the control of obesity. However, the specific mechanism of its regulation of obesity formation remains unclear. In this study, we found that the expression level of IL-33 increased in visceral adipose tissue in mice fed with a high-fat diet (HFD) compared with that in mice fed with a normal diet (ND). In vitro, we also found the expression level of IL-33 was upregulated during the adipogenesis of 3T3-L1 cells. Functional test results showed that knockdown of IL-33 in 3T3-L1 cells differentiation could promote the accumulation of lipid droplets, the content of triglyceride and the expression of adipogenic-related genes (i.e. PPAR-γ, C/EBPα, FABP4, LPL, Adipoq and CD36). In contrast, overexpression of IL-33 inhibits adipogenic differentiation. Meanwhile, the above tests were repeated after over-differentiation of 3T3-L1 cells induced by oleic acid, and the results showed that IL-33 played a more significant role in the regulation of adipogenesis. To explore the mechanism, transcriptome sequencing was performed and results showed that IL-33 regulated the PPAR signaling pathway in 3T3-L1 cells. Further, Western blot and confocal microscopy showed that the inhibition of IL-33 could promote PPAR-γ expression by inhibiting the Wnt/β-catenin signal in 3T3-L1 cells. This study demonstrated that IL-33 was an important regulator of preadipocyte differentiation and inhibited adipogenesis by regulating the Wnt/β-catenin/PPAR-γ signaling pathway, which provided a new insight for further research on IL-33 as a new intervention target for metabolic disorders.
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Affiliation(s)
- Danning Xu
- Department of Laboratory Medicine, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Siqi Zhuang
- Department of Laboratory Medicine, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Hongzhi Chen
- National Clinical Research Center for Metabolic Disease, Key Laboratory of Diabetes Immunology, Ministry of Education, Metabolic Syndrome Research Center, and Department of Metabolism & Endocrinology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Mengjie Jiang
- Department of Laboratory Medicine, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Ping Jiang
- Department of Laboratory Medicine, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Qian Wang
- Department of Laboratory Medicine, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Xuemei Wang
- Department of Laboratory Medicine, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Ruohong Chen
- Department of Laboratory Medicine, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Haoneng Tang
- Department of Laboratory Medicine, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China.
| | - Lingli Tang
- Department of Laboratory Medicine, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China.
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Joldrichsen MR, Kim E, Steiner HE, Jeong YJ, Premanandan C, Hsueh W, Ziouzenkova O, Cormet-Boyaka E, Boyaka PN. Loss of Paneth cells dysregulates gut ILC subsets and enhances weight gain response to high fat diet in a mouse model. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.03.29.587349. [PMID: 38617293 PMCID: PMC11014498 DOI: 10.1101/2024.03.29.587349] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/16/2024]
Abstract
Obesity has been associated with dysbiosis, but innate mechanisms linking intestinal epithelial cell subsets and obesity remain poorly understood. Using mice lacking Paneth cells (Sox9 ΔIEC mice), small intestinal epithelial cells specialized in the production of antimicrobial products and cytokines, we show that dysbiosis alone does not induce obesity or metabolic disorders. Loss of Paneth cells reduced ILC3 and increased ILC2 numbers in the intestinal lamina propria. High-fat diet (HFD) induced higher weight gain and more severe metabolic disorders in Sox9 ΔIEC mice. Further, HFD enhances the number of ILC1 in the intestinal lamina propria of Sox9 ΔIEC mice and increases intestinal permeability and the accumulation of immune cells (inflammatory macrophages and T cells, and B cells) in abdominal fat tissues of obese Sox9 ΔIEC . Transplantation of fecal materials from Sox9 ΔIEC mice in germ-free mice before HFD further confirmed the regulatory role of Paneth cells for gut ILC subsets and the development of obesity.
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11
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Soedono S, Sharlene S, Vo DHN, Averia M, Rosalie EE, Lee YK, Cho KW. Obese visceral adipose dendritic cells downregulate regulatory T cell development through IL-33. Front Immunol 2024; 15:1335651. [PMID: 38566998 PMCID: PMC10985834 DOI: 10.3389/fimmu.2024.1335651] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2023] [Accepted: 03/08/2024] [Indexed: 04/04/2024] Open
Abstract
Regulatory T cells (Tregs) residing in visceral adipose tissue (VAT) play a pivotal role in regulating tissue inflammation and metabolic dysfunction associated with obesity. However, the specific phenotypic and functional characteristics of Tregs in obese VAT, as well as the regulatory mechanisms shaping them, remain elusive. This study demonstrates that obesity selectively reduces Tregs in VAT, characterized by restrained proliferation, heightened PD-1 expression, and diminished ST2 expression. Additionally, obese VAT displays distinctive maturation of dendritic cells (DCs), marked by elevated expressions of MHC-II, CD86, and PD-L1, which are inversely correlated with VAT Tregs. In an in vitro co-culture experiment, only obese VAT DCs, not macrophages or DCs from subcutaneous adipose tissue (SAT) and spleen, result in decreased Treg differentiation and proliferation. Furthermore, Tregs differentiated by obese VAT DCs exhibit distinct characteristics resembling those of Tregs in obese VAT, such as reduced ST2 and IL-10 expression. Mechanistically, obesity lowers IL-33 production in VAT DCs, contributing to the diminished Treg differentiation. These findings collectively underscore the critical role of VAT DCs in modulating Treg generation and shaping Treg phenotype and function during obesity, potentially contributing to the regulation of VAT Treg populations.
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Affiliation(s)
- Shindy Soedono
- Department of Integrated Biomedical Science, Soonchunhyang University, Cheonan, Republic of Korea
- Soonchunhyang Institute of Medi-bio Science (SIMS), Soonchunhyang University, Cheonan, Republic of Korea
| | - Sharlene Sharlene
- Department of Integrated Biomedical Science, Soonchunhyang University, Cheonan, Republic of Korea
- Soonchunhyang Institute of Medi-bio Science (SIMS), Soonchunhyang University, Cheonan, Republic of Korea
| | - Dan Hoang Nguyet Vo
- Department of Integrated Biomedical Science, Soonchunhyang University, Cheonan, Republic of Korea
- Soonchunhyang Institute of Medi-bio Science (SIMS), Soonchunhyang University, Cheonan, Republic of Korea
| | - Maria Averia
- Magister of Biotechnology, Atma Jaya Catholic University of Indonesia, Jakarta, Indonesia
| | - Eufrasia Elaine Rosalie
- Faculty of Biotechnology, Department of Food Technology, Atma Jaya Catholic University of Indonesia, Jakarta, Indonesia
| | - Yun Kyung Lee
- Department of Integrated Biomedical Science, Soonchunhyang University, Cheonan, Republic of Korea
- Soonchunhyang Institute of Medi-bio Science (SIMS), Soonchunhyang University, Cheonan, Republic of Korea
| | - Kae Won Cho
- Department of Integrated Biomedical Science, Soonchunhyang University, Cheonan, Republic of Korea
- Soonchunhyang Institute of Medi-bio Science (SIMS), Soonchunhyang University, Cheonan, Republic of Korea
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Xiao HH, Zhang FR, Li S, Guo FF, Hou JL, Wang SC, Yu J, Li XY, Yang HJ. Xinshubao tablet rescues cognitive dysfunction in a mouse model of vascular dementia: Involvement of neurogenesis and neuroinflammation. Biomed Pharmacother 2024; 172:116219. [PMID: 38310654 DOI: 10.1016/j.biopha.2024.116219] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2023] [Revised: 01/24/2024] [Accepted: 01/25/2024] [Indexed: 02/06/2024] Open
Abstract
Vascular dementia (VaD) represents a severe cognitive dysfunction syndrome closed linked to cardiovascular function. In the present study, we assessed the potential of Xinshubao tablet (XSB), a traditional Chinese prescription widely used for cardiovascular diseases, to mitigate neuropathological damage in a mouse model of VaD and elucidated the underlying mechanisms. Our findings revealed that oral administration of XSB rescued the cardiac dysfunction resulting from bilateral common carotid artery stenosis (BCAS), improved the cerebral blood flow (CBF) and cognitive function, reduced white matter injury, inhibited excessive microglial and astrocytic activation, stimulated hippocampal neurogenesis, and reduced neural apoptosis in the brains of BCAS mice. Mechanistically, RNA-seq analysis indicated that XSB treatment was significantly associated with neuroinflammation, vasculature development, and synaptic transmission, which were further confirmed by q-PCR assays. Western blot results revealed that XSB treatment hindered the nuclear translocation of nuclear factor-κB (NF-κB), thereby suppressing the NF-κB signaling pathway. These results collectively demonstrated that XSB could ameliorate cognitive dysfunction caused by BCAS through regulating CBF, reducing white matter lesions, suppressing glial activation, promoting neurogenesis, and mitigating neuroinflammation. Notably, the NF-κB signaling pathway emerged as a pivotal player in this mechanism.
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Affiliation(s)
- Hong-He Xiao
- Beijing Key Laboratory of Traditional Chinese Medicine Basic Research on Prevention and Treatment for Major Diseases, Experimental Research Center, China Academy of Chinese Medical Sciences, Beijing 100700, China; School of Pharmacy, Liaoning University of Traditional Chinese Medicine, Dalian 116600, China; Fujian Pien Tze Huang Enterprise Key Laboratory of Natural Medicine Research and Development, Zhangzhou Pien Tze Huang Pharmaceutical Co., Ltd., Zhangzhou, Fujian Province 363099, China
| | - Feng-Rong Zhang
- Beijing Key Laboratory of Traditional Chinese Medicine Basic Research on Prevention and Treatment for Major Diseases, Experimental Research Center, China Academy of Chinese Medical Sciences, Beijing 100700, China; Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China
| | - Sen Li
- Beijing Key Laboratory of Traditional Chinese Medicine Basic Research on Prevention and Treatment for Major Diseases, Experimental Research Center, China Academy of Chinese Medical Sciences, Beijing 100700, China
| | - Fei-Fei Guo
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China
| | - Jin-Li Hou
- Beijing Key Laboratory of Traditional Chinese Medicine Basic Research on Prevention and Treatment for Major Diseases, Experimental Research Center, China Academy of Chinese Medical Sciences, Beijing 100700, China
| | - Shi-Cong Wang
- Fujian Pien Tze Huang Enterprise Key Laboratory of Natural Medicine Research and Development, Zhangzhou Pien Tze Huang Pharmaceutical Co., Ltd., Zhangzhou, Fujian Province 363099, China
| | - Juan Yu
- Fujian Pien Tze Huang Enterprise Key Laboratory of Natural Medicine Research and Development, Zhangzhou Pien Tze Huang Pharmaceutical Co., Ltd., Zhangzhou, Fujian Province 363099, China.
| | - Xian-Yu Li
- Beijing Key Laboratory of Traditional Chinese Medicine Basic Research on Prevention and Treatment for Major Diseases, Experimental Research Center, China Academy of Chinese Medical Sciences, Beijing 100700, China.
| | - Hong-Jun Yang
- Beijing Key Laboratory of Traditional Chinese Medicine Basic Research on Prevention and Treatment for Major Diseases, Experimental Research Center, China Academy of Chinese Medical Sciences, Beijing 100700, China; China Academy of Chinese Medical Sciences, Beijing 100700, China.
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13
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Dong L, Gao J, Yu L, Liu S, Zhao Y, Zhang W, Liang Y, Wang H. Polarized Th2 cells attenuate high-fat-diet induced obesity through the suppression of lipogenesis. BMC Immunol 2024; 25:4. [PMID: 38195424 PMCID: PMC10777604 DOI: 10.1186/s12865-024-00598-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2022] [Accepted: 01/03/2024] [Indexed: 01/11/2024] Open
Abstract
Immune cells, such as macrophages, B cells, neutrophils and T cell subsets, have been implicated in the context of obesity. However, the specific role of Th2 cells in adipose tissue function has remained elusive. Eight-week-old male CD3ε─/─ mice were randomly divided into two groups (≥ 5 mice per group): one received intravenous injection of Th2 cells isolated from LATY136F mice, while the other receiving PBS as a control. Both of groups were subjected to a high-fat diet (HFD). The adoptive transfer of polarized Th2 cells led to a significant reduction in obesity following a HFD. This reduction was accompanied by improvements in hepatic steatosis, glucose intolerance, and insulin resistance. Mechanistically, Th2 cell treatment promoted oxidative phosphorylation of adipocytes, thereby contributing to a reduction of lipid droplet accumulation. These findings suggest that Th2 cell therapy represents a novel approach for treating diet-induced obesity and other diseases involving lipid droplet accumulation disorders.
