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1
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Steffen TL, Stafford JD, Bocke CR, Samson WK, Yosten GLC. The anorexigenic peptide nesfatin-1 dampens the B cell response to receptor-mediated stimulation through inhibition of NF-κB signaling. Am J Physiol Regul Integr Comp Physiol 2025; 328:R601-R610. [PMID: 40135734 DOI: 10.1152/ajpregu.00233.2024] [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: 09/24/2024] [Revised: 10/15/2024] [Accepted: 03/17/2025] [Indexed: 03/27/2025]
Abstract
Nesfatin-1, a posttranslational product of the protein encoded by the nucleobindin 2 gene (NUCB2), was functionally identified as an appetite regulatory molecule in rat hypothalamic nuclei. In the years following the discovery, those findings have been corroborated and expanded upon, and we now know that nesfatin-1 is expressed throughout peripheral tissues and exerts physiological effects beyond feeding control. Literature indicates that adipose tissue is one of the peripheral sources of NUCB2/nesfatin-1, and in this setting, it has anti-inflammatory effects that have recently been implicated in regulating chronic inflammation associated with diet-induced obesity. Currently, there are gaps in our understanding of what cell types within the adipose tissue compartment respond to nesfatin-1, in addition to the cellular mechanism(s) of this peptide. In this study, we sought to determine a mechanism by which this peptide might directly interact with the immune system starting with a human B cell line, Raji. We show that nesfatin-1 inhibits lipopolysaccharide (LPS) and B cell receptor (BCR) dual stimulation-mediated B cell growth, stimulation-induced cell death, and secretion of inflammatory mediators. Specifically, there was a reduced fold-change in B cell growth during stimulation which is paired with a reduction in the formation of apoptotic (annexin V+) cells. In addition, nesfatin-1 significantly reduced IgM secretion and modestly reduced TNFα secretion by stimulated B cells. The anti-inflammatory effects of nesfatin-1 overall are likely due to attenuation of NF-κB signaling, via inhibition of IκB degradation, in stimulated B cells.NEW & NOTEWORTHY This study establishes an interaction of nesfatin-1 and a human B cell line, Raji. Nesfatin-1 was shown to limit the B cell response to receptor-mediated stimulation, an action that has potential implications within the immune system and the development of chronic inflammation associated with the obese state. This study, along with previously published works, highlights a need for further research on nesfatin-1's interactions with adipocytes and immune cells.
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Affiliation(s)
- Tara L Steffen
- Department of Pharmacology and Physiology, Saint Louis University School of Medicine, St. Louis, Missouri, United States
| | - Joshua D Stafford
- Department of Pharmacology and Physiology, Saint Louis University School of Medicine, St. Louis, Missouri, United States
| | - Colleen R Bocke
- Department of Pharmacology and Physiology, Saint Louis University School of Medicine, St. Louis, Missouri, United States
| | - Willis K Samson
- Department of Pharmacology and Physiology, Saint Louis University School of Medicine, St. Louis, Missouri, United States
| | - Gina L C Yosten
- Department of Pharmacology and Physiology, Saint Louis University School of Medicine, St. Louis, Missouri, United States
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2
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Zhou H, Gizlenci M, Xiao Y, Martin F, Nakamori K, Zicari EM, Sato Y, Tullius SG. Obesity-associated Inflammation and Alloimmunity. Transplantation 2025; 109:588-596. [PMID: 39192462 PMCID: PMC11868468 DOI: 10.1097/tp.0000000000005183] [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: 08/29/2024]
Abstract
Obesity is a worldwide health problem with a rapidly rising incidence. In organ transplantation, increasing numbers of patients with obesity accumulate on waiting lists and undergo surgery. Obesity is in general conceptualized as a chronic inflammatory disease, potentially impacting alloimmune response and graft function. Here, we summarize our current understanding of cellular and molecular mechanisms that control obesity-associated adipose tissue inflammation and provide insights into mechanisms affecting transplant outcomes, emphasizing on the beneficial effects of weight loss on alloimmune responses.
