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1
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Geuking MB, Thomson CA. The amazing impact of gut microbes on lifelong metabolic health. Cell Host Microbe 2025; 33:603-604. [PMID: 40373742 DOI: 10.1016/j.chom.2025.04.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2025] [Accepted: 04/09/2025] [Indexed: 05/17/2025]
Abstract
A new study published in Science1 reveals a crucial connection between our neonatal gut microbiota composition and the long-term health of our pancreas, specifically focusing on β-cell development and the subsequent lifelong impact microbe-induced β-cell expansion has on metabolic health, including prevention of, and even potential reversal of, diabetes.
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Affiliation(s)
- M B Geuking
- Department of Microbiology, Immunology & Infectious Diseases, Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 1N4, Canada.
| | - C A Thomson
- Department of Physiology & Pharmacology, Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 1N4, Canada
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2
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Jelleschitz J, Heider S, Kehm R, Baumgarten P, Ott C, Schnell V, Grune T, Höhn A. Insulitis and aging: Immune cell dynamics in Langerhans islets. Redox Biol 2025; 82:103587. [PMID: 40101534 PMCID: PMC11957801 DOI: 10.1016/j.redox.2025.103587] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2024] [Revised: 02/07/2025] [Accepted: 03/05/2025] [Indexed: 03/20/2025] Open
Abstract
With increasing age, the risk for age-related type-2-diabetes also increases due to impaired glucose tolerance and insulin secretion. This disease process may be influenced by various factors, including immune cell triggered inflammation and fibrosis. Although immune cells are a necessary component of islets, little is known about immune cell accumulation, immune cell subtype shifts and subsequent influence on glucose metabolism in healthy aging. However, this is critical for understanding the mechanisms that influence β-cell health. Therefore, we studied young and old male C57BL/6J mice, focusing on immune cell composition, patterns of accumulation, and the presence of fibrosis within the pancreatic islets. Our findings demonstrate that insulitis occurs in healthy aged mice without immediate development of a diabetic phenotype. Aged islets exhibited an increase in leukocytes and a shift in immune cell composition. While insulitis typically involves excessive immune cell accumulation, we observed a moderate increase in macrophages and T-cells during aging, which may support β-cell proliferation via cytokine secretion. In fact, aged mice in our study showed an increase in β-cell mass as well as a partially higher insulin secretory capacity, which compensated for the loss of β-cell functionality in insulitic islets and led to improved glucose tolerance. Furthermore, fibrosis which is normally triggered by immune cells, increased with age but appears to reach a steady state, emphasizing the importance of counter-regulatory mechanisms and immune system regulation. Our results suggest, that immune cell subtypes change with age and that non-pathological accumulation of immune-cells may regulate glucose metabolism through secretion of cytokines.
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Affiliation(s)
- Julia Jelleschitz
- Department of Molecular Toxicology, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany
| | - Sophie Heider
- Department of Molecular Toxicology, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany; German Center for Diabetes Research (DZD), München-Neuherberg, Germany
| | - Richard Kehm
- Department of Molecular Toxicology, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany
| | - Patricia Baumgarten
- Department of Molecular Toxicology, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany; DZHK (German Center for Cardiovascular Research), Partner site Berlin, Berlin, Germany
| | - Christiane Ott
- Department of Molecular Toxicology, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany; DZHK (German Center for Cardiovascular Research), Partner site Berlin, Berlin, Germany
| | - Vanessa Schnell
- Department of Molecular Toxicology, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany
| | - Tilman Grune
- Department of Molecular Toxicology, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany; German Center for Diabetes Research (DZD), München-Neuherberg, Germany; DZHK (German Center for Cardiovascular Research), Partner site Berlin, Berlin, Germany
| | - Annika Höhn
- Department of Molecular Toxicology, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany; German Center for Diabetes Research (DZD), München-Neuherberg, Germany.
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3
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Jonsson A, Korsgren O, Hedin A. Transcriptomic characterization of human pancreatic CD206- and CD206 + macrophages. Sci Rep 2025; 15:12037. [PMID: 40199933 PMCID: PMC11978877 DOI: 10.1038/s41598-025-96313-y] [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: 11/26/2024] [Accepted: 03/27/2025] [Indexed: 04/10/2025] Open
Abstract
Macrophages reside in all organs and participate in homeostatic- and immune regulative processes. Little is known about pancreatic macrophage gene expression. In the present study, global gene expression was characterized in human pancreatic macrophage subpopulations. CD206- and CD206 + macrophages were sorted separately from pancreatic islets and exocrine tissue to high purity using flow cytometry, followed by RNA-seq analysis. Comparing CD206- with CD206 + macrophages, CD206- showed enrichment in histones, proliferation and cell cycle regulation, glycolysis and SPP1-associated immunosuppressive polarization while CD206 + showed enrichment in complement and coagulation-, IL-10 and IL-2RA immune regulation, as well as scavenging-related gene sets. Comparing islet CD206- with exocrine CD206-, enrichments in islet samples included two sets involved in immune regulation, while enrichments in exocrine samples included sets related to extracellular matrix and immune activation. Fewer differences were found between CD206 + macrophages, with enrichments in islet samples including two IL2-RA related gene sets, while enrichments in exocrine samples included sets related to extracellular matrix and immune activation. Comparing macrophages between individuals with normoglycemia, elevated HbA1c or type 2 diabetes, only a few diverse differentially expressed genes were identified. This work characterizes global gene expression and identifies differences between CD206- and CD206 + macrophage populations within the human pancreas.
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Affiliation(s)
- Alexander Jonsson
- Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
| | - Olle Korsgren
- Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
- Institute of Medicine, University of Gothenburg, Gothenburg, Sweden
| | - Anders Hedin
- Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
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4
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Hill JH, Bell R, Barrios L, Baird H, Ost K, Greenewood M, Monts JK, Tracy E, Meili CH, Chiaro TR, Weis AM, Guillemin K, Beaudin AE, Murtaugh LC, Stephens WZ, Round JL. Neonatal fungi promote lifelong metabolic health through macrophage-dependent β cell development. Science 2025; 387:eadn0953. [PMID: 40048508 PMCID: PMC12036834 DOI: 10.1126/science.adn0953] [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: 11/21/2023] [Accepted: 11/19/2024] [Indexed: 03/14/2025]
Abstract
Loss of early-life microbial diversity is correlated with diabetes, yet mechanisms by which microbes influence disease remain elusive. We report a critical neonatal window in mice when microbiota disruption results in lifelong metabolic consequences stemming from reduced β cell development. We show evidence for the existence of a similar program in humans and identify specific fungi and bacteria that are sufficient for β cell growth. The microbiota also plays an important role in seeding islet-resident macrophages, and macrophage depletion during development reduces β cells. Candida dubliniensis increases β cells in a macrophage-dependent manner through distinctive cell wall composition and reduces murine diabetes incidence. Provision of C. dubliniensis after β cell ablation or antibiotic treatment improves β cell function. These data identify fungi as critical early-life commensals that promote long-term metabolic health.
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Affiliation(s)
- Jennifer Hampton Hill
- Department of Pathology, Division of Microbiology and Immunology, University of Utah, Salt Lake City, UT, USA
| | - Rickesha Bell
- Department of Pathology, Division of Microbiology and Immunology, University of Utah, Salt Lake City, UT, USA
| | - Logan Barrios
- Department of Pathology, Division of Microbiology and Immunology, University of Utah, Salt Lake City, UT, USA
| | - Halli Baird
- Department of Pathology, Division of Microbiology and Immunology, University of Utah, Salt Lake City, UT, USA
| | - Kyla Ost
- Department of Immunology and Microbiology, University of Colorado Anschutz School of Medicine, Aurora, CO, USA
| | - Morgan Greenewood
- Department of Pathology, Division of Microbiology and Immunology, University of Utah, Salt Lake City, UT, USA
| | - Josh K. Monts
- HSC Flow Cytometry Core, University of Utah, Salt Lake City, UT, USA
| | - Erin Tracy
- Department of Pathology, Division of Microbiology and Immunology, University of Utah, Salt Lake City, UT, USA
| | - Casey H. Meili
- Department of Pharmacology and Toxicology, University of Utah, Salt Lake City, UT, USA
| | - Tyson R. Chiaro
- Department of Pathology, Division of Microbiology and Immunology, University of Utah, Salt Lake City, UT, USA
| | - Allison M. Weis
- Department of Pathology, Division of Microbiology and Immunology, University of Utah, Salt Lake City, UT, USA
| | - Karen Guillemin
- Institute of Molecular Biology, University of Oregon, Eugene, OR, USA
- Humans and the Microbiome Program, Canadian Institute for Advanced Research, Toronto, Ontario, Canada
| | - Anna E. Beaudin
- Department of Pathology, Division of Microbiology and Immunology, University of Utah, Salt Lake City, UT, USA
- Department of Internal Medicine, Division of Hematology and Hematologic Malignancies, and Program in Molecular Medicine, University of Utah, Salt Lake City, UT, USA
| | | | - W. Zac Stephens
- Department of Pathology, Division of Microbiology and Immunology, University of Utah, Salt Lake City, UT, USA
| | - June L. Round
- Department of Pathology, Division of Microbiology and Immunology, University of Utah, Salt Lake City, UT, USA
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5
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Meier DT, de Paula Souza J, Donath MY. Targeting the NLRP3 inflammasome-IL-1β pathway in type 2 diabetes and obesity. Diabetologia 2025; 68:3-16. [PMID: 39496966 DOI: 10.1007/s00125-024-06306-1] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2024] [Accepted: 09/30/2024] [Indexed: 11/06/2024]
Abstract
Increased activity of the NACHT, LRR and PYD domains-containing protein 3 (NLRP3) inflammasome-IL-1β pathway is observed in obesity and contributes to the development of type 2 diabetes and its complications. In this review, we describe the pathological activation of IL-1β by metabolic stress, ageing and the microbiome and present data on the role of IL-1β in metabolism. We explore the physiological role of the IL-1β pathway in insulin secretion and the relationship between circulating levels of IL-1β and the development of diabetes and associated diseases. We highlight the paradoxical nature of IL-1β as both a friend and a foe in glucose regulation and provide details on clinical translation, including the glucose-lowering effects of IL-1 antagonism and its impact on disease modification. We also discuss the potential role of IL-1β in obesity, Alzheimer's disease, fatigue, gonadal dysfunction and related disorders such as rheumatoid arthritis and gout. Finally, we address the safety of NLRP3 inhibition and IL-1 antagonists and the prospect of using this therapeutic approach for the treatment of type 2 diabetes and its comorbidities.
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Affiliation(s)
- Daniel T Meier
- Clinic of Endocrinology, Diabetes and Metabolism, University Hospital Basel, Basel, Switzerland.
- Department of Biomedicine, University of Basel, Basel, Switzerland.
| | - Joyce de Paula Souza
- Clinic of Endocrinology, Diabetes and Metabolism, University Hospital Basel, Basel, Switzerland
- Department of Biomedicine, University of Basel, Basel, Switzerland
| | - Marc Y Donath
- Clinic of Endocrinology, Diabetes and Metabolism, University Hospital Basel, Basel, Switzerland.
- Department of Biomedicine, University of Basel, Basel, Switzerland.
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6
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Lee CZW, Spagnoli FM. Nurturing protectors: Macrophages in the human pancreatic islet. Cell Stem Cell 2024; 31:1553-1554. [PMID: 39515296 DOI: 10.1016/j.stem.2024.10.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2024] [Revised: 10/03/2024] [Accepted: 10/07/2024] [Indexed: 11/16/2024]
Abstract
Two recent publications in Cell Stem Cell, Yang et al.1 and Migliorini et al.,2 utilized pluripotent stem cell-derived co-culture systems to explore the role of macrophages within the pancreatic islet during development and disease states.
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Affiliation(s)
- Christopher Z W Lee
- Centre for Gene Therapy and Regenerative Medicine, King's College London, London, Great Maze Pond, London SE1 9RT, UK
| | - Francesca M Spagnoli
- Centre for Gene Therapy and Regenerative Medicine, King's College London, London, Great Maze Pond, London SE1 9RT, UK.
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7
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Yang L, Han Y, Zhang T, Dong X, Ge J, Roy A, Zhu J, Lu T, Jeya Vandana J, de Silva N, Robertson CC, Xiang JZ, Pan C, Sun Y, Que J, Evans T, Liu C, Wang W, Naji A, Parker SCJ, Schwartz RE, Chen S. Human vascularized macrophage-islet organoids to model immune-mediated pancreatic β cell pyroptosis upon viral infection. Cell Stem Cell 2024; 31:1612-1629.e8. [PMID: 39232561 PMCID: PMC11546835 DOI: 10.1016/j.stem.2024.08.007] [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: 11/17/2023] [Revised: 06/05/2024] [Accepted: 08/09/2024] [Indexed: 09/06/2024]
Abstract
There is a paucity of human models to study immune-mediated host damage. Here, we utilized the GeoMx spatial multi-omics platform to analyze immune cell changes in COVID-19 pancreatic autopsy samples, revealing an accumulation of proinflammatory macrophages. Single-cell RNA sequencing (scRNA-seq) analysis of human islets exposed to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or coxsackievirus B4 (CVB4) viruses identified activation of proinflammatory macrophages and β cell pyroptosis. To distinguish viral versus proinflammatory-macrophage-mediated β cell pyroptosis, we developed human pluripotent stem cell (hPSC)-derived vascularized macrophage-islet (VMI) organoids. VMI organoids exhibited enhanced marker expression and function in both β cells and endothelial cells compared with separately cultured cells. Notably, proinflammatory macrophages within VMI organoids induced β cell pyroptosis. Mechanistic investigations highlighted TNFSF12-TNFRSF12A involvement in proinflammatory-macrophage-mediated β cell pyroptosis. This study established hPSC-derived VMI organoids as a valuable tool for studying immune-cell-mediated host damage and uncovered the mechanism of β cell damage during viral exposure.