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Affiliation(s)
- Lijun Dong
- Henan Key Laboratory of Immunology and Targeted Drug, School of Laboratory Medicine, Xinxiang Medical University, Henan Province, Xinxiang, 453003, PR China
- Division of Vascular and Interventional Radiology, Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, Guangdong, China
| | - Jingtao Gao
- Henan Key Laboratory of Immunology and Targeted Drug, School of Laboratory Medicine, Xinxiang Medical University, Henan Province, Xinxiang, 453003, PR China
| | - Lu Yu
- Henan Key Laboratory of Immunology and Targeted Drug, School of Laboratory Medicine, Xinxiang Medical University, Henan Province, Xinxiang, 453003, PR China
| | - Shibo Liu
- Henan Key Laboratory of Immunology and Targeted Drug, School of Laboratory Medicine, Xinxiang Medical University, Henan Province, Xinxiang, 453003, PR China
| | - Yuxin Zhao
- Department of Immunology, Xinjiang Medical University, Urumqi, PR China
| | - Wen Zhang
- Henan Key Laboratory of Immunology and Targeted Drug, School of Laboratory Medicine, Xinxiang Medical University, Henan Province, Xinxiang, 453003, PR China
| | - Yinming Liang
- Henan Key Laboratory of Immunology and Targeted Drug, School of Laboratory Medicine, Xinxiang Medical University, Henan Province, Xinxiang, 453003, PR China
- Henan Collaborative Innovation Center of Molecular Diagnosis and Laboratory Medicine, Xinxiang Medical University, Xinxiang, PR China
| | - Hui Wang
- Henan Key Laboratory of Immunology and Targeted Drug, School of Laboratory Medicine, Xinxiang Medical University, Henan Province, Xinxiang, 453003, PR China.
- Henan Collaborative Innovation Center of Molecular Diagnosis and Laboratory Medicine, Xinxiang Medical University, Xinxiang, PR China.
- Department of Immunology, Xinjiang Medical University, Urumqi, PR China.
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14
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Xourafa G, Korbmacher M, Roden M. Inter-organ crosstalk during development and progression of type 2 diabetes mellitus. Nat Rev Endocrinol 2024; 20:27-49. [PMID: 37845351 DOI: 10.1038/s41574-023-00898-1] [Citation(s) in RCA: 74] [Impact Index Per Article: 74.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 08/29/2023] [Indexed: 10/18/2023]
Abstract
Type 2 diabetes mellitus (T2DM) is characterized by tissue-specific insulin resistance and pancreatic β-cell dysfunction, which result from the interplay of local abnormalities within different tissues and systemic dysregulation of tissue crosstalk. The main local mechanisms comprise metabolic (lipid) signalling, altered mitochondrial metabolism with oxidative stress, endoplasmic reticulum stress and local inflammation. While the role of endocrine dysregulation in T2DM pathogenesis is well established, other forms of inter-organ crosstalk deserve closer investigation to better understand the multifactorial transition from normoglycaemia to hyperglycaemia. This narrative Review addresses the impact of certain tissue-specific messenger systems, such as metabolites, peptides and proteins and microRNAs, their secretion patterns and possible alternative transport mechanisms, such as extracellular vesicles (exosomes). The focus is on the effects of these messengers on distant organs during the development of T2DM and progression to its complications. Starting from the adipose tissue as a major organ relevant to T2DM pathophysiology, the discussion is expanded to other key tissues, such as skeletal muscle, liver, the endocrine pancreas and the intestine. Subsequently, this Review also sheds light on the potential of multimarker panels derived from these biomarkers and related multi-omics for the prediction of risk and progression of T2DM, novel diabetes mellitus subtypes and/or endotypes and T2DM-related complications.
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Affiliation(s)
- Georgia Xourafa
- Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany
- German Center for Diabetes Research, Partner Düsseldorf, München-Neuherberg, Düsseldorf, Germany
| | - Melis Korbmacher
- Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany
- German Center for Diabetes Research, Partner Düsseldorf, München-Neuherberg, Düsseldorf, Germany
| | - Michael Roden
- Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany.
- German Center for Diabetes Research, Partner Düsseldorf, München-Neuherberg, Düsseldorf, Germany.
- Department of Endocrinology and Diabetology, Medical Faculty and University Hospital Düsseldorf, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany.
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15
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Qi X, Li Z, Han J, Liu W, Xia P, Cai X, Liu X, Liu X, Zhang J, Yu P. Multifaceted roles of T cells in obesity and obesity-related complications: A narrative review. Obes Rev 2023; 24:e13621. [PMID: 37583087 DOI: 10.1111/obr.13621] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2022] [Revised: 03/18/2023] [Accepted: 07/19/2023] [Indexed: 08/17/2023]
Abstract
Obesity is characterized by chronic low-grade inflammatory responses in the adipose tissue, accompanied by pronounced insulin resistance and metabolic anomalies. It affects almost all body organs and eventually leads to diseases such as fatty liver disease, type 2 diabetes mellitus, and atherosclerosis. Recently, T cells have emerged as interesting therapeutic targets because the dysfunction of T cells and their cytokines in the adipose tissue is implicated in obesity-induced inflammation and their complicated onset. Although several recent narrative reviews have provided a brief overview of related evidence in this area, they have mainly focused on either obesity-associated T cell metabolism or modulation of T cell activation in obesity. Moreover, at present, no published review has reported on the multifaceted roles of T cells in obesity and obesity-related complications, even though there has been a significant increase in studies on this topic since 2019. Therefore, this narrative review aims to comprehensively summarize current advances in the mechanistic roles of T cells in the development of obesity and its related complications. Further, we aim to discuss relevant drugs for weight loss as well as the contradictory role of T cells in the same disease so as to highlight key findings regarding this topic and provide a valid basis for future treatment strategies.
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Affiliation(s)
- Xinrui Qi
- The Second Clinical Medical College of Nanchang University, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
- Queen Mary School, Nanchang University, Nanchang, Jiangxi, China
| | - Zhangwang Li
- The Second Clinical Medical College of Nanchang University, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Jiashu Han
- MD Program, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Wenqing Liu
- Queen Mary School, Nanchang University, Nanchang, Jiangxi, China
| | - Panpan Xia
- Department of Endocrinology and Metabolism, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Xia Cai
- Department of Endocrinology and Metabolism, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Xiao Liu
- Department of Cardiology, The Second Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Xu Liu
- Department of Neurology, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Jing Zhang
- Department of Anesthesiology, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Peng Yu
- Department of Endocrinology and Metabolism, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
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16
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Maidana D, Bonanad C, Ortiz-Cortés C, Arroyo-Álvarez A, Barreres-Martín G, Muñoz-Alfonso C, Maicas-Alcaine E, García-Pérez C, Aparici-Redal A, Freitas-Durks V, Esteban-Fernández A. Sex-Related Differences in Heart Failure Diagnosis. Curr Heart Fail Rep 2023; 20:254-262. [PMID: 37310594 DOI: 10.1007/s11897-023-00609-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 05/10/2023] [Indexed: 06/14/2023]
Abstract
PURPOSE OF REVIEW The literature on the importance of sex in heart failure diagnosis is scarce. This review aims to summarize current knowledge on sex differences regarding the diagnosis of heart failure. RECENT FINDINGS Comorbidities are frequent in patients with heart failure, and their prevalence differs between sexes; some differences in symptomatology and diagnostic imaging techniques were also found. Biomarkers also usually show differences between sexes but are not significant enough to establish sex-specific ranges. This article outlines current information related to sex differences in HF diagnosis. Research in this field remains to be done. Maintaining a high diagnostic suspicion, actively searching for the disease, and considering the sex is relevant for early diagnosis and better prognosis. In addition, more studies with equal representation are needed.
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Affiliation(s)
- Daniela Maidana
- INCLIVA Biomedical Research Institute, 46010, Valencia, Spain
| | - Clara Bonanad
- INCLIVA Biomedical Research Institute, 46010, Valencia, Spain.
- Cardiology Department, Clinic University Hospital of Valencia, 46010, Valencia, Spain.
- University of Valencia, Valencia, Spain.
| | | | | | | | | | | | | | | | | | - Alberto Esteban-Fernández
- University of Valencia, Valencia, Spain
- Cardiology Department, University Hospital Severo Ochoa, 28911, Leganés, Madrid, Spain
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17
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Ni H, Chen Y. Differentiation, regulation and function of regulatory T cells in non-lymphoid tissues and tumors. Int Immunopharmacol 2023; 121:110429. [PMID: 37327512 DOI: 10.1016/j.intimp.2023.110429] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2023] [Revised: 05/22/2023] [Accepted: 05/30/2023] [Indexed: 06/18/2023]
Abstract
Regulatory T cells (Tregs) play a substantial role in inhibiting excessive immune response. A large number of studies have focused on the tissue homeostasis maintenance and remodeling characteristics of Tregs in non-lymphoid tissues, such as the skin, colon, lung, brain, muscle, and adipose tissues. Herein, we overview the kinetics of Treg migration to non-lymphoid tissues and adaptation to the specific tissue microenvironment through the development of tissue-specific chemokine receptors, transcription factors, and phenotypes. Additionally, tumor-infiltrating Tregs (Ti-Tregs) play an important role in tumor generation and immunotherapy resistance. The phenotypes of Ti-Tregs are related to the histological location of the tumor and there is a large overlap between the transcripts of Ti-Tregs and those of tissue-specific Tregs. We recapitulate the molecular underpinnings of tissue-specific Tregs, which might shed new light on Treg-based therapeutic targets and biomarkers for inflammatory diseases and cancer.
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Affiliation(s)
- Hongbo Ni
- The First Clinical Medicine Faculty, China Medical University, Shenyang 110001, China
| | - Yinghan Chen
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang 110001, China.
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18
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Patrick MT, Nair RP, He K, Stuart PE, Billi AC, Zhou X, Gudjonsson JE, Oksenberg JR, Elder JT, Tsoi LC. Shared Genetic Risk Factors for Multiple Sclerosis/Psoriasis Suggest Involvement of Interleukin-17 and Janus Kinase-Signal Transducers and Activators of Transcription Signaling. Ann Neurol 2023; 94:384-397. [PMID: 37127916 PMCID: PMC10524664 DOI: 10.1002/ana.26672] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2022] [Revised: 04/24/2023] [Accepted: 04/27/2023] [Indexed: 05/03/2023]
Abstract
OBJECTIVE Psoriasis and multiple sclerosis (MS) are complex immune diseases that are mediated by T cells and share multiple comorbidities. Previous studies have suggested psoriatic patients are at higher risk of MS; however, causal relationships between the two conditions remain unclear. Through epidemiology and genetics, we provide a comprehensive understanding of the relationship, and share molecular factors between psoriasis and MS. METHODS We used logistic regression, trans-disease meta-analysis and Mendelian randomization. Medical claims data were included from 30 million patients, including 141,544 with MS and 742,919 with psoriasis. We used genome-wide association study summary statistics from 11,024 psoriatic, 14,802 MS cases, and 43,039 controls for trans-disease meta-analysis, with additional summary statistics from 5 million individuals for Mendelian randomization. RESULTS Psoriatic patients have a significantly higher risk of MS (4,637 patients with both diseases; odds ratio [OR] 1.07, p = 1.2 × 10-5 ) after controlling for potential confounders. Using inverse variance and equally weighted trans-disease meta-analysis, we revealed >20 shared and opposing (direction of effect) genetic loci outside the major histocompatibility complex that showed significant genetic colocalization (in COLOC and COLOC-SuSiE v5.1.0). Co-expression analysis of genes from these loci further identified distinct clusters that were enriched among pathways for interleukin-17/tumor necrosis factor-α (OR >39, p < 1.6 × 10-3 ) and Janus kinase-signal transducers and activators of transcription (OR 35, p = 1.1 × 10-5 ), including genes, such as TNFAIP3, TYK2, and TNFRSF1A. Mendelian randomization found psoriasis as an exposure has a significant causal effect on MS (OR 1.04, p = 5.8 × 10-3 ), independent of type 1 diabetes (OR 1.05, p = 4.3 × 10-7 ), type 2 diabetes (OR 1.08, p = 2.3 × 10-3 ), inflammatory bowel disease (OR 1.11, p = 1.6 × 10-11 ), and vitamin D level (OR 0.75, p = 9.4 × 10-3 ). INTERPRETATION By investigating the shared genetics of psoriasis and MS, along with their modifiable risk factors, our findings will advance innovations in treatment for patients suffering from comorbidities. ANN NEUROL 2023;94:384-397.