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Affiliation(s)
- Hao Zhou
- Division of Transplant Surgery & Transplant Surgery Research Laboratory, Brigham and Women’s Hospital, Harvard Medical School, Boston, United States
| | - Merih Gizlenci
- Division of Transplant Surgery & Transplant Surgery Research Laboratory, Brigham and Women’s Hospital, Harvard Medical School, Boston, United States
- Department of General, Visceral, Cancer and Transplant Surgery, University Hospital of Cologne, Cologne, Germany
| | - Yao Xiao
- Division of Transplant Surgery & Transplant Surgery Research Laboratory, Brigham and Women’s Hospital, Harvard Medical School, Boston, United States
| | - Friederike Martin
- Division of Transplant Surgery & Transplant Surgery Research Laboratory, Brigham and Women’s Hospital, Harvard Medical School, Boston, United States
- Department of Surgery, CVK/CCM, Charité Universitätsmedizin Berlin, Berlin, Germany
| | - Keita Nakamori
- Division of Transplant Surgery & Transplant Surgery Research Laboratory, Brigham and Women’s Hospital, Harvard Medical School, Boston, United States
- Department of Urology, Osaka Medical and Pharmaceutical University, Takatsuki, Osaka, Japan
| | - Elizabeth M. Zicari
- Division of Transplant Surgery & Transplant Surgery Research Laboratory, Brigham and Women’s Hospital, Harvard Medical School, Boston, United States
- Faculté de Pharmacie, Université Paris Cité, Paris, France
| | - Yuko Sato
- Division of Transplant Surgery & Transplant Surgery Research Laboratory, Brigham and Women’s Hospital, Harvard Medical School, Boston, United States
| | - Stefan G. Tullius
- Division of Transplant Surgery & Transplant Surgery Research Laboratory, Brigham and Women’s Hospital, Harvard Medical School, Boston, United States
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3
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Yin Y, Liu Y, Du L, Wu S. Compromised B-cell homeostasis: Unraveling the link between major depression, infection and autoimmune disorders. J Affect Disord 2025; 374:565-578. [PMID: 39842671 DOI: 10.1016/j.jad.2025.01.095] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/12/2024] [Revised: 10/22/2024] [Accepted: 01/18/2025] [Indexed: 01/24/2025]
Abstract
BACKGROUND Major depression can increase susceptibility to viral infections and autoimmune diseases. B cell responses are crucial for immune defense against infections but can trigger autoimmunity when deregulated. However, it remains unclear whether compromised B-cell homeostasis in major depression contributes to an increased risk of infection and autoimmunity. METHODS Chronic unpredictable mild stress (CUMS) procedure was applied to adult C57BL/6 J mice to generate a reliable depression model. Mice were immunized with (4-hydroxy-3-nitrophenyl) acetyl (NP) keyhole limpet hemocyanin (NP-KLH) to elicit B-cell-mediated humoral immune responses. CUMS mice were subjected to a collagen-induced arthritis model or a Bm12-induced systemic lupus erythematosus model to assess the contribution of major depression to autoimmunity. RNA sequencing was performed to understand the effects of CUMS on B-cell homeostasis at the transcriptomic level. RESULTS CUMS mice exhibited an impaired humoral immune response, as evidenced by reduced germinal centers (GCs), plasma cells, and antigen-specific antibodies. Unimmunized CUMS mice displayed aberrant spontaneous expansion of GC B cells, plasma cells, age-associated B cells and autoantibody production. CUMS mice also demonstrated a greater exacerbation of autoimmune manifestations. RNA sequencing revealed that genes involved in B-cell-mediated immune response were downregulated in B cells from CUMS mice, while the pathways related to autoimmunity seem to be upregulated. LIMITATIONS Further research is needed to understand the specific targets, mechanisms, and role of B cell dysfunction in major depression. CONCLUSIONS Our results provide novel insights into B-cell-dependent mechanisms that involve the association of increased susceptibility to infections and autoimmunity in major depression.
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Affiliation(s)
- Yuye Yin
- College of Bioscience and Biotechnology, Yangzhou University, Yangzhou, Jiangsu, China
| | - Yuan Liu
- Department of Laboratory Medicine, Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, Jiangsu, China
| | - Longfei Du
- Department of Laboratory Medicine, Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, Jiangsu, China
| | - Shusheng Wu
- Department of Neurology, Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, Jiangsu, China.
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Cancro MP. B cells and aging: a historical perspective. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2025:vkaf025. [PMID: 40107285 DOI: 10.1093/jimmun/vkaf025] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/17/2024] [Accepted: 01/21/2025] [Indexed: 03/22/2025]
Affiliation(s)
- Michael P Cancro
- Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, United States
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5
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Pérez-Pérez L, Laidlaw BJ. Polarization of the memory B-cell response. J Leukoc Biol 2025; 117:qiae228. [PMID: 39401326 PMCID: PMC11953070 DOI: 10.1093/jleuko/qiae228] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2024] [Revised: 09/26/2024] [Accepted: 10/11/2024] [Indexed: 03/30/2025] Open
Abstract
Memory B cells are long-lived cells that are induced following infection or vaccination. Upon antigen re-encounter, memory B cells rapidly differentiate into antibody-secreting or germinal center B cells. While memory B cells are an important component of long-term protective immunity following vaccination, they also contribute to the progression of diseases such as autoimmunity and allergy. Numerous subsets of memory B cells have been identified in mice and humans that possess important phenotypic and functional differences. Here, we review the transcriptional circuitry governing memory B-cell differentiation and function. We then summarize emerging evidence that the inflammatory environment in which memory B cells develop has an important role in shaping their phenotype and examine the pathways regulating the development of memory B cells during a type 1-skewed and type 2-skewed immune response.