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Affiliation(s)
- Liuliu Yang
- Department of Surgery, Weill Cornell Medicine, 1300 York Avenue, New York, NY 10065, USA; Center for Genomic Health, Weill Cornell Medicine, 1300 York Avenue, New York, NY 10065, USA; State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Disease, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300020, China; Tianjin Institute of Health Science, Tianjin 301600, China.
| | - Yuling Han
- Department of Surgery, Weill Cornell Medicine, 1300 York Avenue, New York, NY 10065, USA; Center for Genomic Health, Weill Cornell Medicine, 1300 York Avenue, New York, NY 10065, USA; Key Laboratory of Organ Regeneration and Reconstruction, State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China; Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China
| | - Tuo Zhang
- Genomic Resource Core Facility, Weill Cornell Medicine, New York, NY 10065, USA
| | - Xue Dong
- Department of Surgery, Weill Cornell Medicine, 1300 York Avenue, New York, NY 10065, USA
| | - Jian Ge
- Columbia Center for Human Development, Department of Medicine, Columbia University Irving Medical Center, New York, NY 10032, USA
| | - Aadita Roy
- Department of Surgery, Weill Cornell Medicine, 1300 York Avenue, New York, NY 10065, USA
| | - Jiajun Zhu
- Department of Surgery, Weill Cornell Medicine, 1300 York Avenue, New York, NY 10065, USA; Center for Genomic Health, Weill Cornell Medicine, 1300 York Avenue, New York, NY 10065, USA
| | - Tiankun Lu
- Department of Surgery, Weill Cornell Medicine, 1300 York Avenue, New York, NY 10065, USA; Center for Genomic Health, Weill Cornell Medicine, 1300 York Avenue, New York, NY 10065, USA
| | - J Jeya Vandana
- Department of Surgery, Weill Cornell Medicine, 1300 York Avenue, New York, NY 10065, USA; Center for Genomic Health, Weill Cornell Medicine, 1300 York Avenue, New York, NY 10065, USA
| | - Neranjan de Silva
- Department of Surgery, Weill Cornell Medicine, 1300 York Avenue, New York, NY 10065, USA; Center for Genomic Health, Weill Cornell Medicine, 1300 York Avenue, New York, NY 10065, USA
| | - Catherine C Robertson
- Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, USA
| | - Jenny Z Xiang
- Genomic Resource Core Facility, Weill Cornell Medicine, New York, NY 10065, USA
| | - Chendong Pan
- Genomic Resource Core Facility, Weill Cornell Medicine, New York, NY 10065, USA
| | - Yanjie Sun
- Genomic Resource Core Facility, Weill Cornell Medicine, New York, NY 10065, USA
| | - Jianwen Que
- Columbia Center for Human Development, Department of Medicine, Columbia University Irving Medical Center, New York, NY 10032, USA
| | - Todd Evans
- Department of Surgery, Weill Cornell Medicine, 1300 York Avenue, New York, NY 10065, USA; Center for Genomic Health, Weill Cornell Medicine, 1300 York Avenue, New York, NY 10065, USA
| | - Chengyang Liu
- Department of Surgery, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA
| | - Wei Wang
- Department of Surgery, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA
| | - Ali Naji
- Department of Surgery, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA
| | - Stephen C J Parker
- Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, USA; Department of Human Genetics, University of Michigan, Ann Arbor, MI, USA; Department of Biostatistics, University of Michigan, Ann Arbor, MI, USA
| | - Robert E Schwartz
- Division of Gastroenterology and Hepatology, Department of Medicine, Weill Cornell Medicine, 1300 York Avenue, New York, NY 10065, USA; Department of Physiology, Biophysics and Systems Biology, Weill Cornell Medicine, 1300 York Avenue, New York, NY 10065, USA.
| | - Shuibing Chen
- Department of Surgery, Weill Cornell Medicine, 1300 York Avenue, New York, NY 10065, USA; Center for Genomic Health, Weill Cornell Medicine, 1300 York Avenue, New York, NY 10065, USA.
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8
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Migliorini A, Ge S, Atkins MH, Oakie A, Sambathkumar R, Kent G, Huang H, Sing A, Chua C, Gehring AJ, Keller GM, Notta F, Nostro MC. Embryonic macrophages support endocrine commitment during human pancreatic differentiation. Cell Stem Cell 2024; 31:1591-1611.e8. [PMID: 39406230 DOI: 10.1016/j.stem.2024.09.011] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2023] [Revised: 07/02/2024] [Accepted: 09/12/2024] [Indexed: 11/10/2024]
Abstract
Organogenesis is a complex process that relies on a dynamic interplay between extrinsic factors originating from the microenvironment and tissue-specific intrinsic factors. For pancreatic endocrine cells, the local niche consists of acinar and ductal cells as well as neuronal, immune, endothelial, and stromal cells. Hematopoietic cells have been detected in human pancreas as early as 6 post-conception weeks, but whether they play a role during human endocrinogenesis remains unknown. To investigate this, we performed single-nucleus RNA sequencing (snRNA-seq) of the second-trimester human pancreas and identified a wide range of hematopoietic cells, including two distinct subsets of tissue-resident macrophages. Leveraging this discovery, we developed a co-culture system of human embryonic stem cell-derived endocrine-macrophage organoids to model their interaction in vitro. Here, we show that macrophages support the differentiation and viability of endocrine cells in vitro and enhance tissue engraftment, highlighting their potential role in tissue engineering strategies for diabetes.
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Affiliation(s)
- Adriana Migliorini
- McEwen Stem Cell Institute, University Health Network, Toronto, ON M5G 1L7, Canada.
| | - Sabrina Ge
- Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 1L7, Canada; Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada
| | - Michael H Atkins
- McEwen Stem Cell Institute, University Health Network, Toronto, ON M5G 1L7, Canada; Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 1L7, Canada
| | - Amanda Oakie
- McEwen Stem Cell Institute, University Health Network, Toronto, ON M5G 1L7, Canada
| | | | - Gregory Kent
- McEwen Stem Cell Institute, University Health Network, Toronto, ON M5G 1L7, Canada
| | - Haiyang Huang
- McEwen Stem Cell Institute, University Health Network, Toronto, ON M5G 1L7, Canada; Department of Physiology, University of Toronto, Toronto, ON M5S 1A8, Canada
| | - Angel Sing
- McEwen Stem Cell Institute, University Health Network, Toronto, ON M5G 1L7, Canada
| | - Conan Chua
- Toronto Centre for Liver Disease, Toronto General Hospital Research Institute, University Health Network, Toronto, ON M5G 2C4, Canada; Institute of Medical Sciences, University of Toronto, Toronto, ON M5S 1A8, Canada
| | - Adam J Gehring
- Toronto Centre for Liver Disease, Toronto General Hospital Research Institute, University Health Network, Toronto, ON M5G 2C4, Canada; Institute of Medical Sciences, University of Toronto, Toronto, ON M5S 1A8, Canada
| | - Gordon M Keller
- McEwen Stem Cell Institute, University Health Network, Toronto, ON M5G 1L7, Canada; Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 1L7, Canada; Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada
| | - Faiyaz Notta
- Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 1L7, Canada; Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada; PanCuRx Translational Research Initiative, Ontario Institute for Cancer Research, Toronto, ON M5G 0A3, Canada
| | - Maria Cristina Nostro
- McEwen Stem Cell Institute, University Health Network, Toronto, ON M5G 1L7, Canada; Department of Physiology, University of Toronto, Toronto, ON M5S 1A8, Canada; Ajmera Transplant Centre, Toronto General Hospital Research Institute, University Health Network, Toronto, ON M5G 2C4, Canada.
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9
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Golden TN, Garifallou JP, Conine CC, Simmons RA. The effect of intrauterine growth restriction on the developing pancreatic immune system. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.09.19.613902. [PMID: 39386426 PMCID: PMC11463653 DOI: 10.1101/2024.09.19.613902] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 10/12/2024]
Abstract
Immune cells in the pancreas are known to participate in organ development. However, the resident pancreatic immune system has yet to be fully defined. Immune cells also play a role in pathology and are implicated in diseases such as diabetes induced by intrauterine growth restriction (IUGR). We hypothesized that the resident immune system is established during neonatal development and disrupted by IUGR. Using single cell RNAseq and flow cytometry we identified many immune cell populations in the near-term fetus (at embryologic day 22) and neonatal (postnatal day 1, 7, &14) islets, non-endocrine pancreas, and the spleen in the rat. Using flow cytometry, we observed the resident immune system is established during neonatal development in the pancreas and spleen. We identified 9 distinct immune populations in the pancreatic islets and 8 distinct immune populations in the spleen by single cell RNAseq. There were no sex-specific differences in the relative proportion of immune cells in the pancreas or spleen. Finally, we tested if IUGR disrupted the neonatal immune system using bilateral uterine artery ligation. We found significant changes to the percentage of CD11B+ HIS48- and CD8+ T cells in the islets and non-endocrine pancreas and in the spleen. IUGR-induced alterations were influenced by the tissue environment and the sex of the offspring. Future research to define the role of these immune cells in pancreatic development may identify disrupted pathways that contribute to the development of diabetes following IUGR.
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Affiliation(s)
- Thea N. Golden
- Department of Obstetrics and Gynecology, Perelman School of Medicine, University of Pennsylvania
- Center of Excellence in Environmental Toxicology, Perelman School of Medicine, University of Pennsylvania
- Center for Women’s Health and Reproductive Medicine, Perelman School of Medicine, University of Pennsylvania
| | | | - Colin C. Conine
- Center of Excellence in Environmental Toxicology, Perelman School of Medicine, University of Pennsylvania
- Center for Women’s Health and Reproductive Medicine, Perelman School of Medicine, University of Pennsylvania
- Department of Neonatology, Children’s Hospital of Philadelphia
- Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania; Philadelphia, USA
- Institute of Regenerative Medicine, Perelman School of Medicine at the University of Pennsylvania; Philadelphia, USA
- Department of Genetics-Epigenetics Institute, Perelman School of Medicine at the University of Pennsylvania; Philadelphia, USA
| | - Rebecca A. Simmons
- Center of Excellence in Environmental Toxicology, Perelman School of Medicine, University of Pennsylvania
- Center for Women’s Health and Reproductive Medicine, Perelman School of Medicine, University of Pennsylvania
- Department of Neonatology, Children’s Hospital of Philadelphia
- Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania; Philadelphia, USA
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10
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Wensveen FM, Šestan M, Polić B. The immunology of sickness metabolism. Cell Mol Immunol 2024; 21:1051-1065. [PMID: 39107476 PMCID: PMC11364700 DOI: 10.1038/s41423-024-01192-4] [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] [Received: 03/26/2024] [Accepted: 05/29/2024] [Indexed: 09/01/2024] Open
Abstract
Everyone knows that an infection can make you feel sick. Although we perceive infection-induced changes in metabolism as a pathology, they are a part of a carefully regulated process that depends on tissue-specific interactions between the immune system and organs involved in the regulation of systemic homeostasis. Immune-mediated changes in homeostatic parameters lead to altered production and uptake of nutrients in circulation, which modifies the metabolic rate of key organs. This is what we experience as being sick. The purpose of sickness metabolism is to generate a metabolic environment in which the body is optimally able to fight infection while denying vital nutrients for the replication of pathogens. Sickness metabolism depends on tissue-specific immune cells, which mediate responses tailored to the nature and magnitude of the threat. As an infection increases in severity, so do the number and type of immune cells involved and the level to which organs are affected, which dictates the degree to which we feel sick. Interestingly, many alterations associated with metabolic disease appear to overlap with immune-mediated changes observed following infection. Targeting processes involving tissue-specific interactions between activated immune cells and metabolic organs therefore holds great potential for treating both people with severe infection and those with metabolic disease. In this review, we will discuss how the immune system communicates in situ with organs involved in the regulation of homeostasis and how this communication is impacted by infection.
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Affiliation(s)
| | - Marko Šestan
- University of Rijeka Faculty of Medicine, Rijeka, Croatia
| | - Bojan Polić
- University of Rijeka Faculty of Medicine, Rijeka, Croatia
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11
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Szymańczyk S, Kras K, Osiak-Wicha C, Kapica M, Puzio I, Antushevich H, Kuwahara A, Kato I, Arciszewski MB. Immunodetection of selected pancreatic hormones under intragastric administration of apelin-13, a novel endogenous ligand for an angiotensin-like orphan G-protein coupled receptor, in unweaned rats. J Vet Res 2024; 68:461-468. [PMID: 39318524 PMCID: PMC11418381 DOI: 10.2478/jvetres-2024-0042] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2023] [Accepted: 07/30/2024] [Indexed: 09/26/2024] Open
Abstract
Introduction This study investigated the effects of intragastric administration of apelin-13 on the secretion of critical pancreatic hormones in a cohort of three-week-old Wistar rats. The research aimed to uncover apelin's modulatory roles in endocrine interactions dictating metabolic homeostasis during early life. Material and Methods Rats were randomly assigned to control or experimental groups, receiving apelin-13 or saline for 14 days. The study population consisted of three-week-old Wistar rats of both sexes, weighing between 20 and 25 grams. Histological examination, analysis of variance and t-tests were employed to assess significant differences. Results Distinctive alterations in large islet morphology were observed, indicating a notable reduction in size. Additionally, an increase in alpha- and beta-cell density within specific islet sizes was noted, suggesting significant changes in cell populations. The study found a substantial increase in mitotic activity and a decrease in apoptosis in small and medium-sized islets post apelin-13 administration, indicating its potential role in regulating cell survival and proliferation. Conclusion The notable reduction in large islet size coupled with increased alpha and beta cell density implies a targeted impact of apelin-13 on pancreatic cell dynamics. Also, the observed increase in mitotic activity and decrease in apoptosis in small and medium-sized islets suggest its potential regulatory role in cell survival and proliferation within the pancreatic microenvironment.
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Affiliation(s)
| | - Katarzyna Kras
- Department of Animal Anatomy and Histology, Faculty of Veterinary Medicine, University of Life Sciences in Lublin, 20-950Lublin, Poland
| | - Cezary Osiak-Wicha
- Department of Animal Anatomy and Histology, Faculty of Veterinary Medicine, University of Life Sciences in Lublin, 20-950Lublin, Poland
| | | | - Iwona Puzio
- Department of Animal Physiology, Lublin, Poland
| | - Hanna Antushevich
- Kielanowski Institute of Animal Physiology and Nutrition Polish Academy of Sciences, Department of Genetic Engineering, 05-110Jabłonna, Poland
| | - Atsukazu Kuwahara
- Laboratory of Physiology, Institute for Environmental Sciences, University of Shizuoka, 422-8526Shizuoka, Japan
| | - Ikuo Kato
- Department of Bioorganic Chemistry, Faculty of Pharmaceutical Sciences, Hokuriku University, 920-1154Kanazawa, Japan
| | - Marcin B. Arciszewski
- Department of Animal Anatomy and Histology, Faculty of Veterinary Medicine, University of Life Sciences in Lublin, 20-950Lublin, Poland
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12
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Ahamed F, Eppler N, Jones E, Zhang Y. Understanding Macrophage Complexity in Metabolic Dysfunction-Associated Steatotic Liver Disease: Transitioning from the M1/M2 Paradigm to Spatial Dynamics. LIVERS 2024; 4:455-478. [PMID: 39328386 PMCID: PMC11426415 DOI: 10.3390/livers4030033] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 09/28/2024] Open
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) encompasses metabolic dysfunction-associated fatty liver (MASL) and metabolic dysfunction-associated steatohepatitis (MASH), with MASH posing a risk of progression to cirrhosis and hepatocellular carcinoma (HCC). The global prevalence of MASLD is estimated at approximately a quarter of the population, with significant healthcare costs and implications for liver transplantation. The pathogenesis of MASLD involves intrahepatic liver cells, extrahepatic components, and immunological aspects, particularly the involvement of macrophages. Hepatic macrophages are a crucial cellular component of the liver and play important roles in liver function, contributing significantly to tissue homeostasis and swift responses during pathophysiological conditions. Recent advancements in technology have revealed the remarkable heterogeneity and plasticity of hepatic macrophage populations and their activation states in MASLD, challenging traditional classification methods like the M1/M2 paradigm and highlighting the coexistence of harmful and beneficial macrophage phenotypes that are dynamically regulated during MASLD progression. This complexity underscores the importance of considering macrophage heterogeneity in therapeutic targeting strategies, including their distinct ontogeny and functional phenotypes. This review provides an overview of macrophage involvement in MASLD progression, combining traditional paradigms with recent insights from single-cell analysis and spatial dynamics. It also addresses unresolved questions and challenges in this area.