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Affiliation(s)
- Matthew T. Patrick
- Department of Dermatology, University of Michigan Medical School, Ann Arbor, Michigan, United States of America
| | - Rajan P. Nair
- Department of Dermatology, University of Michigan Medical School, Ann Arbor, Michigan, United States of America
| | - Kevin He
- Department of Biostatistics, Center for Statistical Genetics, University of Michigan, Ann Arbor, Michigan, United States of America
| | - Philip E. Stuart
- Department of Dermatology, University of Michigan Medical School, Ann Arbor, Michigan, United States of America
| | - Allison C. Billi
- Department of Dermatology, University of Michigan Medical School, Ann Arbor, Michigan, United States of America
| | - Xiang Zhou
- Department of Biostatistics, Center for Statistical Genetics, University of Michigan, Ann Arbor, Michigan, United States of America
| | - Johann E. Gudjonsson
- Department of Dermatology, University of Michigan Medical School, Ann Arbor, Michigan, United States of America
| | - Jorge R. Oksenberg
- Department of Neurology, University of California, San Francisco, California, United States of America
| | - James T. Elder
- Department of Dermatology, University of Michigan Medical School, Ann Arbor, Michigan, United States of America
| | - Lam C. Tsoi
- Department of Dermatology, University of Michigan Medical School, Ann Arbor, Michigan, United States of America
- Department of Biostatistics, Center for Statistical Genetics, University of Michigan, Ann Arbor, Michigan, United States of America
- Department of Computational Medicine & Bioinformatics, University of Michigan, Ann Arbor, Michigan, United States of America
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Abstract
When discovered in the early 2000s, interleukin-33 (IL-33) was characterized as a potent driver of type 2 immunity and implicated in parasite clearance, as well as asthma, allergy, and lung fibrosis. Yet research in other models has since revealed that IL-33 is a highly pleiotropic molecule with diverse functions. These activities are supported by elusive release mechanisms and diverse expression of the IL-33 receptor, STimulation 2 (ST2), on both immune and stromal cells. Interestingly, IL-33 also supports type 1 immune responses during viral and tumor immunity and after allogeneic hematopoietic stem cell transplantation. Yet the IL-33-ST2 axis is also critical to the establishment of systemic homeostasis and tissue repair and regeneration. Despite these recent findings, the mechanisms by which IL-33 governs the balance between immunity and homeostasis or can support both effective repair and pathogenic fibrosis are poorly understood. As such, ongoing research is trying to understand the potential reparative and regulatory versus pro-inflammatory and pro-fibrotic roles for IL-33 in transplantation. This review provides an overview of the emerging regenerative role of IL-33 in organ homeostasis and tissue repair as it relates to transplantation immunology. It also outlines the known impacts of IL-33 in commonly transplanted solid organs and covers the envisioned roles for IL-33 in ischemia-reperfusion injury, rejection, and tolerance. Finally, we give a comprehensive summary of its effects on different cell populations involved in these processes, including ST2 + regulatory T cells, innate lymphoid cell type 2, as well as significant myeloid cell populations.
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20
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Shirakawa K, Sano M. Drastic transformation of visceral adipose tissue and peripheral CD4 T cells in obesity. Front Immunol 2023; 13:1044737. [PMID: 36685567 PMCID: PMC9846168 DOI: 10.3389/fimmu.2022.1044737] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2022] [Accepted: 12/12/2022] [Indexed: 01/05/2023] Open
Abstract
Obesity has a pronounced effect on the immune response in systemic organs that results in not only insulin resistance but also altered immune responses to infectious diseases and malignant tumors. Obesity-associated microenvironmental changes alter transcriptional expression and metabolism in T cells, leading to alterations in T-cell differentiation, proliferation, function, and survival. Adipokines, cytokines, and lipids derived from obese visceral adipose tissue (VAT) may also contribute to the systemic T-cell phenotype, resulting in obesity-specific pathogenesis. VAT T cells, which have multiple roles in regulating homeostasis and energy utilization and defending against pathogens, are most susceptible to obesity. In particular, many studies have shown that CD4 T cells are deeply involved in the homeostasis of VAT endocrine and metabolic functions and in obesity-related chronic inflammation. In obesity, macrophages and adipocytes in VAT function as antigen-presenting cells and contribute to the obesity-specific CD4 T-cell response by inducing CD4 T-cell proliferation and differentiation into inflammatory effectors via interactions between major histocompatibility complex class II and T-cell receptors. When obesity persists, prolonged stimulation by leptin and circulating free fatty acids, repetitive antigen stimulation, activating stress responses, and hypoxia induce exhaustion of CD4 T cells in VAT. T-cell exhaustion is characterized by restricted effector function, persistent expression of inhibitory receptors, and a transcriptional state distinct from functional effector and memory T cells. Moreover, obesity causes thymic regression, which may result in homeostatic proliferation of obesity-specific T-cell subsets due to changes in T-cell metabolism and gene expression in VAT. In addition to causing T-cell exhaustion, obesity also accelerates cellular senescence of CD4 T cells. Senescent CD4 T cells secrete osteopontin, which causes further VAT inflammation. The obesity-associated transformation of CD4 T cells remains a negative legacy even after weight loss, causing treatment resistance of obesity-related conditions. This review discusses the marked transformation of CD4 T cells in VAT and systemic organs as a consequence of obesity-related microenvironmental changes.
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Affiliation(s)
| | - Motoaki Sano
- Department of Cardiology, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan
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Yu Y, Bai H, Wu F, Chen J, Li B, Li Y. Tissue adaptation of regulatory T cells in adipose tissue. Eur J Immunol 2022; 52:1898-1908. [PMID: 36369886 DOI: 10.1002/eji.202149527] [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: 03/14/2022] [Revised: 08/05/2022] [Accepted: 10/27/2022] [Indexed: 11/15/2022]
Abstract
Foxp3+ regulatory T (Treg) cells critically suppress over-activated immune responses and therefore maintain immune homeostasis. Adipose tissue-resident Treg (AT Treg) cells are known for modulating immunity and metabolism in adipose tissue microenvironment through various physiological signals, as well as their heterogeneous subsets, which potentially play disparate roles in aging and obesity. Recent single-cell studies of Treg cells have revealed specialized trajectories of their tissue adaptation and development in lymphoid tissues and at barrier sites. Here, we reviewed a T Cell Receptor (TCR)-primed environmental cue-boosted model of adipose Treg cells' tissue adaptation, especially in response to IL-33, IFN-α, insulin, and androgen signals, which trigger sophisticated transcriptional cascades and ultimately establish unique transcriptional modules in adipose Treg cell subsets. In addition, we further discuss potential therapeutic strategies against aging and obesity by blocking detrimental environmental cues, strengthening the functions of specific AT Treg subsets and modifying the communications between AT Treg subsets and adipocytes.
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Affiliation(s)
- Yimeng Yu
- Center for Immune-Related Diseases at Shanghai Institute of Immunology, Department of Respiratory and Critical Care Medicine of Ruijin Hospital, Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Hongyu Bai
- Center for Immune-Related Diseases at Shanghai Institute of Immunology, Department of Respiratory and Critical Care Medicine of Ruijin Hospital, Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Fenglin Wu
- Center for Immune-Related Diseases at Shanghai Institute of Immunology, Department of Respiratory and Critical Care Medicine of Ruijin Hospital, Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jieqiong Chen
- Center for Immune-Related Diseases at Shanghai Institute of Immunology, Department of Respiratory and Critical Care Medicine of Ruijin Hospital, Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Bin Li
- Center for Immune-Related Diseases at Shanghai Institute of Immunology, Department of Respiratory and Critical Care Medicine of Ruijin Hospital, Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yangyang Li
- Unit of Immune and Metabolic Regulation, School of Life Science and Technology, ShanghaiTech University, Shanghai, China
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22
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Cytokine and metabolic regulation of adipose tissue Tregs. IMMUNOMETABOLISM (COBHAM (SURREY, ENGLAND)) 2022; 4:e00013. [PMID: 36337732 PMCID: PMC9624380 DOI: 10.1097/in9.0000000000000013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 09/01/2022] [Accepted: 10/08/2022] [Indexed: 01/24/2023]
Abstract
Since their discovery over a decade ago, much has been learned regarding the importance and function of visceral adipose tissue (VAT)-resident regulatory T cells (Tregs). VAT Tregs play a critical role in controlling VAT inflammation and alleviating metabolic disease. However, this population is disrupted in obesity which exacerbates VAT inflammation and metabolic abnormalities. Therefore, understanding the factors governing the accumulation and maintenance of VAT Tregs, both at steady state and under disease conditions, is crucial for identifying the mechanisms underlying obesity-associated metabolic disease and developing novel therapies. Expansion and maintenance of the VAT Treg compartment is strongly influenced by factors in the local tissue microenvironment, including cytokines, T-cell receptor ligands, hormones, and various metabolites. This mini-review will primarily focus on recent advances in our understandings regarding the regulation of mouse epididymal VAT (eVAT) Tregs, which are the most thoroughly characterized VAT Treg population, by tissue microenvironmental factors and cellular metabolic processes. We will also briefly discuss the limited knowledge available regarding the regulation of mouse ovarian VAT (oVAT) Tregs and human omental VAT Tregs, highlight some lingering questions, and provide a prospective view on where the field is heading.
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23
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Regulatory T cells in skeletal muscle repair and regeneration: recent insights. Cell Death Dis 2022; 13:680. [PMID: 35931697 PMCID: PMC9356005 DOI: 10.1038/s41419-022-05142-8] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2022] [Revised: 07/25/2022] [Accepted: 07/27/2022] [Indexed: 01/21/2023]
Abstract
Skeletal muscle repair and regeneration after injury is a multi-stage process, involving a dynamic inflammatory microenvironment consisting of a complex network formed by the interaction of immune cells and their secreted cytokines. The homeostasis of the inflammatory microenvironment determines whether skeletal muscle repair tissues will ultimately form scar tissue or regenerative tissue. Regulatory T cells (Tregs) regulate homeostasis within the immune system and self-immune tolerance, and play a crucial role in skeletal muscle repair and regeneration. Dysregulated Tregs function leads to abnormal repair. In this review, we discuss the role and mechanisms of Tregs in skeletal muscle repair and regeneration after injury and provide new strategies for Treg immunotherapy in skeletal muscle diseases.
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24
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Finding a Niche: Tissue Immunity and Innate Lymphoid Cells. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2022; 1365:57-73. [PMID: 35567741 DOI: 10.1007/978-981-16-8387-9_5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Abstract
The immune system plays essential roles in maintaining homeostasis in mammalian tissues that extend beyond pathogen clearance and host defense. Recently, several homeostatic circuits comprised of paired hematopoietic and non-hematopoietic cells have been described to influence tissue composition and turnover in development and after perturbation. Crucial circuit components include innate lymphoid cells (ILCs), which seed developing organs and shape their resident tissues by influencing progenitor fate decisions, microbial interactions, and neuronal activity. As they develop in tissues, ILCs undergo transcriptional imprinting that encodes receptivity to corresponding signals derived from their resident tissues but ILCs can also shift their transcriptional profiles to adapt to specific types of tissue perturbation. Thus, ILC functions are embedded within their resident tissues, where they constitute key regulators of homeostatic responses that can lead to both beneficial and pathogenic outcomes. Here, we examine the interactions between ILCs and various non-hematopoietic tissue cells, and discuss how specific ILC-tissue cell circuits form essential elements of tissue immunity.
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25
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Vergaro G, Gentile F, Aimo A, Januzzi JL, Richards AM, Lam CSP, de Boer RA, Meems LMG, Latini R, Staszewsky L, Anand IS, Cohn JN, Ueland T, Gullestad L, Aukrust P, Brunner-La Rocca HP, Bayes-Genis A, Lupón J, Yoshihisa A, Takeishi Y, Egstrup M, Gustafsson I, Gaggin HK, Eggers KM, Huber K, Gamble GD, Ling LH, Leong KTG, Yeo PSD, Ong HY, Jaufeerally F, Ng TP, Troughton R, Doughty RN, Devlin G, Lund M, Giannoni A, Passino C, Emdin M. Circulating levels and prognostic cut-offs of sST2, hs-cTnT, and NT-proBNP in women vs. men with chronic heart failure. ESC Heart Fail 2022; 9:2084-2095. [PMID: 35510529 PMCID: PMC9288762 DOI: 10.1002/ehf2.13883] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2021] [Revised: 02/17/2022] [Accepted: 03/02/2022] [Indexed: 11/11/2022] Open
Abstract
Aims To define plasma concentrations, determinants, and optimal prognostic cut‐offs of soluble suppression of tumorigenesis‐2 (sST2), high‐sensitivity cardiac troponin T (hs‐cTnT), and N‐terminal pro‐B‐type natriuretic peptide (NT‐proBNP) in women and men with chronic heart failure (HF). Methods and results Individual data of patients from the Biomarkers In Heart Failure Outpatient Study (BIOS) Consortium with sST2, hs‐cTnT, and NT‐proBNP measured were analysed. The primary endpoint was a composite of 1 year cardiovascular death and HF hospitalization. The secondary endpoints were 5 year cardiovascular and all‐cause death. The cohort included 4540 patients (age 67 ± 12 years, left ventricular ejection fraction 33 ± 13%, 1111 women, 25%). Women showed lower sST2 (24 vs. 27 ng/mL, P < 0.001) and hs‐cTnT level (15 vs. 20 ng/L, P < 0.001), and similar concentrations of NT‐proBNP (1540 vs. 1505 ng/L, P = 0.408). Although the three biomarkers were confirmed as independent predictors of outcome in both sexes, the optimal prognostic cut‐off was lower in women for sST2 (28 vs. 31 ng/mL) and hs‐cTnT (22 vs. 25 ng/L), while NT‐proBNP cut‐off was higher in women (2339 ng/L vs. 2145 ng/L). The use of sex‐specific cut‐offs improved risk prediction compared with the use of previously standardized prognostic cut‐offs and allowed to reclassify the risk of many patients, to a greater extent in women than men, and for hs‐cTnT than sST2 or NT‐proBNP. Specifically, up to 18% men and up to 57% women were reclassified, by using the sex‐specific cut‐off of hs‐cTnT for the endpoint of 5 year cardiovascular death. Conclusions In patients with chronic HF, concentrations of sST2 and hs‐cTnT, but not of NT‐proBNP, are lower in women. Lower sST2 and hs‐cTnT and higher NT‐proBNP cut‐offs for risk stratification could be used in women.
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Affiliation(s)
- Giuseppe Vergaro
- Institute of Life Sciences, Scuola Superiore Sant'Anna and Division of Cardiology and Cardiovascular Medicine, Fondazione Toscana Gabriele Monasterio, via Giuseppe Moruzzi 1, Pisa, 56124, Italy
| | | | - Alberto Aimo
- Institute of Life Sciences, Scuola Superiore Sant'Anna and Division of Cardiology and Cardiovascular Medicine, Fondazione Toscana Gabriele Monasterio, via Giuseppe Moruzzi 1, Pisa, 56124, Italy
| | - James L Januzzi
- Massachusetts General Hospital and Baim Institute for Clinical Research, Boston, MA, USA
| | - A Mark Richards
- Department of Medicine, University of Otago, New Zealand & National University Heart Centre, National University of Singapore, Singapore
| | - Carolyn S P Lam
- National Heart Centre Singapore and Duke-National University of Singapore, Singapore
| | | | - Laura M G Meems
- University Medical Centre Groningen, Groningen, The Netherlands
| | - Roberto Latini
- Istituto di Ricerche Farmacologiche - "Mario Negri" (IRCCS), Milan, Italy
| | - Lidia Staszewsky
- Istituto di Ricerche Farmacologiche - "Mario Negri" (IRCCS), Milan, Italy
| | - Inder S Anand
- University of Minnesota Medical Center, University of Minnesota, Minneapolis, MN, USA.,VA Medical Centre, Minneapolis, MN, USA
| | - Jay N Cohn
- University of Minnesota Medical Center, University of Minnesota, Minneapolis, MN, USA
| | - Thor Ueland
- Oslo University Hospital, Ullevål, Oslo, Norway.,Oslo University Hospital, Rikshospitalet, Oslo, Norway.,Institute of Clinical Medicine, University of Oslo, Oslo, Norway.,K. G. Jebsen Thrombosis Research and Expertise Center, University of Tromsø, Tromsø, Norway
| | - Lars Gullestad
- KG Jebsen Center for Cardiac Research, University of Oslo and Center for Heart Failure Research, Oslo University Hospital, Norway
| | - Pål Aukrust
- Oslo University Hospital, Rikshospitalet, Oslo, Norway
| | | | - Antoni Bayes-Genis
- Hospital Universitari Germans Trias i Pujol, Badalona (Barcelona) and CIBER Cardiovascular, Instituto de Salud Carlos III, Madrid, Spain
| | - Josep Lupón
- Hospital Universitari Germans Trias i Pujol, Badalona (Barcelona) and CIBER Cardiovascular, Instituto de Salud Carlos III, Madrid, Spain
| | - Akiomi Yoshihisa
- First Department of Internal Medicine, Fukushima Medical University, Fukushima, Japan
| | - Yasuchika Takeishi
- First Department of Internal Medicine, Fukushima Medical University, Fukushima, Japan
| | - Michael Egstrup
- Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark
| | - Ida Gustafsson
- Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark
| | - Hanna K Gaggin
- Heart Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Kai M Eggers
- Department of Medical Sciences, Uppsala University, Uppsala, Sweden
| | - Kurt Huber
- Wilhelminenspital and Sigmund Freud University Medical School, Vienna, Austria
| | - Greg D Gamble
- Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand
| | - Lieng H Ling
- Department of Cardiology, National University Heart Centre and National University of Singapore, Singapore
| | | | | | | | | | - Tze P Ng
- Department of Cardiology, National University Heart Centre and National University of Singapore, Singapore
| | - Richard Troughton
- Department of Medicine, University of Otago, New Zealand & National University Heart Centre, National University of Singapore, Singapore
| | - Robert N Doughty
- Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand
| | | | | | - Alberto Giannoni
- Institute of Life Sciences, Scuola Superiore Sant'Anna and Division of Cardiology and Cardiovascular Medicine, Fondazione Toscana Gabriele Monasterio, via Giuseppe Moruzzi 1, Pisa, 56124, Italy
| | - Claudio Passino
- Institute of Life Sciences, Scuola Superiore Sant'Anna and Division of Cardiology and Cardiovascular Medicine, Fondazione Toscana Gabriele Monasterio, via Giuseppe Moruzzi 1, Pisa, 56124, Italy
| | - Michele Emdin
- Institute of Life Sciences, Scuola Superiore Sant'Anna and Division of Cardiology and Cardiovascular Medicine, Fondazione Toscana Gabriele Monasterio, via Giuseppe Moruzzi 1, Pisa, 56124, Italy
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26
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IL-37 isoform D acts as an inhibitor of soluble ST2 to boost type 2 immune homeostasis in white adipose tissue. Cell Death Dis 2022; 8:163. [PMID: 35383145 PMCID: PMC8983676 DOI: 10.1038/s41420-022-00960-3] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2021] [Revised: 03/02/2022] [Accepted: 03/17/2022] [Indexed: 11/08/2022]
Abstract
White adipose tissue (WAT) homeostasis substantiated by type 2 immunity is indispensable to counteract obesity and metabolic disorders. IL-33/suppression of tumorigenicity (ST) 2 signaling promotes type 2 response in WAT, while potential regulators remain to be discovered. We identified human IL-37 isoform D (IL-37D) as an effective trigger for ST2-mediated type 2 immune homeostasis in WAT. IL-37D transgene amplified ST2+ immune cells, promoted M2 macrophage polarization and type 2 cytokine secretion in WAT that mediate beiging and inflammation resolution, thereby increasing energy expenditure, reducing obesity and insulin resistance in high-fat diet (HFD)-fed mice. Mechanistically, either endogenous or exogenous IL-37D inhibited soluble ST2 (sST2) production from WAT challenged with HFD or TNF-α. Recombinant sST2 impaired the beneficial effects of IL-37D transgene in HFD-fed mice, characterized by damaged weight loss, insulin action, and type 2 cytokine secretion from WAT. In adipose-derived stem cells, IL-37D inhibited TNF-α-stimulated sST2 expression through IL-1 receptor 8 (IL-1R8)-dependent NF-κB inactivation. Collectively, human IL-37D suppresses sST2 to boost type 2 immune homeostasis in WAT, which may be a promising therapy target for obesity and metabolic disorders.
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27
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Lee J, Kim D, Min B. Tissue Resident Foxp3+ Regulatory T Cells: Sentinels and Saboteurs in Health and Disease. Front Immunol 2022; 13:865593. [PMID: 35359918 PMCID: PMC8963273 DOI: 10.3389/fimmu.2022.865593] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2022] [Accepted: 02/22/2022] [Indexed: 01/04/2023] Open
Abstract
Foxp3+ regulatory T (Treg) cells are a CD4 T cell subset with unique immune regulatory function that are indispensable in immunity and tolerance. Their indisputable importance has been investigated in numerous disease settings and experimental models. Despite the extensive efforts in determining the cellular and molecular mechanisms operating their functions, our understanding their biology especially in vivo remains limited. There is emerging evidence that Treg cells resident in the non-lymphoid tissues play a central role in regulating tissue homeostasis, inflammation, and repair. Furthermore, tissue-specific properties of those Treg cells that allow them to express tissue specific functions have been explored. In this review, we will discuss the potential mechanisms and key cellular/molecular factors responsible for the homeostasis and functions of tissue resident Treg cells under steady-state and inflammatory conditions.
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Affiliation(s)
- Juyeun Lee
- Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, United States
| | - Dongkyun Kim
- Department of Microbiology and Immunology, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
| | - Booki Min
- Department of Microbiology and Immunology, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
- *Correspondence: Booki Min,
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28
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Simeone P, Tripaldi R, Michelsen A, Ueland T, Liani R, Ciotti S, Birkeland KI, Gulseth HL, Di Castelnuovo A, Cipollone F, Aukrust P, Consoli A, Halvorsen B, Santilli F. Effects of liraglutide vs. lifestyle changes on soluble suppression of tumorigenesis-2 (sST2) and galectin-3 in obese subjects with prediabetes or type 2 diabetes after comparable weight loss. Cardiovasc Diabetol 2022; 21:36. [PMID: 35277168 PMCID: PMC8917620 DOI: 10.1186/s12933-022-01469-w] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/08/2021] [Accepted: 02/18/2022] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Soluble suppression of tumorigenesis-2 (sST2) and galectin (Gal)-3 are two biomarkers related to inflammation, metabolic disturbances and to myocardial fibrosis that characterize several cardiac pathological conditions. Increased circulating levels of these molecules have been associated with risk of cardiovascular death. Treatment with liraglutide, a glucagon-like peptide 1 analog, is associated with weight loss, improved glycemic control, and reduced cardiovascular risk. We wanted to assess (I) potential differences between subjects with prediabetes or type 2 diabetes mellitus (T2DM) and healthy controls in sST2 and Gal-3 circulating levels, and their relationship with glycemic control and markers of beta cell function and myocardial injury; (II) whether liraglutide treatment modulates these markers in subjects with prediabetes or early T2DM independently of weight loss; (III) whether baseline levels of any of these two molecules may predict the response to liraglutide treatment. METHODS Forty metformin-treated obese subjects (BMI ≥ 30) with prediabetes [impaired fasting glucose (IFG) or impaired glucose tolerance (IGT) or both (n = 23)] or newly diagnosed T2DM (n = 17), were randomized to liraglutide or lifestyle counseling until achieving a comparable weight loss (7% of initial body weight). Thirteen subjects were enrolled as healthy controls for baseline sST2 and Gal-3 levels. RESULTS Baseline sST2 levels were comparable between controls and obese patients (p = 0.79) whereas Gal-3 levels were significantly higher in patients as compared to controls (p < 0.001). Liraglutide treatment, but not weight loss achieved by lifestyle counseling, decreased plasma sST2 levels (- 9%, beta = - 14.9, standard deviation 6.9, p = 0.037) while Gal-3 levels did not change. A reduction in serum hs-Troponin I was observed after intervention, due to a 19% (p = 0.29) increase in the lifestyle arm, and a 25% decrease (p = 0.033) in the liraglutide arm (between-group difference p = 0.083). Lower baseline Gal-3 levels predicted a better improvement in beta cell function after liraglutide treatment. CONCLUSIONS Liraglutide-induced reduction in sST2 and possibly hs-TnI suggests that in obese patients with prediabetes or early T2DM this drug may have a positive effect on (cardiac) fibrosis, whereas plasma level of Gal-3 before liraglutide initiation may predict response to the drug in terms of beta cell function improvement. Trial registration Eudract: 2013-001356-36.