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Affiliation(s)
- Forkan Ahamed
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, MS 1018, 3901 Rainbow Boulevard, Kansas City, KS 66160, USA
| | - Natalie Eppler
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, MS 1018, 3901 Rainbow Boulevard, Kansas City, KS 66160, USA
| | - Elizabeth Jones
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, MS 1018, 3901 Rainbow Boulevard, Kansas City, KS 66160, USA
| | - Yuxia Zhang
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, MS 1018, 3901 Rainbow Boulevard, Kansas City, KS 66160, USA
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13
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Yang L, Han Y, Zhang T, Dong X, Ge J, Roy A, Zhu J, Lu T, Vandana JJ, de Silva N, Robertson CC, Xiang JZ, Pan C, Sun Y, Que J, Evans T, Liu C, Wang W, Naji A, Parker SC, Schwartz RE, Chen S. Human Vascularized Macrophage-Islet Organoids to Model Immune-Mediated Pancreatic β cell Pyroptosis upon Viral Infection. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.08.05.606734. [PMID: 39149298 PMCID: PMC11326194 DOI: 10.1101/2024.08.05.606734] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 08/17/2024]
Abstract
There is a paucity of human models to study immune-mediated host damage. Here, we utilized the GeoMx spatial multi-omics platform to analyze immune cell changes in COVID-19 pancreatic autopsy samples, revealing an accumulation of proinflammatory macrophages. Single cell RNA-seq analysis of human islets exposed to SARS-CoV-2 or Coxsackievirus B4 (CVB4) viruses identified activation of proinflammatory macrophages and β cell pyroptosis. To distinguish viral versus proinflammatory macrophage-mediated β cell pyroptosis, we developed human pluripotent stem cell (hPSC)-derived vascularized macrophage-islet (VMI) organoids. VMI organoids exhibited enhanced marker expression and function in both β cells and endothelial cells compared to separately cultured cells. Notably, proinflammatory macrophages within VMI organoids induced β cell pyroptosis. Mechanistic investigations highlighted TNFSF12-TNFRSF12A involvement in proinflammatory macrophage-mediated β cell pyroptosis. This study established hPSC-derived VMI organoids as a valuable tool for studying immune cell-mediated host damage and uncovered mechanism of β cell damage during viral exposure.
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Affiliation(s)
- Liuliu Yang
- Department of Surgery, Weill Cornell Medicine, 1300 York Ave, New York, NY, 10065, USA
- Center for Genomic Health, Weill Cornell Medicine, 1300 York Ave, New York, NY, 10065, USA
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Disease, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300020, China
- Tianjin Institute of Health Science, Tianjin 301600, China
| | - Yuling Han
- Department of Surgery, Weill Cornell Medicine, 1300 York Ave, New York, NY, 10065, USA
- Center for Genomic Health, Weill Cornell Medicine, 1300 York Ave, New York, NY, 10065, USA
- Key Laboratory of Organ Regeneration and Reconstruction, State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China
| | - Tuo Zhang
- Genomic Resource Core Facility, Weill Cornell Medicine, New York, NY 10065, USA
| | - Xue Dong
- Department of Surgery, Weill Cornell Medicine, 1300 York Ave, New York, NY, 10065, USA
| | - Jian Ge
- Columbia Center for Human Development, Department of Medicine, Columbia University Irving Medical Center, New York, NY 10032, USA
| | - Aadita Roy
- Department of Surgery, Weill Cornell Medicine, 1300 York Ave, New York, NY, 10065, USA
| | - Jiajun Zhu
- Department of Surgery, Weill Cornell Medicine, 1300 York Ave, New York, NY, 10065, USA
- Center for Genomic Health, Weill Cornell Medicine, 1300 York Ave, New York, NY, 10065, USA
| | - Tiankun Lu
- Department of Surgery, Weill Cornell Medicine, 1300 York Ave, New York, NY, 10065, USA
- Center for Genomic Health, Weill Cornell Medicine, 1300 York Ave, New York, NY, 10065, USA
| | - J. Jeya Vandana
- Department of Surgery, Weill Cornell Medicine, 1300 York Ave, New York, NY, 10065, USA
- Center for Genomic Health, Weill Cornell Medicine, 1300 York Ave, New York, NY, 10065, USA
| | - Neranjan de Silva
- Department of Surgery, Weill Cornell Medicine, 1300 York Ave, New York, NY, 10065, USA
- Center for Genomic Health, Weill Cornell Medicine, 1300 York Ave, New York, NY, 10065, USA
| | - Catherine C. Robertson
- Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, USA
| | - Jenny Z Xiang
- Genomic Resource Core Facility, Weill Cornell Medicine, New York, NY 10065, USA
| | - Chendong Pan
- Genomic Resource Core Facility, Weill Cornell Medicine, New York, NY 10065, USA
| | - Yanjie Sun
- Genomic Resource Core Facility, Weill Cornell Medicine, New York, NY 10065, USA
| | - Jianwen Que
- Columbia Center for Human Development, Department of Medicine, Columbia University Irving Medical Center, New York, NY 10032, USA
| | - Todd Evans
- Department of Surgery, Weill Cornell Medicine, 1300 York Ave, New York, NY, 10065, USA
- Center for Genomic Health, Weill Cornell Medicine, 1300 York Ave, New York, NY, 10065, USA
| | - Chengyang Liu
- Department of Surgery, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA
| | - Wei Wang
- Department of Surgery, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA
| | - Ali Naji
- Department of Surgery, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA
| | - Stephen C.J. Parker
- Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, USA
- Department of Human Genetics, University of Michigan, Ann Arbor, MI, USA
- Department of Biostatistics, University of Michigan, Ann Arbor, MI, USA
| | - Robert E. Schwartz
- Division of Gastroenterology and Hepatology, Department of Medicine, Weill Cornell Medicine, 1300 York Ave, New York, NY, 10065, USA
- Department of Physiology, Biophysics and Systems Biology, Weill Cornell Medicine, 1300 York Ave, New York, NY, 10065, USA. New York 10021, USA
| | - Shuibing Chen
- Department of Surgery, Weill Cornell Medicine, 1300 York Ave, New York, NY, 10065, USA
- Center for Genomic Health, Weill Cornell Medicine, 1300 York Ave, New York, NY, 10065, USA
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14
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Zhao J, Andreev I, Silva HM. Resident tissue macrophages: Key coordinators of tissue homeostasis beyond immunity. Sci Immunol 2024; 9:eadd1967. [PMID: 38608039 DOI: 10.1126/sciimmunol.add1967] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2023] [Accepted: 03/18/2024] [Indexed: 04/14/2024]
Abstract
Resident tissue macrophages (RTMs) encompass a highly diverse set of cells abundantly present in every tissue and organ. RTMs are recognized as central players in innate immune responses, and more recently their importance beyond host defense has started to be highlighted. Despite sharing a universal name and several canonical markers, RTMs perform remarkably specialized activities tailored to sustain critical homeostatic functions of the organs they reside in. These cells can mediate neuronal communication, participate in metabolic pathways, and secrete growth factors. In this Review, we summarize how the division of labor among different RTM subsets helps support tissue homeostasis. We discuss how the local microenvironment influences the development of RTMs, the molecular processes they support, and how dysregulation of RTMs can lead to disease. Last, we highlight both the similarities and tissue-specific distinctions of key RTM subsets, aiming to coalesce recent classifications and perspectives into a unified view.
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Affiliation(s)
- Jia Zhao
- Laboratory of Immunophysiology, Ragon Institute of Mass General, MIT, and Harvard, Cambridge, MA, USA
- Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA
| | - Ilya Andreev
- Laboratory of Immunophysiology, Ragon Institute of Mass General, MIT, and Harvard, Cambridge, MA, USA
- Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA
| | - Hernandez Moura Silva
- Laboratory of Immunophysiology, Ragon Institute of Mass General, MIT, and Harvard, Cambridge, MA, USA
- Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA
- Howard Hughes Medical Institute, Cambridge, MA, USA
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15
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Villaca CBP, Mastracci TL. Pancreatic Crosstalk in the Disease Setting: Understanding the Impact of Exocrine Disease on Endocrine Function. Compr Physiol 2024; 14:5371-5387. [PMID: 39109973 PMCID: PMC11425433 DOI: 10.1002/cphy.c230008] [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] [Indexed: 08/15/2024]
Abstract
The exocrine and endocrine are functionally distinct compartments of the pancreas that have traditionally been studied as separate entities. However, studies of embryonic development, adult physiology, and disease pathogenesis suggest there may be critical communication between exocrine and endocrine cells. In fact, the incidence of the endocrine disease diabetes secondary to exocrine disease/dysfunction ranges from 25% to 80%, depending on the type and severity of the exocrine pathology. Therefore, it is necessary to investigate how exocrine-endocrine "crosstalk" may impact pancreatic function. In this article, we discuss common exocrine diseases, including cystic fibrosis, acute, hereditary, and chronic pancreatitis, and the impact of these exocrine diseases on endocrine function. Additionally, we review how obesity and fatty pancreas influence exocrine function and the impact on cellular communication between the exocrine and endocrine compartments. Interestingly, in all pathologies, there is evidence that signals from the exocrine disease contribute to endocrine dysfunction and the progression to diabetes. Continued research efforts to identify the mechanisms that underlie the crosstalk between various cell types in the pancreas are critical to understanding normal pancreatic physiology as well as disease states. © 2024 American Physiological Society. Compr Physiol 14:5371-5387, 2024.
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Affiliation(s)
| | - Teresa L Mastracci
- Department of Biology, Indiana University Indianapolis, Indianapolis, Indiana, USA
- Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana, USA
- Center for Diabetes and Metabolic Diseases, Indiana University School of Medicine, Indianapolis, Indiana, USA
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16
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Song AT, Sindeaux RHM, Li Y, Affia H, Agnihotri T, Leclerc S, van Vliet PP, Colas M, Guimond JV, Patey N, Feulner L, Joyal JS, Haddad E, Barreiro L, Andelfinger G. Developmental role of macrophages modeled in human pluripotent stem cell-derived intestinal tissue. Cell Rep 2024; 43:113616. [PMID: 38150367 DOI: 10.1016/j.celrep.2023.113616] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2023] [Revised: 11/22/2023] [Accepted: 12/07/2023] [Indexed: 12/29/2023] Open
Abstract
Macrophages populate the embryo early in gestation, but their role in development is not well defined. In particular, specification and function of macrophages in intestinal development remain little explored. To study this event in the human developmental context, we derived and combined human intestinal organoid and macrophages from pluripotent stem cells. Macrophages migrate into the organoid, proliferate, and occupy the emerging microanatomical niches of epithelial crypts and ganglia. They also acquire a transcriptomic profile similar to that of fetal intestinal macrophages and display tissue macrophage behaviors, such as recruitment to tissue injury. Using this model, we show that macrophages reduce glycolysis in mesenchymal cells and limit tissue growth without affecting tissue architecture, in contrast to the pro-growth effect of enteric neurons. In short, we engineered an intestinal tissue model populated with macrophages, and we suggest that resident macrophages contribute to the regulation of metabolism and growth of the developing intestine.
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Affiliation(s)
- Andrew T Song
- Centre de Recherche, CHU Sainte-Justine, Montréal, QC, Canada; Department of Anatomy and Cell Biology, McGill University, Montréal, QC, Canada.
| | - Renata H M Sindeaux
- Centre de Recherche, CHU Sainte-Justine, Montréal, QC, Canada; Meakins Christie Laboratories, Department of Medicine, Department of Microbiology and Immunology, Department of Pathology Research Institute of McGill University Health Centre, Montréal, QC, Canada
| | - Yuanyi Li
- Centre de Recherche, CHU Sainte-Justine, Montréal, QC, Canada
| | - Hicham Affia
- Centre de Recherche, CHU Sainte-Justine, Montréal, QC, Canada
| | - Tapan Agnihotri
- Centre de Recherche, CHU Sainte-Justine, Montréal, QC, Canada; Department of Pharmacology and Therapeutics, McGill University, Montréal, QC, Canada
| | | | | | - Mathieu Colas
- Centre de Recherche, CHU Sainte-Justine, Montréal, QC, Canada
| | - Jean-Victor Guimond
- CLSC des Faubourgs, CIUSSS du Centre-Sud-de-l'Ile-de-Montréal, Montréal, QC, Canada
| | - Natalie Patey
- Department of Pathology, CHU Sainte-Justine, Université de Montréal, Montréal, QC, Canada
| | - Lara Feulner
- Centre de Recherche, CHU Sainte-Justine, Montréal, QC, Canada
| | - Jean-Sebastien Joyal
- Centre de Recherche, CHU Sainte-Justine, Montréal, QC, Canada; Département de Pédiatrie, Université de Montréal, Montréal, QC, Canada; Department of Pharmacology and Therapeutics, McGill University, Montréal, QC, Canada
| | - Elie Haddad
- Centre de Recherche, CHU Sainte-Justine, Montréal, QC, Canada; Département de Pédiatrie, Université de Montréal, Montréal, QC, Canada
| | - Luis Barreiro
- Centre de Recherche, CHU Sainte-Justine, Montréal, QC, Canada; Genetics Genomics and Systems Biology, University of Chicago, Chicago, IL, USA
| | - Gregor Andelfinger
- Centre de Recherche, CHU Sainte-Justine, Montréal, QC, Canada; Department of Anatomy and Cell Biology, McGill University, Montréal, QC, Canada; Département de Pédiatrie, Université de Montréal, Montréal, QC, Canada.
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17
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Kuhlmann-Hogan A, Cordes T, Xu Z, Kuna RS, Traina KA, Robles-Oteíza C, Ayeni D, Kwong EM, Levy S, Globig AM, Nobari MM, Cheng GZ, Leibel SL, Homer RJ, Shaw RJ, Metallo CM, Politi K, Kaech SM. EGFR-driven lung adenocarcinomas coopt alveolar macrophage metabolism and function to support EGFR signaling and growth. Cancer Discov 2024; 14:733526. [PMID: 38241033 PMCID: PMC11258210 DOI: 10.1158/2159-8290.cd-23-0434] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2023] [Revised: 11/15/2023] [Accepted: 12/21/2023] [Indexed: 01/26/2024]
Abstract
The limited efficacy of currently approved immunotherapies in EGFR-driven lung adenocarcinoma (LUAD) underscores the need to better understand alternative mechanisms governing local immunosuppression to fuel novel therapies. Elevated surfactant and GM-CSF secretion from the transformed epithelium induces tumor-associated alveolar macrophage (TA-AM) proliferation which supports tumor growth by rewiring inflammatory functions and lipid metabolism. TA-AM properties are driven by increased GM-CSF-PPARγ signaling and inhibition of airway GM-CSF or PPARγ in TA-AMs suppresses cholesterol efflux to tumor cells, which impairs EGFR phosphorylation and restrains LUAD progression. In the absence of TA-AM metabolic support, LUAD cells compensate by increasing cholesterol synthesis, and blocking PPARγ in TA-AMs simultaneous with statin therapy further suppresses tumor progression and increases proinflammatory immune responses. These results reveal new therapeutic combinations for immunotherapy resistant EGFR-mutant LUADs and demonstrate how cancer cells can metabolically co-opt TA-AMs through GM-CSF-PPARγ signaling to provide nutrients that promote oncogenic signaling and growth.