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Affiliation(s)
- Paola Simeone
- Department of Medicine and Aging, and Center for Advanced Studies and Technology (CAST), "G. D'Annunzio" University Foundation, Via Luigi Polacchi, 66013, Chieti, Italy
| | - Romina Tripaldi
- Department of Medicine and Aging, and Center for Advanced Studies and Technology (CAST), "G. D'Annunzio" University Foundation, Via Luigi Polacchi, 66013, Chieti, Italy
| | - Annika Michelsen
- Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, University of Oslo, Oslo, Norway
| | - Thor Ueland
- Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, University of Oslo, Oslo, Norway
| | - Rossella Liani
- Department of Medicine and Aging, and Center for Advanced Studies and Technology (CAST), "G. D'Annunzio" University Foundation, Via Luigi Polacchi, 66013, Chieti, Italy
| | - Sonia Ciotti
- Department of Medicine and Aging, and Center for Advanced Studies and Technology (CAST), "G. D'Annunzio" University Foundation, Via Luigi Polacchi, 66013, Chieti, Italy
| | - Kåre I Birkeland
- Department of Transplantation Medicine, Institute of Clinical Medicine, University of Oslo and Oslo University Hospital, Oslo, Norway
| | - Hanne L Gulseth
- Department of Endocrinology, Morbid Obesity and Preventive Medicine, Oslo University Hospital, Oslo, Norway
- Department of Chronic Diseases and Ageing, Norwegian Institute of Public Health, Oslo, Norway
| | | | - Francesco Cipollone
- Department of Medicine and Aging, and Center for Advanced Studies and Technology (CAST), "G. D'Annunzio" University Foundation, Via Luigi Polacchi, 66013, Chieti, Italy
| | - Pål Aukrust
- Section of Clinical Immunology and Infectious Diseases, Oslo University Hospital, Oslo, Norway
| | - Agostino Consoli
- Department of Medicine and Aging, and Center for Advanced Studies and Technology (CAST), "G. D'Annunzio" University Foundation, Via Luigi Polacchi, 66013, Chieti, Italy
| | - Bente Halvorsen
- Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, University of Oslo, Oslo, Norway
| | - Francesca Santilli
- Department of Medicine and Aging, and Center for Advanced Studies and Technology (CAST), "G. D'Annunzio" University Foundation, Via Luigi Polacchi, 66013, Chieti, Italy.
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29
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Murphy JM, Ngai L, Mortha A, Crome SQ. Tissue-Dependent Adaptations and Functions of Innate Lymphoid Cells. Front Immunol 2022; 13:836999. [PMID: 35359972 PMCID: PMC8960279 DOI: 10.3389/fimmu.2022.836999] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2021] [Accepted: 02/11/2022] [Indexed: 12/21/2022] Open
Abstract
Tissue-resident immune cells reside in distinct niches across organs, where they contribute to tissue homeostasis and rapidly respond to perturbations in the local microenvironment. Innate lymphoid cells (ILCs) are a family of innate immune cells that regulate immune and tissue homeostasis. Across anatomical locations throughout the body, ILCs adopt tissue-specific fates, differing from circulating ILC populations. Adaptations of ILCs to microenvironmental changes have been documented in several inflammatory contexts, including obesity, asthma, and inflammatory bowel disease. While our understanding of ILC functions within tissues have predominantly been based on mouse studies, development of advanced single cell platforms to study tissue-resident ILCs in humans and emerging patient-based data is providing new insights into this lymphocyte family. Within this review, we discuss current concepts of ILC fate and function, exploring tissue-specific functions of ILCs and their contribution to health and disease across organ systems.
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Affiliation(s)
- Julia M. Murphy
- Department of Immunology, University of Toronto, Toronto, ON, Canada
- Toronto General Hospital Research Institute, University Health Network, Toronto, ON, Canada
- Ajmera Transplant Centre, University Health Network, Toronto, ON, Canada
| | - Louis Ngai
- Department of Immunology, University of Toronto, Toronto, ON, Canada
| | - Arthur Mortha
- Department of Immunology, University of Toronto, Toronto, ON, Canada
| | - Sarah Q. Crome
- Department of Immunology, University of Toronto, Toronto, ON, Canada
- Toronto General Hospital Research Institute, University Health Network, Toronto, ON, Canada
- Ajmera Transplant Centre, University Health Network, Toronto, ON, Canada
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30
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Fooks AN, Beppu LY, Frias AB, D'Cruz LM. Adipose tissue regulatory T cells: differentiation and function. Int Rev Immunol 2022; 42:323-333. [PMID: 35212593 PMCID: PMC9402810 DOI: 10.1080/08830185.2022.2044808] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2022] [Revised: 02/09/2022] [Accepted: 02/15/2022] [Indexed: 10/19/2022]
Abstract
Rising obesity levels, worldwide, are resulting in substantial increases in cardiovascular disease, diabetes, kidney disease, musculoskeletal disorders, and certain cancers, and obesity-associated illnesses are estimated to cause ∼4 million deaths worldwide per year. A common theme in this disease epidemic is the chronic systemic inflammation that accompanies obesity. CD4+ Foxp3+ regulatory T cells residing in visceral adipose tissues (VAT Tregs) are a unique immune cell population that play essential functions in restricting obesity-associated systemic inflammation through regulation of adipose tissue homeostasis. The distinct transcriptional program that defines VAT Tregs has been described, but directly linking VAT Treg differentiation and function to improving insulin sensitivity has proven more complex. Here we review new findings which have clarified how VAT Tregs differentiate, and how distinct VAT Treg subsets regulate VAT homeostasis, energy expenditure, and insulin sensitivity.
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Affiliation(s)
- Allen N Fooks
- Department of Immunology, University of Pittsburgh, Biomedical Science Tower, Pittsburgh, PA, USA
| | - Lisa Y Beppu
- Department of Immunology, University of Pittsburgh, Biomedical Science Tower, Pittsburgh, PA, USA
| | - Adolfo B Frias
- Department of Immunology, University of Pittsburgh, Biomedical Science Tower, Pittsburgh, PA, USA
| | - Louise M D'Cruz
- Department of Immunology, University of Pittsburgh, Biomedical Science Tower, Pittsburgh, PA, USA
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31
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Lau ES, Binek A, Parker SJ, Shah SH, Zanni MV, Van Eyk JE, Ho JE. Sexual Dimorphism in Cardiovascular Biomarkers: Clinical and Research Implications. Circ Res 2022; 130:578-592. [PMID: 35175850 PMCID: PMC8883873 DOI: 10.1161/circresaha.121.319916] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
Sex-based differences in cardiovascular disease presentation, diagnosis, and response to therapies are well established, but mechanistic understanding and translation to clinical applications are limited. Blood-based biomarkers have become an important tool for interrogating biologic pathways. Understanding sexual dimorphism in the relationship between biomarkers and cardiovascular disease will enhance our insights into cardiovascular disease pathogenesis in women, with potential to translate to improved individualized care for men and women with or at risk for cardiovascular disease. In this review, we examine how biologic sex associates with differential levels of blood-based biomarkers and influences the effect of biomarkers on disease outcomes. We further summarize key differences in blood-based cardiovascular biomarkers along central biologic pathways, including myocardial stretch/injury, inflammation, adipose tissue metabolism, and fibrosis pathways in men versus women. Finally, we present recommendations for leveraging our current knowledge of sex differences in blood-based biomarkers for future research and clinical innovation.
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Affiliation(s)
- Emily S. Lau
- Division of Cardiology, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Aleksandra Binek
- Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - Sarah J. Parker
- Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - Svati H. Shah
- Division of Cardiology, Duke University School of Medicine, Durham, North Carolina, USA
| | - Markella V. Zanni
- Metabolism Unit, Division of Endocrinology, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Jennifer E Van Eyk
- Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - Jennifer E. Ho
- Division of Cardiovascular Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA
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32
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Antuna-Puente B, Fellahi S, McAvoy C, Fève B, Bastard JP. Interleukins in adipose tissue: Keeping the balance. Mol Cell Endocrinol 2022; 542:111531. [PMID: 34910978 DOI: 10.1016/j.mce.2021.111531] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/26/2021] [Revised: 12/01/2021] [Accepted: 12/08/2021] [Indexed: 02/06/2023]
Abstract
The role of the immune system is to defend the host and preserve the functionality in response to stress. This function is not limited to infection or injury as it also plays a role in the response to overnutrition. Indeed, low-grade chronic activation of the immune system associated with overnutrition may be deleterious, contributing importantly to diabetes and long-term complications, such as cardiovascular disorders. Increasing evidence shows that adipose tissue participates in the obesity-related inflammatory response and that interleukins are one of the key players, either as a pro-inflammatory response to the metabolic dysregulation or to restore homeostasis. The crosstalk between adipocytes and immune cells through some important interleukins and their role in metabolic disruption is the topic of this review.