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Affiliation(s)
- Alexandra Kuhlmann-Hogan
- Department of Immunobiology, Yale School of Medicine, New Haven, CT
- Nomis Center for Immunobiology and Microbial Pathogenesis, Salk Institute for Biological Studies, La Jolla, CA
| | - Thekla Cordes
- Molecular and Cellular Biology Laboratory, Salk Institute for Biological Studies, La Jolla, CA
- Department of Bioinformatics and Biochemistry, Braunshweig Integrated Centre of Systems Biology (BRICS), Technishe Universität Braunschweig, Germany
- Research Group Cellular Metabolism in Infection, Helmholtz Centre for Infection Research, Braunschweig, Germany
| | - Ziyan Xu
- Nomis Center for Immunobiology and Microbial Pathogenesis, Salk Institute for Biological Studies, La Jolla, CA
- Division of Biological Sciences, University of California San Diego, La Jolla, CA
| | - Ramya S. Kuna
- Molecular and Cellular Biology Laboratory, Salk Institute for Biological Studies, La Jolla, CA
| | - Kacie A. Traina
- Nomis Center for Immunobiology and Microbial Pathogenesis, Salk Institute for Biological Studies, La Jolla, CA
| | | | - Deborah Ayeni
- Departments of Pathology and Internal Medicine, (Section of Medical Oncology), Yale School of Medicine, New Haven, CT
| | - Elizabeth M. Kwong
- Department of Pediatrics, University of California San Diego School of Medicine, La Jolla, CA
- Sanford Consortium for Regenerative Medicine, La Jolla, CA
| | - Stellar Levy
- Departments of Pathology and Internal Medicine, (Section of Medical Oncology), Yale School of Medicine, New Haven, CT
| | - Anna-Maria Globig
- Nomis Center for Immunobiology and Microbial Pathogenesis, Salk Institute for Biological Studies, La Jolla, CA
| | - Matthew M. Nobari
- Division of Pulmonary and Critical Sleep Medicine, University of California San Diego Department of Medicine, La Jolla, CA
| | - George Z. Cheng
- Division of Pulmonary and Critical Sleep Medicine, University of California San Diego Department of Medicine, La Jolla, CA
| | - Sandra L. Leibel
- Department of Pediatrics, University of California San Diego School of Medicine, La Jolla, CA
- Sanford Consortium for Regenerative Medicine, La Jolla, CA
| | - Robert J. Homer
- Departments of Pathology and Internal Medicine (Section of Pulmonary, Critical Care and Sleep Medicine), Yale University School of Medicine, New Haven, CT
| | - Reuben J. Shaw
- Molecular and Cellular Biology Laboratory, Salk Institute for Biological Studies, La Jolla, CA
| | - Christian M. Metallo
- Molecular and Cellular Biology Laboratory, Salk Institute for Biological Studies, La Jolla, CA
| | - Katerina Politi
- Departments of Pathology and Internal Medicine, (Section of Medical Oncology), Yale School of Medicine, New Haven, CT
- Yale Cancer Center, Yale School of Medicine, New Haven, CT
| | - Susan M. Kaech
- Nomis Center for Immunobiology and Microbial Pathogenesis, Salk Institute for Biological Studies, La Jolla, CA
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18
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Agerskov RH, Nyeng P. Innervation of the pancreas in development and disease. Development 2024; 151:dev202254. [PMID: 38265192 DOI: 10.1242/dev.202254] [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] [Indexed: 01/25/2024]
Abstract
The autonomic nervous system innervates the pancreas by sympathetic, parasympathetic and sensory branches during early organogenesis, starting with neural crest cell invasion and formation of an intrinsic neuronal network. Several studies have demonstrated that signals from pancreatic neural crest cells direct pancreatic endocrinogenesis. Likewise, autonomic neurons have been shown to regulate pancreatic islet formation, and have also been implicated in type I diabetes. Here, we provide an overview of recent progress in mapping pancreatic innervation and understanding the interactions between pancreatic neurons, epithelial morphogenesis and cell differentiation. Finally, we discuss pancreas innervation as a factor in the development of diabetes.
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Affiliation(s)
- Rikke Hoegsberg Agerskov
- Roskilde University, Department of Science and Environment, Universitetsvej 1, building 28, Roskilde 4000, Denmark
| | - Pia Nyeng
- Roskilde University, Department of Science and Environment, Universitetsvej 1, building 28, Roskilde 4000, Denmark
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19
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Bosch AJT, Keller L, Steiger L, Rohm TV, Wiedemann SJ, Low AJY, Stawiski M, Rachid L, Roux J, Konrad D, Wueest S, Tugues S, Greter M, Böni-Schnetzler M, Meier DT, Cavelti-Weder C. CSF1R inhibition with PLX5622 affects multiple immune cell compartments and induces tissue-specific metabolic effects in lean mice. Diabetologia 2023; 66:2292-2306. [PMID: 37792013 PMCID: PMC10627931 DOI: 10.1007/s00125-023-06007-1] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/25/2023] [Accepted: 07/07/2023] [Indexed: 10/05/2023]
Abstract
AIMS/HYPOTHESIS Colony stimulating factor 1 (CSF1) promotes the proliferation, differentiation and survival of macrophages, which have been implicated in both beneficial and detrimental effects on glucose metabolism. However, the physiological role of CSF1 signalling in glucose homeostasis and the potential therapeutic implications of modulating this pathway are not known. We aimed to study the composition of tissue macrophages (and other immune cells) following CSF1 receptor (CSF1R) inhibition and elucidate the metabolic consequences of CSF1R inhibition. METHODS We assessed immune cell populations in various organs by flow cytometry, and tissue-specific metabolic effects by hyperinsulinaemic-euglycaemic clamps and insulin secretion assays in mice fed a chow diet containing PLX5622 (a CSF1R inhibitor) or a control diet. RESULTS CSF1R inhibition depleted macrophages in multiple tissues while simultaneously increasing eosinophils and group 2 innate lymphoid cells. These immunological changes were consistent across different organs and were sex independent and reversible after cessation of the PLX5622. CSF1R inhibition improved hepatic insulin sensitivity but concomitantly impaired insulin secretion. In healthy islets, we found a high frequency of IL-1β+ islet macrophages. Their depletion by CSF1R inhibition led to downregulation of macrophage-related pathways and mediators of cytokine activity, including Nlrp3, suggesting IL-1β as a candidate insulin secretagogue. Partial restoration of physiological insulin secretion was achieved by injecting recombinant IL-1β prior to glucose stimulation in mice lacking macrophages. CONCLUSIONS/INTERPRETATION Macrophages and macrophage-derived factors, such as IL-1β, play an important role in physiological insulin secretion. A better understanding of the tissue-specific effects of CSF1R inhibition on immune cells and glucose homeostasis is crucial for the development of targeted immune-modulatory treatments in metabolic disease. DATA AVAILABILITY The RNA-Seq dataset is available in the Gene Expression Omnibus (GEO) under the accession number GSE189434 ( http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE189434 ).
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Affiliation(s)
- Angela J T Bosch
- Department of Biomedicine, University of Basel, Basel, Switzerland
| | - Lena Keller
- Department of Biomedicine, University of Basel, Basel, Switzerland
| | - Laura Steiger
- Department of Biomedicine, University of Basel, Basel, Switzerland
| | - Theresa V Rohm
- Department of Biomedicine, University of Basel, Basel, Switzerland
| | | | - Andy J Y Low
- Department of Biomedicine, University of Basel, Basel, Switzerland
| | - Marc Stawiski
- Department of Biomedicine, University of Basel, Basel, Switzerland
| | - Leila Rachid
- Department of Biomedicine, University of Basel, Basel, Switzerland
| | - Julien Roux
- Department of Biomedicine, University of Basel, Basel, Switzerland
- Swiss Institute of Bioinformatics, Basel, Switzerland
| | - Daniel Konrad
- Division of Pediatric Endocrinology and Diabetology, University Children's Hospital, University of Zurich, Zurich, Switzerland
- Children's Research Centre, University Children's Hospital, University of Zurich, Zurich, Switzerland
| | - Stephan Wueest
- Division of Pediatric Endocrinology and Diabetology, University Children's Hospital, University of Zurich, Zurich, Switzerland
- Children's Research Centre, University Children's Hospital, University of Zurich, Zurich, Switzerland
| | - Sonia Tugues
- Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland
| | - Melanie Greter
- Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland
| | | | - Daniel T Meier
- Department of Biomedicine, University of Basel, Basel, Switzerland
| | - Claudia Cavelti-Weder
- Department of Biomedicine, University of Basel, Basel, Switzerland.
- Department of Endocrinology, Diabetology and Clinical Nutrition, University Hospital Zurich (USZ), University of Zurich (UZH), Zurich, Switzerland.
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20
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Kuhlmann-Hogan A, Cordes T, Xu Z, Traina KA, Robles-Oteíza C, Ayeni D, Kwong EM, Levy SR, Nobari M, Cheng GZ, Shaw R, Leibel SL, Metallo CM, Politi K, Kaech SM. EGFR + lung adenocarcinomas coopt alveolar macrophage metabolism and function to support EGFR signaling and growth. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.04.15.536974. [PMID: 37131637 PMCID: PMC10153136 DOI: 10.1101/2023.04.15.536974] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/04/2023]
Abstract
The limited efficacy of currently approved immunotherapies in EGFR-mutant lung adenocarcinoma (LUAD) underscores the need to better understand mechanisms governing local immunosuppression. Elevated surfactant and GM-CSF secretion from the transformed epithelium induces tumor-associated alveolar macrophages (TA-AM) to proliferate and support tumor growth by rewiring inflammatory functions and lipid metabolism. TA-AM properties are driven by increased GM-CSF-PPARγ signaling and inhibition of airway GM-CSF or PPARγ in TA-AMs suppresses cholesterol efflux to tumor cells, which impairs EGFR phosphorylation and restrains LUAD progression. In the absence of TA-AM metabolic support, LUAD cells compensate by increasing cholesterol synthesis, and blocking PPARγ in TA-AMs simultaneous with statin therapy further suppresses tumor progression and increases T cell effector functions. These results reveal new therapeutic combinations for immunotherapy resistant EGFR-mutant LUADs and demonstrate how such cancer cells can metabolically co-opt TA-AMs through GM-CSF-PPARγ signaling to provide nutrients that promote oncogenic signaling and growth.
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21
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Root KM, Akhaphong B, Cedars MA, Molin AM, Huchthausen ME, Laule CF, Regal RR, Alejandro EU, Regal JF. Critical Role for Macrophages in the Developmental Programming of Pancreatic β-Cell Area in Offspring of Hypertensive Pregnancies. Diabetes 2022; 71:2597-2611. [PMID: 36125850 PMCID: PMC9750952 DOI: 10.2337/db22-0404] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/29/2022] [Accepted: 09/06/2022] [Indexed: 01/11/2023]
Abstract
Preeclampsia is a pregnancy-specific complication with long-term negative outcomes for offspring, including increased susceptibility to type 2 diabetes (T2D) in adulthood. In a rat reduced uteroplacental perfusion pressure (RUPP) model of chronic placental ischemia, maternal hypertension in conjunction with intrauterine growth restriction mimicked aspects of preeclampsia and resulted in female embryonic day 19 (e19) offspring with reduced β-cell area and increased β-cell apoptosis compared with offspring of sham pregnancies. Decreased pancreatic β-cell area persisted to postnatal day 13 (PD13) in females and could influence whether T2D developed in adulthood. Macrophage changes also occurred in islets in T2D. Therefore, we hypothesized that macrophages are crucial to reduction in pancreatic β-cell area in female offspring after chronic placental ischemia. Macrophage marker CD68 mRNA expression was significantly elevated in e19 and PD13 islets isolated from female RUPP offspring compared with sham. Postnatal injections of clodronate liposomes into female RUPP and sham offspring on PD2 and PD9 significantly depleted macrophages compared with injections of control liposomes. Depletion of macrophages rescued reduced β-cell area and increased β-cell proliferation and size in RUPP offspring. Our studies suggest that the presence of macrophages is important for reduced β-cell area in female RUPP offspring and changes in macrophages could contribute to development of T2D in adulthood.
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Affiliation(s)
- Kate M. Root
- Department of Biomedical Sciences, University of Minnesota Medical School, Duluth, MN
| | - Brian Akhaphong
- Department of Integrative Biology and Physiology, University of Minnesota Medical School, Minneapolis, MN
| | - Melissa A. Cedars
- Department of Biomedical Sciences, University of Minnesota Medical School, Duluth, MN
| | - Alexa M. Molin
- Department of Biomedical Sciences, University of Minnesota Medical School, Duluth, MN
| | | | - Connor F. Laule
- Department of Biomedical Sciences, University of Minnesota Medical School, Duluth, MN
- Department of Neuroscience and Pharmacology, University of Iowa Carver College of Medicine, Iowa City, IA
| | - Ronald R. Regal
- Department of Biomedical Sciences, University of Minnesota Medical School, Duluth, MN
| | - Emilyn U. Alejandro
- Department of Integrative Biology and Physiology, University of Minnesota Medical School, Minneapolis, MN
| | - Jean F. Regal
- Department of Biomedical Sciences, University of Minnesota Medical School, Duluth, MN
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22
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Jaganjac M, Zarkovic N. Lipid Peroxidation Linking Diabetes and Cancer: The Importance of 4-Hydroxynonenal. Antioxid Redox Signal 2022; 37:1222-1233. [PMID: 36242098 DOI: 10.1089/ars.2022.0146] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Significance: It is commonly believed that diabetes mellitus may be associated with cancer. Hence, diabetic patients are at higher risk for hepatocellular carcinoma, pancreatic cancer, colorectal cancer, and breast cancer, but the mechanisms that may link these two severe diseases are not well understood. Recent Advances: A number of factors have been suggested to promote tumorigenesis in diabetic patients, including insulin resistance, hyperglycemia, dyslipidemia, inflammation, and elevated insulin-like growth factor-1 (IGF-1), which may also promote pro-oxidants, and thereby alter redox homeostasis. The consequent oxidative stress associated with lipid peroxidation appears to be a possible pathogenic link between cancer and diabetes. Critical Issues: Having summarized the above aspects of diabetes and cancer pathology, we propose that the major bioactive product of oxidative degradation of polyunsaturated fatty acids (PUFAs), the reactive aldehyde 4-hydroxynonenal (4-HNE), which is also considered a second messenger of free radicals, may be the key pathogenic factor linking diabetes and cancer. Future Directions: Because the bioactivities of 4-HNE are cell-type and concentration-dependent, are often associated with inflammation, and are involved in signaling processes that regulate antioxidant activities, proliferation, differentiation, and apoptosis, we believe that further research in this direction could reveal options for better control of diabetes and cancer. Controlling the production of 4-HNE to avoid its cytotoxicity to normal but not cancer cells while preventing its diabetogenic activities could be an important aspect of modern integrative biomedicine. Antioxid. Redox Signal. 37, 1222-1233.
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Affiliation(s)
- Morana Jaganjac
- Laboratory for Oxidative Stress, Division of Molecular Medicine, Ruder Boskovic Institute, Zagreb, Croatia
| | - Neven Zarkovic
- Laboratory for Oxidative Stress, Division of Molecular Medicine, Ruder Boskovic Institute, Zagreb, Croatia
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23
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Li H, Meng Y, He S, Tan X, Zhang Y, Zhang X, Wang L, Zheng W. Macrophages, Chronic Inflammation, and Insulin Resistance. Cells 2022; 11:cells11193001. [PMID: 36230963 PMCID: PMC9562180 DOI: 10.3390/cells11193001] [Citation(s) in RCA: 108] [Impact Index Per Article: 36.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2022] [Revised: 09/08/2022] [Accepted: 09/22/2022] [Indexed: 11/16/2022] Open
Abstract
The prevalence of obesity has reached alarming levels, which is considered a major risk factor for several metabolic diseases, including type 2 diabetes (T2D), non-alcoholic fatty liver, atherosclerosis, and ischemic cardiovascular disease. Obesity-induced chronic, low-grade inflammation may lead to insulin resistance, and it is well-recognized that macrophages play a major role in such inflammation. In the current review, the molecular mechanisms underlying macrophages, low-grade tissue inflammation, insulin resistance, and T2D are described. Also, the role of macrophages in obesity-induced insulin resistance is presented, and therapeutic drugs and recent advances targeting macrophages for the treatment of T2D are introduced.
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Affiliation(s)
- He Li
- Beijing City Key Laboratory of Drug Delivery Technology and Novel Formulation, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China
| | - Ya Meng
- Beijing City Key Laboratory of Drug Delivery Technology and Novel Formulation, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China
| | - Shuwang He
- Shandong DYNE Marine Biopharmaceutical Co., Ltd., Rongcheng 264300, China
| | - Xiaochuan Tan
- Beijing City Key Laboratory of Drug Delivery Technology and Novel Formulation, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China
| | - Yujia Zhang
- Beijing City Key Laboratory of Drug Delivery Technology and Novel Formulation, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China
| | - Xiuli Zhang
- Beijing City Key Laboratory of Drug Delivery Technology and Novel Formulation, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China
| | - Lulu Wang
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100050, China
- Correspondence: (L.W.); (W.Z.); Tel.: +86-010-63165233 (W.Z.)
| | - Wensheng Zheng
- Beijing City Key Laboratory of Drug Delivery Technology and Novel Formulation, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China
- Correspondence: (L.W.); (W.Z.); Tel.: +86-010-63165233 (W.Z.)
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24
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Yip L, Alkhataybeh R, Taylor C, Fuhlbrigge R, Fathman CG. Identification of Novel Disease-Relevant Genes and Pathways in the Pathogenesis of Type 1 Diabetes: A Potential Defect in Pancreatic Iron Homeostasis. Diabetes 2022; 71:1490-1507. [PMID: 35499603 PMCID: PMC9233262 DOI: 10.2337/db21-0948] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/22/2021] [Accepted: 04/06/2022] [Indexed: 11/13/2022]
Abstract
Multiple pathways contribute to the pathophysiological development of type 1 diabetes (T1D); however, the exact mechanisms involved are unclear. We performed differential gene expression analysis in pancreatic islets of NOD mice versus age-matched congenic NOD.B10 controls to identify genes that may contribute to disease pathogenesis. Novel genes related to extracellular matrix development and glucagon and insulin signaling/secretion were changed in NOD mice during early inflammation. During "respective" insulitis, the expression of genes encoding multiple chemosensory olfactory receptors were upregulated, and during "destructive" insulitis, the expression of genes involved in antimicrobial defense and iron homeostasis were downregulated. Islet inflammation reduced the expression of Hamp that encodes hepcidin. Hepcidin is expressed in β-cells and serves as the key regulator of iron homeostasis. We showed that Hamp and hepcidin levels were lower, while iron levels were higher in the pancreas of 12-week-old NOD versus NOD.B10 mice, suggesting that a loss of iron homeostasis may occur in the islets during the onset of "destructive" insulitis. Interestingly, we showed that the severity of NOD disease correlates with dietary iron intake. NOD mice maintained on low-iron diets had a lower incidence of hyperglycemia, while those maintained on high-iron diets had an earlier onset and higher incidence of disease, suggesting that high iron exposure combined with a loss of pancreatic iron homeostasis may exacerbate NOD disease. This mechanism may explain the link seen between high iron exposure and the increased risk for T1D in humans.
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Affiliation(s)
- Linda Yip
- Division of Immunology and Rheumatology, Department of Medicine, Stanford University, Stanford, CA
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25
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Magalhaes MS, Potter HG, Ahlback A, Gentek R. Developmental programming of macrophages by early life adversity. INTERNATIONAL REVIEW OF CELL AND MOLECULAR BIOLOGY 2022; 368:213-259. [PMID: 35636928 DOI: 10.1016/bs.ircmb.2022.02.003] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
Macrophages are central elements of all organs, where they have a multitude of physiological and pathological functions. The first macrophages are produced during fetal development, and most adult organs retain populations of fetal-derived macrophages that self-maintain without major input of hematopoietic stem cell-derived monocytes. Their developmental origins make macrophages highly susceptible to environmental perturbations experienced in early life, in particular the fetal period. It is now well recognized that such adverse developmental conditions contribute to a wide range of diseases later in life. This chapter explores the notion that macrophages are key targets of environmental adversities during development, and mediators of their long-term impact on health and disease. We first briefly summarize our current understanding of macrophage ontogeny and their biology in tissues and consider potential mechanisms by which environmental stressors may mediate fetal programming. We then review evidence for programming of macrophages by adversities ranging from maternal immune activation and diet to environmental pollutants and toxins, which have disease relevance for different organ systems. Throughout this chapter, we contemplate appropriate experimental strategies to study macrophage programming. We conclude by discussing how our current knowledge of macrophage programming could be conceptualized, and finally highlight open questions in the field and approaches to address them.
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Affiliation(s)
- Marlene S Magalhaes
- Centre for Inflammation Research & Centre for Reproductive Health, Queens Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom
| | - Harry G Potter
- Centre for Inflammation Research & Centre for Reproductive Health, Queens Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom
| | - Anna Ahlback
- Centre for Inflammation Research & Centre for Reproductive Health, Queens Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom
| | - Rebecca Gentek
- Centre for Inflammation Research & Centre for Reproductive Health, Queens Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom.
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26
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Bartolomé A, Suda N, Yu J, Zhu C, Son J, Ding H, Califano A, Accili D, Pajvani UB. Notch-mediated Ephrin signaling disrupts islet architecture and β cell function. JCI Insight 2022; 7:157694. [PMID: 35167496 PMCID: PMC8986078 DOI: 10.1172/jci.insight.157694] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2021] [Accepted: 02/09/2022] [Indexed: 11/23/2022] Open
Abstract
Altered islet architecture is associated with β cell dysfunction and type 2 diabetes (T2D) progression, but molecular effectors of islet spatial organization remain mostly unknown. Although Notch signaling is known to regulate pancreatic development, we observed “reactivated” β cell Notch activity in obese mouse models. To test the repercussions and reversibility of Notch effects, we generated doxycycline-dependent, β cell–specific Notch gain-of-function mice. As predicted, we found that Notch activation in postnatal β cells impaired glucose-stimulated insulin secretion and glucose intolerance, but we observed a surprising remnant glucose intolerance after doxycycline withdrawal and cessation of Notch activity, associated with a marked disruption of normal islet architecture. Transcriptomic screening of Notch-active islets revealed increased Ephrin signaling. Commensurately, exposure to Ephrin ligands increased β cell repulsion and impaired murine and human pseudoislet formation. Consistent with our mouse data, Notch and Ephrin signaling were increased in metabolically inflexible β cells in patients with T2D. These studies suggest that β cell Notch/Ephrin signaling can permanently alter islet architecture during a morphogenetic window in early life.
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Affiliation(s)
- Alberto Bartolomé
- Departamento de Fisiopatología Endocrina y del Sistema Nervioso, IIBm Alberto Sols (CSIC/UAM), Madrid, Spain
| | - Nina Suda
- Department of Medicine, Columbia University, New York, United States of America
| | - Junjie Yu
- Department of Medicine, Columbia University, New York, United States of America
| | - Changyu Zhu
- Department of Medicine, Columbia University, New York, United States of America
| | - Jinsook Son
- Department of Medicine, Columbia University, New York, United States of America
| | - Hongxu Ding
- Systems Biology, Columbia University College of Physicians & Surgeons, New York, United States of America
| | - Andrea Califano
- Systems Biology, Columbia University College of Physicians & Surgeons, New York, United States of America
| | - Domenico Accili
- Department of Medicine, Columbia University, New York, United States of America
| | - Utpal B Pajvani
- Department of Medicine, Columbia University, New York, United States of America
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27
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Bartolomé A. Stem Cell-Derived β Cells: A Versatile Research Platform to Interrogate the Genetic Basis of β Cell Dysfunction. Int J Mol Sci 2022; 23:501. [PMID: 35008927 PMCID: PMC8745644 DOI: 10.3390/ijms23010501] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2021] [Revised: 12/27/2021] [Accepted: 12/29/2021] [Indexed: 02/07/2023] Open
Abstract
Pancreatic β cell dysfunction is a central component of diabetes progression. During the last decades, the genetic basis of several monogenic forms of diabetes has been recognized. Genome-wide association studies (GWAS) have also facilitated the identification of common genetic variants associated with an increased risk of diabetes. These studies highlight the importance of impaired β cell function in all forms of diabetes. However, how most of these risk variants confer disease risk, remains unanswered. Understanding the specific contribution of genetic variants and the precise role of their molecular effectors is the next step toward developing treatments that target β cell dysfunction in the era of personalized medicine. Protocols that allow derivation of β cells from pluripotent stem cells, represent a powerful research tool that allows modeling of human development and versatile experimental designs that can be used to shed some light on diabetes pathophysiology. This article reviews different models to study the genetic basis of β cell dysfunction, focusing on the recent advances made possible by stem cell applications in the field of diabetes research.
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Affiliation(s)
- Alberto Bartolomé
- Instituto de Investigaciones Biomédicas Alberto Sols, CSIC-UAM, 28029 Madrid, Spain
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28
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Ma Z, Ruedl C. Turnover Kinetics of Pancreatic Macrophages in Lean and Obese Diabetic Mice. Front Endocrinol (Lausanne) 2022; 13:858422. [PMID: 35909564 PMCID: PMC9326506 DOI: 10.3389/fendo.2022.858422] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/19/2022] [Accepted: 06/07/2022] [Indexed: 12/02/2022] Open
Abstract
Pancreatic resident macrophages, a heterogeneous family of cells with distinct origins and phenotypes, are the main myeloid cells in exocrine and endocrine tissues. Adult exocrine F4/80hi macrophages consist of three different subsets based on the embryonic marker Tim-4 and MHC II expression. Their frequencies shift during aging and obesity with the Tim-4-MHCII+ fraction becoming the predominant subpopulation in the inter acinar stroma. Endocrine resident F4/80hi macrophages are more homogenous and represent the prevalent leukocyte fraction residing within the islets in both lean and obese mice. We used an adult fate mapping mouse model to characterize turnover kinetics within the pancreatic resident macrophages under normal homeostasis and obese diabetic conditions. We demonstrate that islet resident macrophages show unique replenishment kinetics, with embryonic macrophages being gradually replaced by bone marrow-derived monocytes with increasing age. Their replenishment was independent of the CCL2/CCR2 axis. Furthermore, we confirmed that both exocrine Tim-4+MHCIIlow and Tim-4+MHCII+ fractions are long-lived and primarily independent from bone marrow-derived monocytes. In contrast, exocrine Tim-4-MHCII+ macrophages are gradually replaced through a CCR2-dependent influx of bone marrow-derived monocytes in aging. Moreover, we show that obesity and type 2 diabetes do not affect the turnover kinetics of any macrophage subpopulation residing in the pancreas. Our study uncovers new insights on pancreatic macrophage biology in aging and obesity.
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29
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Abstract
Pancreatic islets are the body's central rheostat that regulates glucose homeostasis through the production of different hormones, including β cell-derived insulin. During obesity-induced type 2 diabetes (T2D), islet β cells become dysfunctional and inadequate insulin secretion no longer ensures glycemic control. T2D is associated with a chronic low-grade inflammation that manifests in several metabolic organs including the pancreatic islets. Growing evidence suggests that components of the innate immune system, and especially macrophages, play a crucial role in regulating islet homeostasis. Yet, the phenotypes and functions of islet macrophages in physiology and during T2D have only started to attract attention and remain unclear. In this review, the current knowledge about islet inflammation and macrophages will be summarized in humans and rodent models. Recent findings on the cellular and molecular mechanisms involved in islet remodeling and β cell function during obesity and T2D will be discussed.
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Affiliation(s)
- Joyceline Cuenco
- Centre de Recherche des Cordeliers, INSERM, IMMEDIAB Laboratory, Sorbonne Université, Université de Paris, Paris, France
| | - Elise Dalmas
- Centre de Recherche des Cordeliers, INSERM, IMMEDIAB Laboratory, Sorbonne Université, Université de Paris, Paris, France.
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30
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Böni-Schnetzler M, Méreau H, Rachid L, Wiedemann SJ, Schulze F, Trimigliozzi K, Meier DT, Donath MY. IL-1beta promotes the age-associated decline of beta cell function. iScience 2021; 24:103250. [PMID: 34746709 PMCID: PMC8554531 DOI: 10.1016/j.isci.2021.103250] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2021] [Revised: 09/03/2021] [Accepted: 10/07/2021] [Indexed: 11/08/2022] Open
Abstract
Aging is the prime risk factor for the development of type 2 diabetes. We investigated the role of the interleukin-1 (IL-1) system on insulin secretion in aged mice. During aging, expression of the protective IL-1 receptor antagonist decreased in islets, whereas IL-1beta gene expression increased specifically in the CD45 + islet immune cell fraction. One-year-old mice with a whole-body knockout of IL-1beta had higher insulin secretion in vivo and in isolated islets, along with enhanced proliferation marker Ki67 and elevated size and number of islets. Myeloid cell-specific IL-1beta knockout preserved glucose-stimulated insulin secretion during aging, whereas it declined in control mice. Isolated islets from aged myeloIL-1beta ko mice secreted more insulin along with increased expression of Ins2, Kir6.2, and of the cell-cycle gene E2f1. IL-1beta treatment of isolated islets reduced E2f1, Ins2, and Kir6.2 expression in beta cells. We conclude that IL-1beta contributes the age-associated decline of beta cell function.