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Affiliation(s)
- Barbara Antuna-Puente
- Infection Disease Division, Department of Medicine, Queen's University, Kingston, ON, Canada.
| | - Soraya Fellahi
- Assistance Publique-Hôpitaux de Paris, Hôpitaux Universitaires Henri Mondor, Département de Biochimie-pharmacologie-biologie Moléculaire-génétique Médicale, Créteil, France; Sorbonne Université-Inserm, Centre de Recherche Saint-Antoine UMR S_938, 75012, Paris Institut Hospitalo-Universitaire de Cardio-Métabolisme et Nutrition (ICAN), Paris, France
| | - Chloé McAvoy
- Unité de Recherche Clinique de L'Est Parisien (URC-Est), Hôpital Saint Antoine, Paris, France
| | - Bruno Fève
- Sorbonne Université-Inserm, Centre de Recherche Saint-Antoine UMR S_938, 75012, Paris Institut Hospitalo-Universitaire de Cardio-Métabolisme et Nutrition (ICAN), Paris, France; Assistance Publique- Hôpitaux de Paris -Hôpital Saint-Antoine, Service D'Endocrinologie-Diabétologie, Centre de Référence des Maladies Rares de L'Insulino-Sécrétion et de L'Insulino-Sensibilité (PRISIS), 75012, Paris, France
| | - Jean-Philippe Bastard
- Assistance Publique-Hôpitaux de Paris, Hôpitaux Universitaires Henri Mondor, Département de Biochimie-pharmacologie-biologie Moléculaire-génétique Médicale, Créteil, France; FHU-SENEC, INSERM U955 and Université Paris Est (UPEC), UMR U955, Faculté de Santé, Créteil, France
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Abstract
Our understanding of the functions of the IL-1 superfamily cytokine and damage-associated molecular pattern IL-33 continues to evolve with our understanding of homeostasis and immunity. The early findings that IL-33 is a potent driver of type 2 immune responses promoting parasite expulsion, but also inflammatory diseases like allergy and asthma, have been further supported. Yet, as the importance of a type 2 response in tissue repair and homeostasis has emerged, so has the fundamental importance of IL-33 to these processes. In this review, we outline an evolving understanding of IL-33 immunobiology, paying particular attention to how IL-33 directs a network of ST2+ regulatory T cells, reparative and regulatory macrophages, and type 2 innate lymphoid cells that are fundamental to tissue development, homeostasis, and repair. Expected final online publication date for the Annual Review of Immunology, Volume 40 is April 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
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Affiliation(s)
- Gaelen K. Dwyer
- Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
- Thomas E. Starzl Transplantation Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
- Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
| | - Louise M. D'Cruz
- Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
| | - Hēth R. Turnquist
- Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
- Thomas E. Starzl Transplantation Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
- Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
- McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
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34
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Chen H, Sun L, Feng L, Yin Y, Zhang W. Role of Innate lymphoid Cells in Obesity and Insulin Resistance. Front Endocrinol (Lausanne) 2022; 13:855197. [PMID: 35574038 PMCID: PMC9091334 DOI: 10.3389/fendo.2022.855197] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2022] [Accepted: 03/24/2022] [Indexed: 12/12/2022] Open
Abstract
Obesity, a growing chronic metabolic disease, greatly increases the risk of metabolic syndrome which includes type 2 diabetes, fatty liver and cardiovascular diseases. Obesity-associated metabolic diseases significantly contribute to mortality and reduce life expectancy. Recently, innate lymphoid cells (ILCs) have emerged as crucial regulators of metabolic homeostasis and tissue inflammation. This review focuses on the roles of ILCs in different metabolic tissues, including adipose tissue, liver, pancreas, and intestine. We briefly outline the relationship between obesity, inflammation, and insulin resistance. We then discuss how ILCs in distinct metabolic organs may function to maintain metabolic homeostasis and contribute to obesity and its associated metabolic diseases. The potential of ILCs as the therapeutic target for obesity and insulin resistance is also addressed.
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Affiliation(s)
- Hong Chen
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, and Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Peking University, Beijing, China
| | - Lijun Sun
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, and Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Peking University, Beijing, China
| | - Lu Feng
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, and Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Peking University, Beijing, China
| | - Yue Yin
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, and Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Peking University, Beijing, China
- *Correspondence: Weizhen Zhang, ; Yue Yin,
| | - Weizhen Zhang
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, and Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Peking University, Beijing, China
- Department of Surgery, University of Michigan Medical Center, Ann Arbor, MI, United States
- *Correspondence: Weizhen Zhang, ; Yue Yin,
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35
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T Regulatory Cells in the Visceral Adipose Tissues. IMMUNOMETABOLISM 2021; 4. [PMID: 35070445 PMCID: PMC8774286 DOI: 10.20900/immunometab20220002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/02/2022]
Abstract
CD4+ Foxp3+ T regulatory cells (Tregs) residing in the visceral adipose tissues (VAT) have profound effects on local and systemic metabolism. Although many of the molecular characteristics of VAT resident Tregs have been identified, how these cells promote metabolic homeostasis is still unclear. Several new publications help to illuminate the molecular mechanisms that underpin VAT resident Treg function and will be discussed here.
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36
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Zhang M, Duffen JL, Nocka KH, Kasaian MT. IL-13 Controls IL-33 Activity through Modulation of ST2. THE JOURNAL OF IMMUNOLOGY 2021; 207:3070-3080. [PMID: 34789557 DOI: 10.4049/jimmunol.2100655] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/06/2021] [Accepted: 10/13/2021] [Indexed: 12/12/2022]
Abstract
IL-33 is a multifunctional cytokine that mediates local inflammation upon tissue damage. IL-33 is known to act on multiple cell types including group 2 innate lymphoid cells (ILC2s), Th2 cells, and mast cells to drive production of Th2 cytokines including IL-5 and IL-13. IL-33 signaling activity through transmembrane ST2L can be inhibited by soluble ST2 (sST2), which acts as a decoy receptor. Previous findings suggested that modulation of IL-13 levels in mice lacking decoy IL-13Rα2, or mice lacking IL-13, impacted responsiveness to IL-33. In this study, we used Il13 -/- mice to investigate whether IL-13 regulates IL-33 activity by modulating the transmembrane and soluble forms of ST2. In Il13 -/- mice, the effects of IL-33 administration were exacerbated relative to wild type (WT). Il13 -/- mice administered IL-33 i.p. had heightened splenomegaly, more immune cells in the peritoneum including an expanded ST2L+ ILC2 population, increased eosinophilia in the spleen and peritoneum, and reduced sST2 in the circulation and peritoneum. In the spleen, lung, and liver of mice given IL-33, gene expression of both isoforms of ST2 was increased in Il13 -/- mice relative to WT. We confirmed fibroblasts to be an IL-13-responsive cell type that can regulate IL-33 activity through production of sST2. This study elucidates the important regulatory activity that IL-13 exerts on IL-33 through induction of IL-33 decoy receptor sST2 and through modulation of ST2L+ ILC2s.
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Affiliation(s)
- Melvin Zhang
- Inflammation and Immunology Research Unit, Pfizer, Inc., Cambridge, MA
| | - Jennifer L Duffen
- Inflammation and Immunology Research Unit, Pfizer, Inc., Cambridge, MA
| | - Karl H Nocka
- Inflammation and Immunology Research Unit, Pfizer, Inc., Cambridge, MA
| | - Marion T Kasaian
- Inflammation and Immunology Research Unit, Pfizer, Inc., Cambridge, MA
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37
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Goldberg EL, Shchukina I, Youm YH, Ryu S, Tsusaka T, Young KC, Camell CD, Dlugos T, Artyomov MN, Dixit VD. IL-33 causes thermogenic failure in aging by expanding dysfunctional adipose ILC2. Cell Metab 2021; 33:2277-2287.e5. [PMID: 34473956 PMCID: PMC9067336 DOI: 10.1016/j.cmet.2021.08.004] [Citation(s) in RCA: 54] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2021] [Revised: 06/02/2021] [Accepted: 08/09/2021] [Indexed: 12/15/2022]
Abstract
Aging impairs the integrated immunometabolic responses, which have evolved to maintain core body temperature in homeotherms to survive cold stress, infections, and dietary restriction. Adipose tissue inflammation regulates the thermogenic stress response, but how adipose tissue-resident cells instigate thermogenic failure in the aged are unknown. Here, we define alterations in the adipose-resident immune system and identify that type 2 innate lymphoid cells (ILC2s) are lost in aging. Restoration of ILC2 numbers in aged mice to levels seen in adults through IL-33 supplementation failed to rescue old mice from metabolic impairment and increased cold-induced lethality. Transcriptomic analyses revealed intrinsic defects in aged ILC2, and adoptive transfer of adult ILC2s are sufficient to protect old mice against cold. Thus, the functional defects in adipose ILC2s during aging drive thermogenic failure.
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Affiliation(s)
- Emily L Goldberg
- Department of Physiology, University of California, San Francisco, San Francisco, CA, USA.
| | - Irina Shchukina
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA
| | - Yun-Hee Youm
- Department of Comparative Medicine, Yale School of Medicine, New Haven, CT, USA
| | - Seungjin Ryu
- Department of Comparative Medicine, Yale School of Medicine, New Haven, CT, USA
| | - Takeshi Tsusaka
- Department of Physiology, University of California, San Francisco, San Francisco, CA, USA
| | - Kyrlia C Young
- Department of Physiology, University of California, San Francisco, San Francisco, CA, USA
| | - Christina D Camell
- Department of Biochemistry, Molecular Biology, and Molecular Biophysics, University of Minnesota, Minneapolis, MN, USA
| | - Tamara Dlugos
- Department of Comparative Medicine, Yale School of Medicine, New Haven, CT, USA
| | - Maxim N Artyomov
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA
| | - Vishwa Deep Dixit
- Department of Comparative Medicine, Yale School of Medicine, New Haven, CT, USA; Department of Immunobiology, Yale School of Medicine, New Haven, CT, USA; Yale Center for Research on Aging, Yale University, New Haven, CT, USA.
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38
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Narasimhan A, Flores RR, Robbins PD, Niedernhofer LJ. Role of Cellular Senescence in Type II Diabetes. Endocrinology 2021; 162:6345039. [PMID: 34363464 PMCID: PMC8386762 DOI: 10.1210/endocr/bqab136] [Citation(s) in RCA: 61] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/15/2021] [Indexed: 01/10/2023]
Abstract
Cellular senescence is a cell fate that occurs in response to numerous types of stress and can promote tissue repair or drive inflammation and disruption of tissue homeostasis depending on the context. Aging and obesity lead to an increase in the senescent cell burden in multiple organs. Senescent cells release a myriad of senescence-associated secretory phenotype factors that directly mediate pancreatic β-cell dysfunction, adipose tissue dysfunction, and insulin resistance in peripheral tissues, which promote the onset of type II diabetes mellitus. In addition, hyperglycemia and metabolic changes seen in diabetes promote cellular senescence. Diabetes-induced cellular senescence contributes to various diabetic complications. Thus, type II diabetes is both a cause and consequence of cellular senescence. This review summarizes recent studies on the link between aging, obesity, and diabetes, focusing on the role of cellular senescence in disease processes.
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Affiliation(s)
- Akilavalli Narasimhan
- Institute on the Biology of Aging and Metabolism, Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota Medical School, 55455, USA
| | - Rafael R Flores
- Institute on the Biology of Aging and Metabolism, Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota Medical School, 55455, USA
| | - Paul D Robbins
- Institute on the Biology of Aging and Metabolism, Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota Medical School, 55455, USA
| | - Laura J Niedernhofer
- Institute on the Biology of Aging and Metabolism, Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota Medical School, 55455, USA
- Correspondence: Laura J. Niedernhofer, MD, PhD, Institute on the Biology of Aging and Metabolism, Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota Medical School, 6-155 Jackson Hall, 321 Church Street, SE, Minneapolis, MN 55455, USA.
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39
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Sjaastad LE, Owen DL, Tracy SI, Farrar MA. Phenotypic and Functional Diversity in Regulatory T Cells. Front Cell Dev Biol 2021; 9:715901. [PMID: 34631704 PMCID: PMC8495164 DOI: 10.3389/fcell.2021.715901] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2021] [Accepted: 09/03/2021] [Indexed: 12/14/2022] Open
Abstract
The concept that a subset of T cells exists that specifically suppresses immune responses was originally proposed over 50 years ago. It then took the next 30 years to solidify the concept of regulatory T cells (Tregs) into the paradigm we understand today - namely a subset of CD4+ FOXP3+ T-cells that are critical for controlling immune responses to self and commensal or environmental antigens that also play key roles in promoting tissue homeostasis and repair. Expression of the transcription factor FOXP3 is a defining feature of Tregs, while the cytokine IL2 is necessary for robust Treg development and function. While our initial conception of Tregs was as a monomorphic lineage required to suppress all types of immune responses, recent work has demonstrated extensive phenotypic and functional diversity within the Treg population. In this review we address the ontogeny, phenotype, and function of the large number of distinct effector Treg subsets that have been defined over the last 15 years.