Islets from aged mice have increased IL-1beta and decreased IL-1Ra expression Islet immune cells are the source of increased IL-1beta expression during aging Myeloid-cell-specific IL-1beta knockout preserves insulin secretion in aged mice IL-1beta targets genes regulating insulin secretion and proliferation during aging
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Affiliation(s)
- Marianne Böni-Schnetzler
- Endocrinology, Diabetes, and Metabolism, University Hospital of Basel, 4031 Basel, Switzerland.,Department of Biomedicine, Diabetes Research, University of Basel, 4031 Basel, Switzerland
| | - Hélène Méreau
- Endocrinology, Diabetes, and Metabolism, University Hospital of Basel, 4031 Basel, Switzerland.,Department of Biomedicine, Diabetes Research, University of Basel, 4031 Basel, Switzerland
| | - Leila Rachid
- Endocrinology, Diabetes, and Metabolism, University Hospital of Basel, 4031 Basel, Switzerland.,Department of Biomedicine, Diabetes Research, University of Basel, 4031 Basel, Switzerland
| | - Sophia J Wiedemann
- Endocrinology, Diabetes, and Metabolism, University Hospital of Basel, 4031 Basel, Switzerland.,Department of Biomedicine, Diabetes Research, University of Basel, 4031 Basel, Switzerland
| | - Friederike Schulze
- Endocrinology, Diabetes, and Metabolism, University Hospital of Basel, 4031 Basel, Switzerland.,Department of Biomedicine, Diabetes Research, University of Basel, 4031 Basel, Switzerland
| | - Kelly Trimigliozzi
- Endocrinology, Diabetes, and Metabolism, University Hospital of Basel, 4031 Basel, Switzerland.,Department of Biomedicine, Diabetes Research, University of Basel, 4031 Basel, Switzerland
| | - Daniel T Meier
- Endocrinology, Diabetes, and Metabolism, University Hospital of Basel, 4031 Basel, Switzerland.,Department of Biomedicine, Diabetes Research, University of Basel, 4031 Basel, Switzerland
| | - Marc Y Donath
- Endocrinology, Diabetes, and Metabolism, University Hospital of Basel, 4031 Basel, Switzerland.,Department of Biomedicine, Diabetes Research, University of Basel, 4031 Basel, Switzerland
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31
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Mukhuty A, Fouzder C, Kundu R. Fetuin-A secretion from β-cells leads to accumulation of macrophages in islets, aggravates inflammation and impairs insulin secretion. J Cell Sci 2021; 134:272470. [PMID: 34643217 DOI: 10.1242/jcs.258507] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2021] [Accepted: 09/27/2021] [Indexed: 12/29/2022] Open
Abstract
Elevated fetuin-A levels, chemokines and islet-resident macrophages are crucial factors associated with obesity-mediated type 2 diabetes (T2D). Here, the aim of the study was to investigate the effect of MIN6 (a mouse insulinoma cell line)-derived fetuin-A (also known as AHSG) in macrophage polarization and decipher the effect of M1 type pro-inflammatory macrophages in commanding over insulin secretion. MIN6 and islet-derived fetuin-A induced expression of the M1 type macrophage markers Emr1 (also known as Adgre1), Cd68 and CD11c (Itgax) (∼1.8 fold) along with increased cytokine secretion. Interestingly, suppression of fetuin-A in MIN6 successfully reduced M1 markers by ∼1.5 fold. MIN6-derived fetuin-A also induced chemotaxis of macrophages in a Boyden chamber chemotaxis assay. Furthermore, high-fat feeding in mice showed elevated cytokine and fetuin-A content in serum and islets, and also migration and polarization of macrophages to the islets, while β-cells failed to meet the increased insulin demand. Moreover, in MIN6 culture, M1 macrophages sharply decreased insulin secretion by ∼2.8 fold. Altogether our results support an association of fetuin-A with islet inflammation and β-cell dysfunction, owing to its role as a key chemoattractant and macrophage polarizing factor.
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Affiliation(s)
- Alpana Mukhuty
- Cell Signaling Laboratory, Department of Zoology, Visva-Bharati University, Santiniketan 731 235, India
| | - Chandrani Fouzder
- Cell Signaling Laboratory, Department of Zoology, Visva-Bharati University, Santiniketan 731 235, India
| | - Rakesh Kundu
- Cell Signaling Laboratory, Department of Zoology, Visva-Bharati University, Santiniketan 731 235, India
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32
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Understanding the heterogeneity and functions of metabolic tissue macrophages. Semin Cell Dev Biol 2021; 119:130-139. [PMID: 34561168 DOI: 10.1016/j.semcdb.2021.09.002] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2021] [Revised: 09/06/2021] [Accepted: 09/06/2021] [Indexed: 02/08/2023]
Abstract
Growing evidence places tissue-resident macrophages as essential gatekeepers of metabolic organ homeostasis, including the adipose tissue and the pancreatic islets. Therein, macrophages may adopt specific phenotypes and ensure local functions. Recent advances in single cell genomic analyses provide a comprehensive map of adipose tissue macrophage subsets and their potential roles are now better apprehended. Whether they are beneficial or detrimental, macrophages overall contribute to the proper adipose tissue expansion under steady state and during obesity. By contrast, macrophages residing inside pancreatic islets, which may exert fundamental functions to fine tune insulin secretion, have only started to attract attention and their cellular heterogeneity remains to be established. The present review will focus on the latest findings exploring the phenotype and the properties of macrophages in adipose tissue and pancreatic islets, questioning early beliefs and future perspectives in the field of immunometabolism.
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Abstract
In this review, Lee and Olefsky discuss the characteristics of chronic inflammation in the major metabolic tissues and how obesity triggers these events, including a focus on the role of adipose tissue hypoxia and macrophage-derived exosomes. Obesity is the most common cause of insulin resistance, and the current obesity epidemic is driving a parallel rise in the incidence of T2DM. It is now widely recognized that chronic, subacute tissue inflammation is a major etiologic component of the pathogenesis of insulin resistance and metabolic dysfunction in obesity. Here, we summarize recent advances in our understanding of immunometabolism. We discuss the characteristics of chronic inflammation in the major metabolic tissues and how obesity triggers these events, including a focus on the role of adipose tissue hypoxia and macrophage-derived exosomes. Last, we also review current and potential new therapeutic strategies based on immunomodulation.
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Affiliation(s)
- Yun Sok Lee
- Department of Medicine, Division of Endocrinology and Metabolism, University of California at San Diego, La Jolla, California 92093, USA
| | - Jerrold Olefsky
- Department of Medicine, Division of Endocrinology and Metabolism, University of California at San Diego, La Jolla, California 92093, USA
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34
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Abstract
The immune and endocrine systems collectively control homeostasis in the body. The endocrine system ensures that values of essential factors and nutrients such as glucose, electrolytes and vitamins are maintained within threshold values. The immune system resolves local disruptions in tissue homeostasis, caused by pathogens or malfunctioning cells. The immediate goals of these two systems do not always align. The immune system benefits from optimal access to nutrients for itself and restriction of nutrient availability to all other organs to limit pathogen replication. The endocrine system aims to ensure optimal nutrient access for all organs, limited only by the nutrients stores that the body has available. The actual state of homeostatic parameters such as blood glucose levels represents a careful balance based on regulatory signals from the immune and endocrine systems. This state is not static but continuously adjusted in response to changes in the current metabolic needs of the body, the amount of resources it has available and the level of threats it encounters. This balance is maintained by the ability of the immune and endocrine systems to interact and co-regulate systemic metabolism. In context of metabolic disease, this system is disrupted, which impairs functionality of both systems. The failure of the endocrine system to retain levels of nutrients such as glucose within threshold values impairs functionality of the immune system. In addition, metabolic stress of organs in context of obesity is perceived by the immune system as a disruption in local homeostasis, which it tries to resolve by the excretion of factors which further disrupt normal metabolic control. In this chapter, we will discuss how the immune and endocrine systems interact under homeostatic conditions and during infection with a focus on blood glucose regulation. In addition, we will discuss how this system fails in the context of metabolic disease.
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Coderre L, Debieche L, Plourde J, Rabasa-Lhoret R, Lesage S. The Potential Causes of Cystic Fibrosis-Related Diabetes. Front Endocrinol (Lausanne) 2021; 12:702823. [PMID: 34394004 PMCID: PMC8361832 DOI: 10.3389/fendo.2021.702823] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Accepted: 07/06/2021] [Indexed: 12/16/2022] Open
Abstract
Cystic fibrosis (CF) is a genetic disease caused by mutations in the cystic fibrosis transmembrane conductance regulator gene (CFTR). Cystic fibrosis-related diabetes (CFRD) is the most common comorbidity, affecting more than 50% of adult CF patients. Despite this high prevalence, the etiology of CFRD remains incompletely understood. Studies in young CF children show pancreatic islet disorganization, abnormal glucose tolerance, and delayed first-phase insulin secretion suggesting that islet dysfunction is an early feature of CF. Since insulin-producing pancreatic β-cells express very low levels of CFTR, CFRD likely results from β-cell extrinsic factors. In the vicinity of β-cells, CFTR is expressed in both the exocrine pancreas and the immune system. In the exocrine pancreas, CFTR mutations lead to the obstruction of the pancreatic ductal canal, inflammation, and immune cell infiltration, ultimately causing the destruction of the exocrine pancreas and remodeling of islets. Both inflammation and ductal cells have a direct effect on insulin secretion and could participate in CFRD development. CFTR mutations are also associated with inflammatory responses and excessive cytokine production by various immune cells, which infiltrate the pancreas and exert a negative impact on insulin secretion, causing dysregulation of glucose homeostasis in CF adults. In addition, the function of macrophages in shaping pancreatic islet development may be impaired by CFTR mutations, further contributing to the pancreatic islet structural defects as well as impaired first-phase insulin secretion observed in very young children. This review discusses the different factors that may contribute to CFRD.
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Affiliation(s)
- Lise Coderre
- Immunology-Oncology Section, Maisonneuve-Rosemont Hospital Research Center, Montréal, QC, Canada
| | - Lyna Debieche
- Immunology-Oncology Section, Maisonneuve-Rosemont Hospital Research Center, Montréal, QC, Canada
- Département de médecine, Université de Montréal, Montréal, QC, Canada
| | - Joëlle Plourde
- Immunology-Oncology Section, Maisonneuve-Rosemont Hospital Research Center, Montréal, QC, Canada
- Département de médecine, Université de Montréal, Montréal, QC, Canada
| | - Rémi Rabasa-Lhoret
- Division of Cardiovascular and Metabolic Diseases, Institut de recherche clinique de Montréal, Montréal, QC, Canada
- Département de nutrition, Université de Montréal, Montréal, QC, Canada
- Cystic Fibrosis Clinic, Centre Hospitalier de l’Université de Montréal (CHUM), Montréal, QC, Canada
| | - Sylvie Lesage
- Immunology-Oncology Section, Maisonneuve-Rosemont Hospital Research Center, Montréal, QC, Canada
- Département de microbiologie, infectiologie et immunologie, Université de Montréal, Montréal, QC, Canada
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Keshvari S, Caruso M, Teakle N, Batoon L, Sehgal A, Patkar OL, Ferrari-Cestari M, Snell CE, Chen C, Stevenson A, Davis FM, Bush SJ, Pridans C, Summers KM, Pettit AR, Irvine KM, Hume DA. CSF1R-dependent macrophages control postnatal somatic growth and organ maturation. PLoS Genet 2021; 17:e1009605. [PMID: 34081701 PMCID: PMC8205168 DOI: 10.1371/journal.pgen.1009605] [Citation(s) in RCA: 46] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2021] [Revised: 06/15/2021] [Accepted: 05/17/2021] [Indexed: 12/12/2022] Open
Abstract
Homozygous mutation of the Csf1r locus (Csf1rko) in mice, rats and humans leads to multiple postnatal developmental abnormalities. To enable analysis of the mechanisms underlying the phenotypic impacts of Csf1r mutation, we bred a rat Csf1rko allele to the inbred dark agouti (DA) genetic background and to a Csf1r-mApple reporter transgene. The Csf1rko led to almost complete loss of embryonic macrophages and ablation of most adult tissue macrophage populations. We extended previous analysis of the Csf1rko phenotype to early postnatal development to reveal impacts on musculoskeletal development and proliferation and morphogenesis in multiple organs. Expression profiling of 3-week old wild-type (WT) and Csf1rko livers identified 2760 differentially expressed genes associated with the loss of macrophages, severe hypoplasia, delayed hepatocyte maturation, disrupted lipid metabolism and the IGF1/IGF binding protein system. Older Csf1rko rats developed severe hepatic steatosis. Consistent with the developmental delay in the liver Csf1rko rats had greatly-reduced circulating IGF1. Transfer of WT bone marrow (BM) cells at weaning without conditioning repopulated resident macrophages in all organs, including microglia in the brain, and reversed the mutant phenotypes enabling long term survival and fertility. WT BM transfer restored osteoclasts, eliminated osteopetrosis, restored bone marrow cellularity and architecture and reversed granulocytosis and B cell deficiency. Csf1rko rats had an elevated circulating CSF1 concentration which was rapidly reduced to WT levels following BM transfer. However, CD43hi non-classical monocytes, absent in the Csf1rko, were not rescued and bone marrow progenitors remained unresponsive to CSF1. The results demonstrate that the Csf1rko phenotype is autonomous to BM-derived cells and indicate that BM contains a progenitor of tissue macrophages distinct from hematopoietic stem cells. The model provides a unique system in which to define the pathways of development of resident tissue macrophages and their local and systemic roles in growth and organ maturation.
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Affiliation(s)
- Sahar Keshvari
- Mater Research Institute-University of Queensland, Translational Research Institute, Woolloongabba, Brisbane, Qld, Australia
| | - Melanie Caruso
- Mater Research Institute-University of Queensland, Translational Research Institute, Woolloongabba, Brisbane, Qld, Australia
| | - Ngari Teakle
- Mater Research Institute-University of Queensland, Translational Research Institute, Woolloongabba, Brisbane, Qld, Australia
| | - Lena Batoon
- Mater Research Institute-University of Queensland, Translational Research Institute, Woolloongabba, Brisbane, Qld, Australia
| | - Anuj Sehgal
- Mater Research Institute-University of Queensland, Translational Research Institute, Woolloongabba, Brisbane, Qld, Australia
| | - Omkar L. Patkar
- Mater Research Institute-University of Queensland, Translational Research Institute, Woolloongabba, Brisbane, Qld, Australia
| | - Michelle Ferrari-Cestari
- Mater Research Institute-University of Queensland, Translational Research Institute, Woolloongabba, Brisbane, Qld, Australia
| | - Cameron E. Snell
- Mater Research Institute-University of Queensland, Translational Research Institute, Woolloongabba, Brisbane, Qld, Australia
| | - Chen Chen
- School of Biomedical Sciences, University of Queensland, St Lucia, Qld, Australia
| | - Alex Stevenson
- Mater Research Institute-University of Queensland, Translational Research Institute, Woolloongabba, Brisbane, Qld, Australia
| | - Felicity M. Davis
- Mater Research Institute-University of Queensland, Translational Research Institute, Woolloongabba, Brisbane, Qld, Australia
| | - Stephen J. Bush
- Nuffield Department of Clinical Medicine, John Radcliffe Hospital, University of Oxford, Oxford, United Kingdom
| | - Clare Pridans
- Centre for Inflammation Research and Simons Initiative for the Developing Brain, Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh, United Kingdom
| | - Kim M. Summers
- Mater Research Institute-University of Queensland, Translational Research Institute, Woolloongabba, Brisbane, Qld, Australia
| | - Allison R. Pettit
- Mater Research Institute-University of Queensland, Translational Research Institute, Woolloongabba, Brisbane, Qld, Australia
| | - Katharine M. Irvine
- Mater Research Institute-University of Queensland, Translational Research Institute, Woolloongabba, Brisbane, Qld, Australia
- * E-mail: (KMI); (DAH)
| | - David A. Hume
- Mater Research Institute-University of Queensland, Translational Research Institute, Woolloongabba, Brisbane, Qld, Australia
- * E-mail: (KMI); (DAH)
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Li SY, Gu X, Heinrich A, Hurley EG, Capel B, DeFalco T. Loss of Mafb and Maf distorts myeloid cell ratios and disrupts fetal mouse testis vascularization and organogenesis†. Biol Reprod 2021; 105:958-975. [PMID: 34007995 DOI: 10.1093/biolre/ioab098] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2020] [Revised: 04/20/2021] [Accepted: 05/11/2021] [Indexed: 12/19/2022] Open
Abstract
Testis differentiation is initiated when Sry in pre-Sertoli cells directs the gonad toward a male-specific fate. Sertoli cells are essential for testis development, but cell types within the interstitial compartment, such as immune and endothelial cells, are also critical for organ formation. Our previous work implicated macrophages in fetal testis morphogenesis, but little is known about genes underlying immune cell development during organogenesis. Here we examine the role of the immune-associated genes Mafb and Maf in mouse fetal gonad development, and we demonstrate that deletion of these genes leads to aberrant hematopoiesis manifested by supernumerary gonadal monocytes. Mafb; Maf double knockout embryos underwent initial gonadal sex determination normally, but exhibited testicular hypervascularization, testis cord formation defects, Leydig cell deficit, and a reduced number of germ cells. In general, Mafb and Maf alone were dispensable for gonad development; however, when both genes were deleted, we observed significant defects in testicular morphogenesis, indicating that Mafb and Maf work redundantly during testis differentiation. These results demonstrate previously unappreciated roles for Mafb and Maf in immune and vascular development and highlight the importance of interstitial cells in gonadal differentiation.
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Affiliation(s)
- Shu-Yun Li
- Division of Reproductive Sciences, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA
| | - Xiaowei Gu
- Division of Reproductive Sciences, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA
| | - Anna Heinrich
- Division of Reproductive Sciences, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA
| | - Emily G Hurley
- Division of Reproductive Sciences, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.,Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45267 USA.,Department of Obstetrics and Gynecology, University of Cincinnati College of Medicine, Cincinnati, OH 45267 USA
| | - Blanche Capel
- Department of Cell Biology, Duke University Medical Center, Durham, NC 27710 USA
| | - Tony DeFalco
- Division of Reproductive Sciences, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.,Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45267 USA
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Abstract
Tissue-resident macrophages are present in most tissues with developmental, self-renewal, or functional attributes that do not easily fit into a textbook picture of a plastic and multifunctional macrophage originating from hematopoietic stem cells; nor does it fit a pro- versus anti-inflammatory paradigm. This review presents and discusses current knowledge on the developmental biology of macrophages from an evolutionary perspective focused on the function of macrophages, which may aid in study of developmental, inflammatory, tumoral, and degenerative diseases. We also propose a framework to investigate the functions of macrophages in vivo and discuss how inherited germline and somatic mutations may contribute to the roles of macrophages in diseases.
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Affiliation(s)
- Nehemiah Cox
- Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA;
| | - Maria Pokrovskii
- Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA;
| | - Rocio Vicario
- Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA;
| | - Frederic Geissmann
- Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA;
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Cotechini T, Atallah A, Grossman A. Tissue-Resident and Recruited Macrophages in Primary Tumor and Metastatic Microenvironments: Potential Targets in Cancer Therapy. Cells 2021; 10:960. [PMID: 33924237 PMCID: PMC8074766 DOI: 10.3390/cells10040960] [Citation(s) in RCA: 40] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2021] [Revised: 04/16/2021] [Accepted: 04/17/2021] [Indexed: 12/24/2022] Open
Abstract
Macrophages within solid tumors and metastatic sites are heterogenous populations with different developmental origins and substantially contribute to tumor progression. A number of tumor-promoting phenotypes associated with both tumor- and metastasis-associated macrophages are similar to innate programs of embryonic-derived tissue-resident macrophages. In contrast to recruited macrophages originating from marrow precursors, tissue-resident macrophages are seeded before birth and function to coordinate tissue remodeling and maintain tissue integrity and homeostasis. Both recruited and tissue-resident macrophage populations contribute to tumor growth and metastasis and are important mediators of resistance to chemotherapy, radiation therapy, and immune checkpoint blockade. Thus, targeting various macrophage populations and their tumor-promoting phenotypes holds therapeutic promise. Here, we discuss various macrophage populations as regulators of tumor progression, immunity, and immunotherapy. We provide an overview of macrophage targeting strategies, including therapeutics designed to induce macrophage depletion, impair recruitment, and induce repolarization. We also provide a perspective on the therapeutic potential for macrophage-specific acquisition of trained immunity as an anti-cancer agent and discuss the therapeutic potential of exploiting macrophages and their traits to reduce tumor burden.
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Affiliation(s)
- Tiziana Cotechini
- Department of Biomedical and Molecular Sciences, Queen’s University, Kingston, ON K7L 3N6, Canada; (A.A.); (A.G.)
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40
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Saunders DC, Aamodt KI, Richardson TM, Hopkirk AJ, Aramandla R, Poffenberger G, Jenkins R, Flaherty DK, Prasad N, Levy SE, Powers AC, Brissova M. Coordinated interactions between endothelial cells and macrophages in the islet microenvironment promote β cell regeneration. NPJ Regen Med 2021; 6:22. [PMID: 33824346 PMCID: PMC8024255 DOI: 10.1038/s41536-021-00129-z] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2020] [Accepted: 02/24/2021] [Indexed: 12/14/2022] Open
Abstract
Endogenous β cell regeneration could alleviate diabetes, but proliferative stimuli within the islet microenvironment are incompletely understood. We previously found that β cell recovery following hypervascularization-induced β cell loss involves interactions with endothelial cells (ECs) and macrophages (MΦs). Here we show that proliferative ECs modulate MΦ infiltration and phenotype during β cell loss, and recruited MΦs are essential for β cell recovery. Furthermore, VEGFR2 inactivation in quiescent ECs accelerates islet vascular regression during β cell recovery and leads to increased β cell proliferation without changes in MΦ phenotype or number. Transcriptome analysis of β cells, ECs, and MΦs reveals that β cell proliferation coincides with elevated expression of extracellular matrix remodeling molecules and growth factors likely driving activation of proliferative signaling pathways in β cells. Collectively, these findings suggest a new β cell regeneration paradigm whereby coordinated interactions between intra-islet MΦs, ECs, and extracellular matrix mediate β cell self-renewal.
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Affiliation(s)
- Diane C Saunders
- Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, USA
- Department of Medicine, Division of Diabetes, Endocrinology, and Metabolism, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Kristie I Aamodt
- Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, USA
| | - Tiffany M Richardson
- Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, USA
| | - Alexander J Hopkirk
- Department of Medicine, Division of Diabetes, Endocrinology, and Metabolism, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Radhika Aramandla
- Department of Medicine, Division of Diabetes, Endocrinology, and Metabolism, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Greg Poffenberger
- Department of Medicine, Division of Diabetes, Endocrinology, and Metabolism, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Regina Jenkins
- Department of Medicine, Division of Diabetes, Endocrinology, and Metabolism, Vanderbilt University Medical Center, Nashville, TN, USA
| | - David K Flaherty
- Flow Cytometry Shared Resource, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Nripesh Prasad
- Hudson Alpha Institute of Biotechnology, Huntsville, AL, USA
| | - Shawn E Levy
- Hudson Alpha Institute of Biotechnology, Huntsville, AL, USA
| | - Alvin C Powers
- Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, USA.
- Department of Medicine, Division of Diabetes, Endocrinology, and Metabolism, Vanderbilt University Medical Center, Nashville, TN, USA.
- VA Tennessee Valley Healthcare, Nashville, TN, USA.
| | - Marcela Brissova
- Department of Medicine, Division of Diabetes, Endocrinology, and Metabolism, Vanderbilt University Medical Center, Nashville, TN, USA.
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41
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Golden TN, Simmons RA. Immune dysfunction in developmental programming of type 2 diabetes mellitus. Nat Rev Endocrinol 2021; 17:235-245. [PMID: 33526907 PMCID: PMC7969450 DOI: 10.1038/s41574-020-00464-z] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 12/17/2020] [Indexed: 01/30/2023]
Abstract
Intrauterine growth restriction (IUGR) is a common complication of pregnancy and increases the risk of the offspring developing type 2 diabetes mellitus (T2DM) later in life. Alterations in the immune system are implicated in the pathogenesis of IUGR-induced T2DM. The development of the fetal immune system is a delicate balance as it must remain tolerant of maternal antigens whilst also preparing for the post-birth environment. In addition, the fetal immune system is susceptible to an altered intrauterine milieu caused by maternal and placental inflammatory mediators or secondary to nutrient and oxygen deprivation. Pancreatic-resident macrophages populate the pancreas during fetal development, and their phenotype is dynamic through the neonatal period. Furthermore, macrophages in the islets are instrumental in islet development as they influence β-cell proliferation and islet neogenesis. In addition, cytokines, derived from β-cells and macrophages, are important to islet homeostasis in the fetus and adult and, when perturbed, can cause islet dysfunction. Several activated immune pathways have been identified in the islets of people who experienced IUGR, with alternations in the levels of IL-1β and IL-4 as well as changes in TGFβ signalling. Leptin levels are also altered. Immunomodulation has shown therapeutic benefit in T2DM and might be particularly useful in IUGR-induced T2DM.
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Affiliation(s)
- Thea N Golden
- Center for Research on Reproduction and Women's Health, Perelman School of Medicine University of Pennsylvania, Philadelphia, PA, USA
- Center of Excellence in Environmental Toxicology, Perelman School of Medicine University of Pennsylvania, Philadelphia, PA, USA
| | - Rebecca A Simmons
- Center for Research on Reproduction and Women's Health, Perelman School of Medicine University of Pennsylvania, Philadelphia, PA, USA.
- Center of Excellence in Environmental Toxicology, Perelman School of Medicine University of Pennsylvania, Philadelphia, PA, USA.
- Division of Neonatology, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
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Sun ZY, Yu TY, Jiang FX, Wang W. Functional maturation of immature β cells: A roadblock for stem cell therapy for type 1 diabetes. World J Stem Cells 2021; 13:193-207. [PMID: 33815669 PMCID: PMC8006013 DOI: 10.4252/wjsc.v13.i3.193] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2020] [Revised: 01/19/2021] [Accepted: 02/25/2021] [Indexed: 02/06/2023] Open
Abstract
Type 1 diabetes mellitus (T1DM) is a chronic autoimmune disease caused by the specific destruction of pancreatic islet β cells and is characterized as the absolute insufficiency of insulin secretion. Current insulin replacement therapy supplies insulin in a non-physiological way and is associated with devastating complications. Experimental islet transplantation therapy has been proven to restore glucose homeostasis in people with severe T1DM. However, it is restricted by many factors such as severe shortage of donor sources, progressive loss of donor cells, high cost, etc. As pluripotent stem cells have the potential to give rise to all cells including islet β cells in the body, stem cell therapy for diabetes has attracted great attention in the academic community and the general public. Transplantation of islet β-like cells differentiated from human pluripotent stem cells (hPSCs) has the potential to be an excellent alternative to islet transplantation. In stem cell therapy, obtaining β cells with complete insulin secretion in vitro is crucial. However, after much research, it has been found that the β-like cells obtained by in vitro differentiation still have many defects, including lack of adult-type glucose stimulated insulin secretion, and multi-hormonal secretion, suggesting that in vitro culture does not allows for obtaining fully mature β-like cells for transplantation. A large number of studies have found that many transcription factors play important roles in the process of transforming immature to mature human islet β cells. Furthermore, PDX1, NKX6.1, SOX9, NGN3, PAX4, etc., are important in inducing hPSC differentiation in vitro. The absent or deficient expression of any of these key factors may lead to the islet development defect in vivo and the failure of stem cells to differentiate into genuine functional β-like cells in vitro. This article reviews β cell maturation in vivo and in vitro and the vital roles of key molecules in this process, in order to explore the current problems in stem cell therapy for diabetes.
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Affiliation(s)
- Zi-Yi Sun
- Department of Endocrinology, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361100, Fujian Province, China
| | - Ting-Yan Yu
- Department of Endocrinology, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361100, Fujian Province, China
| | - Fang-Xu Jiang
- Department of Endocrinology, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361100, Fujian Province, China
| | - Wei Wang
- Department of Endocrinology, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361100, Fujian Province, China.
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Denroche HC, Miard S, Sallé-Lefort S, Picard F, Verchere CB. T cells accumulate in non-diabetic islets during ageing. IMMUNITY & AGEING 2021; 18:8. [PMID: 33622333 PMCID: PMC7901217 DOI: 10.1186/s12979-021-00221-4] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/28/2020] [Accepted: 02/11/2021] [Indexed: 12/25/2022]
Abstract
Background The resident immune population of pancreatic islets has roles in islet development, beta cell physiology, and the pathology of diabetes. These roles have largely been attributed to islet macrophages, comprising 90% of islet immune cells (in the absence of islet autoimmunity), and, in the case of type 1 diabetes, to infiltrating autoreactive T cells. In adipose, tissue-resident and recruited T and B cells have been implicated in the development of insulin resistance during diet-induced obesity and ageing, but whether this is paralleled in the pancreatic islets is not known. Here, we investigated the non-macrophage component of resident islet immune cells in islets isolated from C57BL/6 J male mice during ageing (3 to 24 months of age) and following similar weight gain achieved by 12 weeks of 60% high fat diet. Immune cells were also examined by flow cytometry in cadaveric non-diabetic human islets. Results Immune cells comprised 2.7 ± 1.3% of total islet cells in non-diabetic mouse islets, and 2.3 ± 1.7% of total islet cells in non-diabetic human islets. In 3-month old mice on standard diet, B and T cells each comprised approximately 2–4% of the total islet immune cell compartment, and approximately 0.1% of total islet cells. A similar amount of T cells were present in non-diabetic human islets. The majority of islet T cells expressed the αβ T cell receptor, and were comprised of CD8-positive, CD4-positive, and regulatory T cells, with a minor population of γδ T cells. Interestingly, the number of islet T cells increased linearly (R2 = 0.9902) with age from 0.10 ± 0.05% (3 months) to 0.38 ± 0.11% (24 months) of islet cells. This increase was uncoupled from body weight, and was not phenocopied by a degree similar weight gain induced by high fat diet in mice. Conclusions This study reveals that T cells are a part of the normal islet immune population in mouse and human islets, and accumulate in islets during ageing in a body weight-independent manner. Though comprising only a small subset of the immune cells within islets, islet T cells may play a role in the physiology of islet ageing. Supplementary Information The online version contains supplementary material available at 10.1186/s12979-021-00221-4.