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Affiliation(s)
- Louisa E. Sjaastad
- Department of Laboratory Medicine and Pathology, Center for Immunology, Masonic Cancer Center, University of Minnesota, Minneapolis, MN, United States
| | - David L. Owen
- Department of Laboratory Medicine and Pathology, Center for Immunology, Masonic Cancer Center, University of Minnesota, Minneapolis, MN, United States
| | - Sean I. Tracy
- Department of Laboratory Medicine and Pathology, Center for Immunology, Masonic Cancer Center, University of Minnesota, Minneapolis, MN, United States
- Division of Hematology, Oncology and Transplantation, Department of Medicine, University of Minnesota, Minneapolis, MN, United States
| | - Michael A. Farrar
- Department of Laboratory Medicine and Pathology, Center for Immunology, Masonic Cancer Center, University of Minnesota, Minneapolis, MN, United States
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40
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Painter JD, Akbari O. Type 2 Innate Lymphoid Cells: Protectors in Type 2 Diabetes. Front Immunol 2021; 12:727008. [PMID: 34489979 PMCID: PMC8416625 DOI: 10.3389/fimmu.2021.727008] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2021] [Accepted: 07/29/2021] [Indexed: 12/13/2022] Open
Abstract
Type 2 innate lymphoid cells (ILC2) are the innate counterparts of Th2 cells and are critically involved in the maintenance of homeostasis in a variety of tissues. Instead of expressing specific antigen receptors, ILC2s respond to external stimuli such as alarmins released from damage. These cells help control the delicate balance of inflammation in adipose tissue, which is a determinant of metabolic outcome. ILC2s play a key role in the pathogenesis of type 2 diabetes mellitus (T2DM) through their protective effects on tissue homeostasis. A variety of crosstalk takes place between resident adipose cells and ILC2s, with each interaction playing a key role in controlling this balance. ILC2 effector function is associated with increased browning of adipose tissue and an anti-inflammatory immune profile. Trafficking and maintenance of ILC2 populations are critical for tissue homeostasis. The metabolic environment and energy source significantly affect the number and function of ILC2s in addition to affecting their interactions with resident cell types. How ILC2s react to changes in the metabolic environment is a clear determinant of the severity of disease. Treating sources of metabolic instability via critical immune cells provides a clear avenue for modulation of systemic homeostasis and new treatments of T2DM.
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Affiliation(s)
- Jacob D Painter
- Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
| | - Omid Akbari
- Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
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41
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Shao Q, Gu J, Zhou J, Wang Q, Li X, Deng Z, Lu L. Tissue Tregs and Maintenance of Tissue Homeostasis. Front Cell Dev Biol 2021; 9:717903. [PMID: 34490267 PMCID: PMC8418123 DOI: 10.3389/fcell.2021.717903] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Accepted: 07/28/2021] [Indexed: 12/21/2022] Open
Abstract
Regulatory T cells (Tregs) specifically expressing Forkhead box P3 (Foxp3) play roles in suppressing the immune response and maintaining immune homeostasis. After maturation in the thymus, Tregs leave the thymus and migrate to lymphoid tissues or non-lymphoid tissues. Increasing evidence indicates that Tregs with unique characteristics also have significant effects on non-lymphoid peripheral tissues. Tissue-resident Tregs, also called tissue Tregs, do not recirculate in the blood or lymphatics and attain a unique phenotype distinct from common Tregs in circulation. This review first summarizes the phenotype, function, and cytokine expression of these Tregs in visceral adipose tissue, skin, muscle, and other tissues. Then, how Tregs are generated, home, and are attracted to and remain resident in the tissue are discussed. Finally, how an increased understanding of these tissue Tregs might guide clinical treatment is discussed.
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Affiliation(s)
- Qing Shao
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.,Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, China.,Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, Nanjing Medical University Affiliated Cancer Hospital, Nanjing, China.,Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, China
| | - Jian Gu
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.,Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, China.,Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, Nanjing Medical University Affiliated Cancer Hospital, Nanjing, China.,Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, China
| | - Jinren Zhou
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.,Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, China.,Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, Nanjing Medical University Affiliated Cancer Hospital, Nanjing, China.,Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, China
| | - Qi Wang
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.,Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, China.,Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, Nanjing Medical University Affiliated Cancer Hospital, Nanjing, China.,Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, China
| | - Xiangyu Li
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.,Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, China.,Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, Nanjing Medical University Affiliated Cancer Hospital, Nanjing, China.,Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, China
| | - Zhenhua Deng
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.,Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, China.,Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, Nanjing Medical University Affiliated Cancer Hospital, Nanjing, China.,Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, China
| | - Ling Lu
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.,Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, China.,Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, Nanjing Medical University Affiliated Cancer Hospital, Nanjing, China.,Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, China
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42
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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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43
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Abstract
The FOXP3+CD4+ regulatory T (Treg) cells located in non-lymphoid tissues differ in phenotype and function from their lymphoid organ counterparts. Tissue Treg cells have distinct transcriptomes, T cell receptor repertoires and growth and survival factor dependencies that arm them to survive and operate in their home tissue. Their functions extend beyond immune surveillance to tissue homeostasis, including regulation of local and systemic metabolism, promotion of tissue repair and regeneration, and control of the proliferation, differentiation and fate of non-lymphoid cell progenitors. Treg cells in diverse tissues share a common FOXP3+CD4+ precursor located within lymphoid organs. This precursor undergoes definitive specialization once in the home tissue, following a multilayered array of common and tissue-distinct transcriptional programmes. Our deepening knowledge of tissue Treg cell biology will inform ongoing attempts to harness Treg cells for precision immunotherapeutics.
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44
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Insulin signaling establishes a developmental trajectory of adipose regulatory T cells. Nat Immunol 2021; 22:1175-1185. [DOI: 10.1038/s41590-021-01010-3] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2021] [Accepted: 07/22/2021] [Indexed: 12/11/2022]
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45
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Liu H, Li X, Chen R, Liu D, Tong C. Effect of left or right gastric artery interventional embolization on obesity and ghrelin/leptin expression in pigs. Am J Transl Res 2021; 13:5444-5451. [PMID: 34150142 PMCID: PMC8205808] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2020] [Accepted: 01/27/2021] [Indexed: 06/12/2023]
Abstract
OBJECTIVE To investigate the effect of left or right gastric artery interventional embolization on obesity and ghrelin/leptin expression in pigs. METHODS Thirty-two female Wuzhishan pigs aged 3-4 months were randomly divided into four groups, with eight pigs in each group: obesity + left gastric artery embolization group, obesity + right gastric artery embolization group, obesity + sham surgery group and healthy control group. The body weight and serum levels of ghrelin, leptin, interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) before the operation, one month and three months after the operation, and the gastric pathology three months after the operation were compared. RESULTS The preoperative body weight, ghrelin level, leptin level, IL-6 level and TNF-α level of the obesity + sham surgery group, obesity + left gastric artery embolization group and obesity + right gastric artery embolization group were higher than those of the healthy control group (all P<0.05). One month after the operation, the body weight, ghrelin level, leptin level, IL-6 level and TNF-α level of the obesity + sham surgery group, obesity + left gastric artery embolization group and obesity + right gastric artery embolization group were higher than those of the healthy control group. The body weight, ghrelin level, IL-6 level and TNF-α level of the obesity + sham surgery group were higher than those of the obesity + left artery embolization group and obesity + right gastric artery embolization group (all P<0.05). Three months after the operation, the body weight, ghrelin level, leptin level, IL-6 level and TNF-α level of the obesity + sham surgery group were higher than those of the obesity + left artery embolization group, obesity + right artery embolization group and the healthy control group (all P<0.05). CONCLUSION Left or right gastric artery interventional embolization in pigs can effectively reduce body weight, which may be related to the reduced secretion of ghrelin, leptin and inflammatory factors. However, the clinical application and safety of left or right gastric artery embolization still need further study.
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Affiliation(s)
- Hui Liu
- Department of Interventional Radiology, Central South University, Xiangya School of Medicine Affiliated Haikou HospitalHaikou, Hainan Province, China
| | - Xiangying Li
- Department of Radiology, Central South University, Xiangya School of Medicine Affiliated Haikou HospitalHaikou, Hainan Province, China
| | - Rihui Chen
- Department of Interventional Radiology, Central South University, Xiangya School of Medicine Affiliated Haikou HospitalHaikou, Hainan Province, China
| | - Dingcheng Liu
- Department of Interventional Radiology, Central South University, Xiangya School of Medicine Affiliated Haikou HospitalHaikou, Hainan Province, China
| | - Chao Tong
- Department of Interventional Radiology, Central South University, Xiangya School of Medicine Affiliated Haikou HospitalHaikou, Hainan Province, China
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Liébana-García R, Olivares M, Bullich-Vilarrubias C, López-Almela I, Romaní-Pérez M, Sanz Y. The gut microbiota as a versatile immunomodulator in obesity and associated metabolic disorders. Best Pract Res Clin Endocrinol Metab 2021; 35:101542. [PMID: 33980476 DOI: 10.1016/j.beem.2021.101542] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Obesity has reached epidemic proportions and is associated with chronic-low-grade inflammation and metabolic morbidities. Energy-dense diets and a sedentary lifestyle are determinants of obesity. The gut microbiome is a novel biological factor involved in obesity via interactions with the host and the diet. The gut microbiome act as a synergistic force protecting or aggravating the effects of the diet on the metabolic phenotype. The role of the microbiome in the regulation of intestinal and systemic immunity is one of the mechanisms by which it contributes to the host's response to the diet and to the pathophysiology of diet-induced obesity. Here, we review the mechanisms whereby "obesogenic" diets and the microbiome impact immunity, locally and systemically, focusing on the consequences in the gut-adipose tissue axis. We also review the structural and microbial metabolites that influence immunity and how advances in this field could help design microbiome-informed strategies to tackle obesity-related disorders more effectively.
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Affiliation(s)
- Rebeca Liébana-García
- Microbial Ecology, Nutrition & Health Research Unit, Institute of Agrochemistry and Food Technology, Spanish National Research Council (IATA-CSIC), Valencia, Spain.
| | - Marta Olivares
- Microbial Ecology, Nutrition & Health Research Unit, Institute of Agrochemistry and Food Technology, Spanish National Research Council (IATA-CSIC), Valencia, Spain.
| | - Clara Bullich-Vilarrubias
- Microbial Ecology, Nutrition & Health Research Unit, Institute of Agrochemistry and Food Technology, Spanish National Research Council (IATA-CSIC), Valencia, Spain.
| | - Inmaculada López-Almela
- Microbial Ecology, Nutrition & Health Research Unit, Institute of Agrochemistry and Food Technology, Spanish National Research Council (IATA-CSIC), Valencia, Spain.
| | - Marina Romaní-Pérez
- Microbial Ecology, Nutrition & Health Research Unit, Institute of Agrochemistry and Food Technology, Spanish National Research Council (IATA-CSIC), Valencia, Spain.
| | - Yolanda Sanz
- Microbial Ecology, Nutrition & Health Research Unit, Institute of Agrochemistry and Food Technology, Spanish National Research Council (IATA-CSIC), Valencia, Spain.
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47
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Tang H, Liu N, Feng X, Yang Y, Fang Y, Zhuang S, Dai Y, Liu M, Tang L. Circulating levels of IL-33 are elevated by obesity and positively correlated with metabolic disorders in Chinese adults. J Transl Med 2021; 19:52. [PMID: 33541367 PMCID: PMC7863234 DOI: 10.1186/s12967-021-02711-x] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2020] [Accepted: 01/21/2021] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Interleukin-33 (IL-33) plays a pivotal role in regulating innate immune response and metabolic homeostasis. However, whether its circulating level is correlated with obesity and metabolic disorders in humans remains largely unknown. We aimed to address this gap by determining IL-33 serum level and its downstream type 2 inflammatory cytokines interleukin-5 (IL-5) and interleukin-13 (IL-13) in overweight/obese population, and analyzing the specific associations between IL-33 and obesity metabolic phenotypes. METHODS 217 subjects were enrolled and divided into three groups: healthy control (HC) subjects, metabolically healthy overweight/obese (MHOO) subjects and metabolically unhealthy overweight/obese (MUOO) subjects. Circulating levels of IL-33, IL-5 and IL-13 were measured using ELISA analyses. Multivariate regression analyses were further performed to determine the independent association between IL-33 and obesity metabolic phenotypes. RESULTS Circulating levels of IL-33 were significantly elevated in subjects of MUOO group compared with HC group and MHOO group, while no significant difference was observed between the latter two groups in IL-33 levels. Consistent with this, serum levels of IL-5/13 were higher in the MUOO group compared with HC and MHOO groups. After adjusted for all confounders, MUOO phenotype was significantly associated with increased IL-33 serum levels (OR = 1.70; 95% CI 1.09-2.64; p = 0.019). With the MHOO group as the reference population, higher circulating level of IL-33 was also positively associated with MUOO phenotype after adjusting for confounders (OR = 1.50; 95% CI 1.20-1.88; p = 2.91E-4). However, there was no significant association between MHOO phenotype and IL-33 levels (p = 0.942). Trend analysis further confirmed the positive correlation between MUOO phenotype and IL-33 level (p for trend = 0.019). Additionally, IL-33 was significantly and positively correlated with diastolic blood pressure (DBP), total cholesterol (TC), alanine aminotransferase (ALT), aspartate aminotransferase (AST), white blood cell (WBC), neutrophil and IL-5 only in MUOO group, while inversely correlated with high density lipoprotein cholesterol (HDL-C) in MHOO subjects. CONCLUSION Circulating levels of IL-33 were significantly elevated in overweight/obese Chinese adults with metabolic disorders. Increased levels of IL-33 were positively associated with metabolically unhealthy overweight/obese phenotype and several metabolic syndrome risk factors.