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Affiliation(s)
- Heather C Denroche
- Canucks for Kids Fund Childhood Diabetes Laboratories, BC Children's Hospital Research Institute, Department of Surgery, University of British Columbia, Vancouver, British Columbia, Canada
| | - Stéphanie Miard
- Institut universitaire de cardiologie et de pneumologie de Québec, Université Laval, Québec, Québec, Canada
| | | | - Frédéric Picard
- Institut universitaire de cardiologie et de pneumologie de Québec, Université Laval, Québec, Québec, Canada.,Faculté de pharmacie, Université Laval, Québec, Québec, Canada
| | - C Bruce Verchere
- Canucks for Kids Fund Childhood Diabetes Laboratories, BC Children's Hospital Research Institute, Department of Surgery, University of British Columbia, Vancouver, British Columbia, Canada. .,Departments of Surgery and Pathology & Laboratory Medicine, BC Children's Hospital Research Institute, Centre for Molecular Medicine and Therapeutics, University of British Columbia, 950 West 28th Ave, Vancouver, British Columbia, V5Z 4H4, Canada.
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Zakharov PN, Hu H, Wan X, Unanue ER. Single-cell RNA sequencing of murine islets shows high cellular complexity at all stages of autoimmune diabetes. J Exp Med 2021; 217:151619. [PMID: 32251514 PMCID: PMC7971127 DOI: 10.1084/jem.20192362] [Citation(s) in RCA: 87] [Impact Index Per Article: 21.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2019] [Revised: 02/11/2020] [Accepted: 03/02/2020] [Indexed: 12/22/2022] Open
Abstract
Tissue-specific autoimmune diseases are driven by activation of diverse immune cells in the target organs. However, the molecular signatures of immune cell populations over time in an autoimmune process remain poorly defined. Using single-cell RNA sequencing, we performed an unbiased examination of diverse islet-infiltrating cells during autoimmune diabetes in the nonobese diabetic mouse. The data revealed a landscape of transcriptional heterogeneity across the lymphoid and myeloid compartments. Memory CD4 and cytotoxic CD8 T cells appeared early in islets, accompanied by regulatory cells with distinct phenotypes. Surprisingly, we observed a dramatic remodeling in the islet microenvironment, in which the resident macrophages underwent a stepwise activation program. This process resulted in polarization of the macrophage subpopulations into a terminal proinflammatory state. This study provides a single-cell atlas defining the staging of autoimmune diabetes and reveals that diabetic autoimmunity is driven by transcriptionally distinct cell populations specialized in divergent biological functions.
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Affiliation(s)
- Pavel N Zakharov
- Division of Immunobiology, Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO
| | - Hao Hu
- Division of Immunobiology, Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO
| | - Xiaoxiao Wan
- Division of Immunobiology, Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO
| | - Emil R Unanue
- Division of Immunobiology, Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO
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Cosentino C, Regazzi R. Crosstalk between Macrophages and Pancreatic β-Cells in Islet Development, Homeostasis and Disease. Int J Mol Sci 2021; 22:ijms22041765. [PMID: 33578952 PMCID: PMC7916718 DOI: 10.3390/ijms22041765] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2020] [Revised: 02/04/2021] [Accepted: 02/06/2021] [Indexed: 12/29/2022] Open
Abstract
Macrophages are highly heterogeneous and plastic immune cells with peculiar characteristics dependent on their origin and microenvironment. Following pathogen infection or damage, circulating monocytes can be recruited in different tissues where they differentiate into macrophages. Stimuli present in the surrounding milieu induce the polarisation of macrophages towards a pro-inflammatory or anti-inflammatory profile, mediating inflammatory or homeostatic responses, respectively. However, macrophages can also derive from embryonic hematopoietic precursors and reside in specific tissues, actively participating in the development and the homeostasis in physiological conditions. Pancreatic islet resident macrophages are present from the prenatal stages onwards and show specific surface markers and functions. They localise in close proximity to β-cells, being exquisite sensors of their secretory ability and viability. Over the years, the crucial role of macrophages in β-cell differentiation and homeostasis has been highlighted. In addition, macrophages are emerging as central players in the initiation of autoimmune insulitis in type 1 diabetes and in the low-grade chronic inflammation characteristic of obesity and type 2 diabetes pathogenesis. The present work reviews the current knowledge in the field, with a particular focus on the mechanisms of communication between β-cells and macrophages that have been described so far.
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Affiliation(s)
- Cristina Cosentino
- Department of Fundamental Neurosciences, University of Lausanne, Rue du Bugnon 9, CH-1005 Lausanne, Switzerland;
| | - Romano Regazzi
- Department of Fundamental Neurosciences, University of Lausanne, Rue du Bugnon 9, CH-1005 Lausanne, Switzerland;
- Department of Biomedical Sciences, University of Lausanne, Rue du Bugnon 7, CH-1005 Lausanne, Switzerland
- Correspondence: ; Tel.: +41-21-692-52-80; Fax: +41-21-692-52-55
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Collier JJ, Batdorf HM, Martin TM, Rohli KE, Burk DH, Lu D, Cooley CR, Karlstad MD, Jackson JW, Sparer TE, Zhang J, Mynatt RL, Burke SJ. Pancreatic, but not myeloid-cell, expression of interleukin-1alpha is required for maintenance of insulin secretion and whole body glucose homeostasis. Mol Metab 2021; 44:101140. [PMID: 33285301 PMCID: PMC7772372 DOI: 10.1016/j.molmet.2020.101140] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/25/2020] [Revised: 11/03/2020] [Accepted: 12/02/2020] [Indexed: 02/07/2023] Open
Abstract
OBJECTIVE The expression of the interleukin-1 receptor type I (IL-1R) is enriched in pancreatic islet β-cells, signifying that ligands activating this pathway are important for the health and function of the insulin-secreting cell. Using isolated mouse, rat, and human islets, we identified the cytokine IL-1α as a highly inducible gene in response to IL-1R activation. In addition, IL-1α is elevated in mouse and rat models of obesity and Type 2 diabetes. Since less is known about the biology of IL-1α relative to IL-1β in pancreatic tissue, our objective was to investigate the contribution of IL-1α to pancreatic β-cell function and overall glucose homeostasis in vivo. METHODS We generated a novel mouse line with conditional IL-1α alleles and subsequently produced mice with either pancreatic- or myeloid lineage-specific deletion of IL-1α. RESULTS Using this in vivo approach, we discovered that pancreatic (IL-1αPdx1-/-), but not myeloid-cell, expression of IL-1α (IL-1αLysM-/-) was required for the maintenance of whole body glucose homeostasis in both male and female mice. Moreover, pancreatic deletion of IL-1α led to impaired glucose tolerance with no change in insulin sensitivity. This observation was consistent with our finding that glucose-stimulated insulin secretion was reduced in islets isolated from IL-1αPdx1-/- mice. Alternatively, IL-1αLysM-/- mice (male and female) did not have any detectable changes in glucose tolerance, respiratory quotient, physical activity, or food intake when compared with littermate controls. CONCLUSIONS Taken together, we conclude that there is an important physiological role for pancreatic IL-1α to promote glucose homeostasis by supporting glucose-stimulated insulin secretion and islet β-cell mass in vivo.
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Affiliation(s)
- J Jason Collier
- Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, LA, 70808, USA; Department of Biological Sciences, Louisiana State University, Baton Rouge, LA, 70803, USA
| | - Heidi M Batdorf
- Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, LA, 70808, USA
| | - Thomas M Martin
- Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, LA, 70808, USA; Department of Biological Sciences, Louisiana State University, Baton Rouge, LA, 70803, USA
| | - Kristen E Rohli
- Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, LA, 70808, USA
| | - David H Burk
- Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, LA, 70808, USA
| | - Danhong Lu
- Sarah W. Stedman Nutrition and Metabolism Center, Duke Molecular Physiology Institute, Duke University Medical Center, Durham, NC, 27704, USA
| | - Chris R Cooley
- Department of Surgery, University of Tennessee Health Science Center, Knoxville, TN, 37920, USA
| | - Michael D Karlstad
- Department of Surgery, University of Tennessee Health Science Center, Knoxville, TN, 37920, USA
| | - Joseph W Jackson
- Department of Microbiology, University of Tennessee, Knoxville, TN, 37996, USA
| | - Tim E Sparer
- Department of Microbiology, University of Tennessee, Knoxville, TN, 37996, USA
| | - Jingying Zhang
- Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, LA, 70808, USA
| | - Randall L Mynatt
- Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, LA, 70808, USA
| | - Susan J Burke
- Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, LA, 70808, USA.
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Burke SJ, Collier JJ. Special Issue: Islet Inflammation and Metabolic Homeostasis. Metabolites 2021; 11:metabo11020077. [PMID: 33525362 PMCID: PMC7910950 DOI: 10.3390/metabo11020077] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2021] [Accepted: 01/26/2021] [Indexed: 11/16/2022] Open
Abstract
This special issue was commissioned to offer a source of distinct viewpoints and novel data that capture some of the subtleties of the pancreatic islet, especially in relation to adaptive changes that influence metabolic homeostasis [...].
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Affiliation(s)
- Susan J. Burke
- Laboratory of Immunogenetics, Pennington Biomedical Research Center, Baton Rouge, LA 70808, USA
- Correspondence: (S.J.B.); (J.J.C.); Tel.: +1-225-763-2532 (S.J.B.); +1-225-763-2884 (J.J.C.)
| | - J. Jason Collier
- Laboratory of Islet Biology and Inflammation, Pennington Biomedical Research Center, Baton Rouge, LA 70808, USA
- Department of Biological Sciences, Louisiana State University, Baton Rouge, LA 70803, USA
- Correspondence: (S.J.B.); (J.J.C.); Tel.: +1-225-763-2532 (S.J.B.); +1-225-763-2884 (J.J.C.)
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Bijnen M, Bajénoff M. Gland Macrophages: Reciprocal Control and Function within Their Niche. Trends Immunol 2021; 42:120-136. [PMID: 33423933 DOI: 10.1016/j.it.2020.12.006] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2020] [Revised: 12/07/2020] [Accepted: 12/08/2020] [Indexed: 11/30/2022]
Abstract
The human body contains dozens of endocrine and exocrine glands, which regulate physiological processes by secreting hormones and other factors. Glands can be subdivided into contiguous tissue modules, each consisting of an interdependent network of cells that together perform particular tissue functions. Among those cells are macrophages, a diverse type of immune cells endowed with trophic functions. In this review, we discuss recent findings on how resident macrophages support tissue modules within glands via the creation of mutually beneficial cell-cell circuits. A better comprehension of gland macrophage function and local control within their niche is essential to achieve a refined understanding of gland physiology in homeostasis and disease.
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Affiliation(s)
- Mitchell Bijnen
- Aix Marseille University, CNRS, INSERM, Centre d'Immunologie de Marseille-Luminy, Marseille, France.
| | - Marc Bajénoff
- Aix Marseille University, CNRS, INSERM, Centre d'Immunologie de Marseille-Luminy, Marseille, France
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Parv K, Westerlund N, Merchant K, Komijani M, Lindsay RS, Christoffersson G. Phagocytosis and Efferocytosis by Resident Macrophages in the Mouse Pancreas. Front Endocrinol (Lausanne) 2021; 12:606175. [PMID: 34113315 PMCID: PMC8185276 DOI: 10.3389/fendo.2021.606175] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/14/2020] [Accepted: 04/28/2021] [Indexed: 12/31/2022] Open
Abstract
The tissue microenvironment in the mouse pancreas has been shown to promote very different polarizations of resident macrophages with islet-resident macrophages displaying an inflammatory "M1" profile and macrophages in the exocrine tissue mostly displaying an alternatively activated "M2" profile. The impact of this polarization on tissue homeostasis and diabetes development is unclear. In this study, the ability of pancreas-resident macrophages to phagocyte bacterial and endogenous debris was investigated. Mouse endocrine and exocrine tissues were separated, and tissue-resident macrophages were isolated by magnetic immunolabeling. Isolated macrophages were subjected to flow cytometry for polarization markers and qPCR for phagocytosis-related genes. Functional in vitro investigations included phagocytosis and efferocytosis assays using pH-sensitive fluorescent bacterial particles and dead fluorescent neutrophils, respectively. Intravital confocal imaging of in situ phagocytosis and efferocytosis in the pancreas was used to confirm findings in vivo. Gene expression analysis revealed no significant overall difference in expression of most phagocytosis-related genes in islet-resident vs. exocrine-resident macrophages included in the analysis. In this study, pancreas-resident macrophages were shown to differ in their ability to phagocyte bacterial and endogenous debris depending on their microenvironment. This difference in abilities may be one of the factors polarizing islet-resident macrophages to an inflammatory state since phagocytosis has been found to imprint macrophage heterogeneity. It remains unclear if this difference has any implications in the development of islet dysfunction or autoimmunity.
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Affiliation(s)
- Kristel Parv
- Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden
| | | | - Kevin Merchant
- Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden
| | - Milad Komijani
- Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden
| | - Robin S. Lindsay
- Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden
| | - Gustaf Christoffersson
- Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden
- Science for Life Laboratory, Uppsala University, Uppsala, Sweden
- *Correspondence: Gustaf Christoffersson,
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Zirpel H, Roep BO. Islet-Resident Dendritic Cells and Macrophages in Type 1 Diabetes: In Search of Bigfoot's Print. Front Endocrinol (Lausanne) 2021; 12:666795. [PMID: 33912139 PMCID: PMC8072455 DOI: 10.3389/fendo.2021.666795] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/11/2021] [Accepted: 03/08/2021] [Indexed: 12/12/2022] Open
Abstract
The classical view of type 1 diabetes assumes that the autoimmune mediated targeting of insulin producing ß-cells is caused by an error of the immune system. Malfunction and stress of beta cells added the target tissue at the center of action. The innate immune system, and in particular islet-resident cells of the myeloid lineage, could function as a link between stressed ß-cells and activation and recognition by the adaptive immune system. We survey the role of islet-resident macrophages and dendritic cells in healthy islet homeostasis and pathophysiology of T1D. Knowledge of islet-resident antigen presenting cells in rodents is substantial, but quite scarce in humans, in particular regarding dendritic cells. Differences in blood between healthy and diseased individuals were reported, but it remains elusive to what extend these contribute to T1D onset. Increasing our understanding of the interaction between ß-cells and innate immune cells may provide new insights into disease initiation and development that could ultimately point to future treatment options. Here we review current knowledge of islet-resident macrophages and dendritic cells, place these in context of current clinical trials, and guide future research.
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