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Affiliation(s)
- Haoneng Tang
- Department of Laboratory Medicine, The Second Xiangya Hospital, Central South University, Changsha, 410011, China
| | - Ning Liu
- Department of Laboratory Medicine, The Second Xiangya Hospital, Central South University, Changsha, 410011, China
- Medical College, Yueyang Vocational and Technical College, Yueyang, 414000, China
| | - Xiaojing Feng
- Department of Laboratory Medicine, The Second Xiangya Hospital, Central South University, Changsha, 410011, China
| | - Yanyi Yang
- Health Management Center, The Second Xiangya Hospital, Central South University, Changsha, 410011, China
| | - Yiyuan Fang
- Department of Laboratory Medicine, The Second Xiangya Hospital, Central South University, Changsha, 410011, China
| | - Siqi Zhuang
- Department of Laboratory Medicine, The Second Xiangya Hospital, Central South University, Changsha, 410011, China
| | - Yufeng Dai
- Department of Laboratory Medicine, The Second Xiangya Hospital, Central South University, Changsha, 410011, China
| | - Meilian Liu
- Department of Biochemistry and Molecular Biology, University of New Mexico Health Sciences Center, Albuquerque, NM, USA
- Department of Metabolism and Endocrinology, Metabolic Syndrome Research Center, Key Laboratory of Diabetes Immunology, Ministry of Education, National Clinical Research Center for Metabolic Diseases, The Second Xiangya Hospital, Central South University, Changsha, 410011, China
| | - Lingli Tang
- Department of Laboratory Medicine, The Second Xiangya Hospital, Central South University, Changsha, 410011, China.
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Cediel G, Codina P, Spitaleri G, Domingo M, Santiago-Vacas E, Lupón J, Bayes-Genis A. Gender-Related Differences in Heart Failure Biomarkers. Front Cardiovasc Med 2021; 7:617705. [PMID: 33469552 PMCID: PMC7813809 DOI: 10.3389/fcvm.2020.617705] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2020] [Accepted: 12/09/2020] [Indexed: 12/13/2022] Open
Abstract
Important differences in comorbidities and clinical characteristics exist between women and men with heart failure (HF). In particular, differences in the kinetics of biological circulating biomarkers—a critical component of cardiovascular care—are highly relevant. Most circulating HF biomarkers are assessed daily by clinicians without taking sex into account, despite the multiple gender-related differences observed in plasma concentrations. Even in health, compared to men, women tend to exhibit higher levels of natriuretic peptides and galectin-3 and lower levels of cardiac troponins and the cardiac stress marker, soluble ST2. Many biological factors can provide a reliable explanation for these differences, like body composition, fat distribution, or menopausal status. Notwithstanding, these sex-specific differences in biomarker levels do not reflect different pathobiological mechanisms in HF between women and men, and they do not necessarily imply a need to use different diagnostic cut-off levels in clinical practice. To date, the sex-specific prognostic value of HF biomarkers for risk stratification is an unresolved issue that future research must elucidate. This review outlines current evidence regarding gender-related differences in circulating biomarkers widely used in HF, the pathophysiological mechanisms underlying these differences, and their clinical relevance.
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Affiliation(s)
- Germán Cediel
- Heart Institute, Hospital Universitari Germans Trias i Pujol, Badalona, Spain.,Department of Medicine, CIBERCV, Autonomous University of Barcelona, Barcelona, Spain
| | - Pau Codina
- Heart Institute, Hospital Universitari Germans Trias i Pujol, Badalona, Spain.,Department of Medicine, CIBERCV, Autonomous University of Barcelona, Barcelona, Spain
| | - Giosafat Spitaleri
- Heart Institute, Hospital Universitari Germans Trias i Pujol, Badalona, Spain.,Department of Medicine, CIBERCV, Autonomous University of Barcelona, Barcelona, Spain
| | - Mar Domingo
- Heart Institute, Hospital Universitari Germans Trias i Pujol, Badalona, Spain.,Department of Medicine, CIBERCV, Autonomous University of Barcelona, Barcelona, Spain
| | - Evelyn Santiago-Vacas
- Heart Institute, Hospital Universitari Germans Trias i Pujol, Badalona, Spain.,Department of Medicine, CIBERCV, Autonomous University of Barcelona, Barcelona, Spain
| | - Josep Lupón
- Heart Institute, Hospital Universitari Germans Trias i Pujol, Badalona, Spain.,Department of Medicine, CIBERCV, Autonomous University of Barcelona, Barcelona, Spain
| | - Antoni Bayes-Genis
- Heart Institute, Hospital Universitari Germans Trias i Pujol, Badalona, Spain.,Department of Medicine, CIBERCV, Autonomous University of Barcelona, Barcelona, Spain
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Wang W, Wu J, Ji M, Wu C. Exogenous interleukin-33 promotes hepatocellular carcinoma growth by remodelling the tumour microenvironment. J Transl Med 2020; 18:477. [PMID: 33308251 PMCID: PMC7733302 DOI: 10.1186/s12967-020-02661-w] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2020] [Accepted: 12/03/2020] [Indexed: 11/25/2022] Open
Abstract
Background Interleukin-33 (IL-33) is an effective inducer of pro-inflammatory cytokines regulating innate and adaptive immunity. Inflammation could be a double-edged sword, promoting or inhibiting tumour growth. To date, the roles and mechanisms of IL-33 in tumours remain controversial. Here, we examined the effect of exogenous IL-33 on the biological characteristics of hepatocellular carcinoma (HCC) and the possible mechanism of action. Methods In this study, IL-33 expression in the tissues of 69 HCC patients was detected and its relationship with prognosis was evaluated. After establishing a mouse HCC model and IL-33 treatment operation, the infiltration of splenic myeloid-derived suppressor (MDSCs), dendritic (DCs), regulatory T, and natural killer (NK) cells was detected by flow cytometry analysis, and the vascular density of the tumour tissues was detected by immunohistochemistry to reveal the mechanism of IL-33 in HCC proliferation. Finally, the Cancer Genome Atlas database was used to analyse Gene Ontology terms the and Kyoto Encyclopaedia of Genes and Genomes pathway. Moreover, the chi-square test, two-tailed unpaired Student’s t-test, and multiple t-tests were performed using SPSS version 23.0 and GraphPad Prism 8.0 software. Results The IL-33 expression level was negatively correlated with the overall survival of HCC patients, suggesting its potential clinical significance in the prognosis of HCC. We found that systemic IL-33 administration significantly promoted the tumour size in vivo. Furthermore, the IL-33-treated mice presented decreased frequencies of tumouricidal NK and CD69+ CD8+ T cells. After IL-33 treatment, the incidence of monocytic MDSCs and conventional DCs increased, while that of granulocytic MDSCs decreased. Moreover, IL-33 promoted the formation of intracellular neovascularization. Therefore, IL-33 accelerated HCC progression by increasing the accumulation of immunosuppressive cells and neovascularization formation. Finally, we found that the transcription of IL-33 was closely related to the PI3K-Akt and MAPK pathways in Gene Set Enrichment Analysis plots, which were involved in the tumourigenesis and pathogenesis of HCC. Conclusions Taken together, IL-33 may be a key tumour promoter of HCC proliferation and tumourigenicity, an important mediator, and a potential therapeutic target for regulating HCC progression.
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Affiliation(s)
- Wenxiu Wang
- Department of Tumour Biological Treatment, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu, China
| | - Jun Wu
- Department of Oncology, The Third Affiliated Hospital of Soochow University, 185 Juqian Street, Changzhou, 213003, Jiangsu, China
| | - Mei Ji
- Department of Oncology, The Third Affiliated Hospital of Soochow University, 185 Juqian Street, Changzhou, 213003, Jiangsu, China
| | - Changping Wu
- Department of Tumour Biological Treatment, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu, China. .,Department of Oncology, The Third Affiliated Hospital of Soochow University, 185 Juqian Street, Changzhou, 213003, Jiangsu, China.
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50
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Youngblood R, Flesher CG, Delproposto J, Baker NA, Neeley CK, Li F, Lumeng CN, Shea LD, O'Rourke RW. Regulation of adipose tissue inflammation and systemic metabolism in murine obesity by polymer implants loaded with lentiviral vectors encoding human interleukin-4. Biotechnol Bioeng 2020; 117:3891-3901. [PMID: 32729936 PMCID: PMC8358590 DOI: 10.1002/bit.27523] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2020] [Revised: 07/26/2020] [Accepted: 07/28/2020] [Indexed: 11/08/2022]
Abstract
Dysfunctional adipose tissue plays a central role in the pathogenesis of the obesity-related metabolic disease, including type 2 diabetes. Targeting adipose tissue using biopolymer implants is a novel therapeutic approach for metabolic disease. We transplanted porous poly(lactide-co-glycolide) (PLG) implants coated with human interleukin-4 (hIL-4)-expressing lentivirus into epididymal white adipose tissue (eWAT) of mice fed a high-fat diet. Tissue and systemic inflammation and metabolism were studied with flow cytometry, immunohistochemistry, quantitative real-time polymerase chain reaction, adipose tissue histology, and in vivo glucose tolerance testing at 2 and 10 weeks of a high-fat diet. PLG implants carrying hIL-4-expressing lentivirus implanted into epididymal white adipose tissue of mice-regulated adipose tissue inflammation, including increased CD3+ CD4+ T-cell frequency, increased eWAT adipocyte hypertrophy, and decreased FASN and ATGL expression, along with reduced fasting blood glucose levels. These effects were observed in early obesity but were not maintained in established obesity. Local delivery of bioimplants loaded with cytokine-expressing lentivirus vectors to adipose tissue influences tissue inflammation and systemic metabolism in early obesity. Further study will be required to show more durable metabolic effects. These data demonstrate that polymer biomaterials implanted into adipose tissue have the potential to modulate local tissue and systemic inflammation and metabolism.
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Affiliation(s)
- Richard Youngblood
- Department of Biomedical Engineering, University of Michigan, Ann Arbor, Michigan
| | - Carmen G Flesher
- Department of Surgery, University of Michigan Medical School, Ann Arbor, Michigan
| | - Jennifer Delproposto
- Department of Pediatrics and Communicable Diseases, University of Michigan Medical School, Ann Arbor, Michigan
| | - Nicki A Baker
- Department of Surgery, University of Michigan Medical School, Ann Arbor, Michigan
| | - Christopher K Neeley
- Department of Surgery, University of Michigan Medical School, Ann Arbor, Michigan
| | - Fanghua Li
- Department of Biomedical Engineering, University of Michigan, Ann Arbor, Michigan
| | - Carey N Lumeng
- Department of Pediatrics and Communicable Diseases, University of Michigan Medical School, Ann Arbor, Michigan
- Graduate Program in Immunology, Veterans Affairs Ann Arbor Healthcare System, Ann Arbor, Michigan
- Graduate Program in Cellular and Molecular Biology, Veterans Affairs Ann Arbor Healthcare System, Ann Arbor, Michigan
| | - Lonnie D Shea
- Department of Biomedical Engineering, University of Michigan, Ann Arbor, Michigan
| | - Robert W O'Rourke
- Department of Surgery, University of Michigan Medical School, Ann Arbor, Michigan
- Department of Surgery, Veterans Affairs Ann Arbor Healthcare System, Ann Arbor, Michigan
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