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Affiliation(s)
- Lizzette Pérez-Pérez
- Division of Allergy and Immunology, Department of Medicine, Washington University School of Medicine, 425 S Euclid Ave, St. Louis, MO 63110, United States
| | - Brian J Laidlaw
- Division of Allergy and Immunology, Department of Medicine, Washington University School of Medicine, 425 S Euclid Ave, St. Louis, MO 63110, United States
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6
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Winslow GM, Levack R. Know Your ABCs: Discovery, Differentiation, and Targeting of T-Bet+ B Cells. Immunol Rev 2025; 330:e13440. [PMID: 39844597 PMCID: PMC11754996 DOI: 10.1111/imr.13440] [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] [Revised: 12/22/2024] [Accepted: 01/01/2025] [Indexed: 01/24/2025]
Abstract
Since their first description in 2008, T-bet+ B cells have emerged as a clinically important B cell subset. Now commonly known as ABCs (Age-associated B Cells), they are uniquely characterized by their expression of the transcription factor T-bet. Indeed, this singular factor defines this B cell subset. This review will describe the discovery of T-bet+ B cells, their role in bacterial infection as T cell-independent (TI) plasmablasts, as well as long-term follicular helper T cell-dependent (TD) IgM+ and switched memory cells (i.e., T-bet+ ABCs), and later discoveries of their role(s) in diverse immunological responses. These studies highlight a critical, although limited, role of T-bet in IgG2a class switching, a function central to the cells' role in immunity and autoimmunity. Given their association with autoimmunity, pharmacological targeting is an attractive strategy for reducing or eliminating the B cells. T-bet+ ABCs express a number of characteristic cell surface markers, including CD11c, CD11b, CD73, and the adenosine 2a receptor (A2aR). Accordingly, A2aR agonist administration effectively targeted T-bet+ ABCs in vivo. Moreover, agonist treatment of lupus-prone mice reduced autoantibodies and disease symptoms. This latter work highlights the potential therapeutic use of adenosine agonists for treating autoimmune diseases involving T-bet+ ABCs.
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Affiliation(s)
- Gary M. Winslow
- Department of Microbiology and ImmunologyUpstate Medical UniversitySyracuseNew YorkUSA
| | - Russell Levack
- Department of ImmunologyUniversity of PittsburghPittsburghPennsylvaniaUSA
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Knox JJ, Karolyi K, Monslow J, Cromley D, Rader DJ, Puré E, Cancro MP. T-bet-expressing B cells promote atherosclerosis in apolipoprotein E-deficient mice. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2025; 214:vkae027. [PMID: 40073097 PMCID: PMC11952879 DOI: 10.1093/jimmun/vkae027] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/10/2024] [Accepted: 11/18/2024] [Indexed: 03/14/2025]
Abstract
The humoral immune system influences the development of atherosclerosis, but the contributions of specific memory B cell subsets and IgG isotypes are poorly understood. We assessed the relationship between atherosclerosis and age-associated B cells (ABCs), a T-bet-expressing memory B cell subset that is enriched for IgG2c production and implicated in humoral autoimmunity. We found increased numbers of splenic CD11c+ ABCs in 6-mo-old, chow-fed Apoe-/- mice versus C57BL/6 control mice, which were exacerbated by high-fat diet. Deletion of T-bet in the B lineage in high-fat diet-fed Apoe-/- mice reduced aortic lesion area, and this correlated with decreased splenic CD11c+ B cells and reduced serum oxidized low-density lipoprotein-specific IgG2c. Our findings suggest that T-bet-expressing B cells are atherogenic agents in the Apoe-/- model and indicate that interventions to inhibit a T-bet-driven humoral response may improve atherosclerotic disease.
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Affiliation(s)
- James J Knox
- Department of Pathology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
| | - Katalin Karolyi
- Department of Pathology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
| | - James Monslow
- Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, United States
| | - Debra Cromley
- Division of Translational Medicine and Human Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
| | - Daniel J Rader
- Division of Translational Medicine and Human Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
| | - Ellen Puré
- Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, United States
| | - Michael P Cancro
- Department of Pathology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
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Palacios PA, Santibañez Á, Aguirre-Muñoz F, Gutiérrez-Vera C, Niño de Zepeda-Carrizo V, Góngora-Pimentel M, Müller M, Cáceres M, Kalergis AM, Carreño LJ. Can invariant Natural Killer T cells drive B cell fate? a look at the humoral response. Front Immunol 2025; 16:1505883. [PMID: 40040714 PMCID: PMC11876049 DOI: 10.3389/fimmu.2025.1505883] [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] [Subscribe] [Scholar Register] [Received: 10/03/2024] [Accepted: 01/21/2025] [Indexed: 03/06/2025] Open
Abstract
Invariant Natural Killer T (NKT) cells represent a unique subset of innate-like T cells that express both NK cell and T cell receptors. These cells are rapidly activated by glycolipid antigens presented via CD1d molecules on antigen-presenting cells (APCs), including B cells, dendritic cells (DCs), and macrophages, or through cytokine-dependent mechanisms. Their ability to produce a wide range of cytokines and express costimulatory molecules underscores their critical role in bridging innate and adaptive immunity. B cells, traditionally recognized for their role in antibody production, also act as potent APCs due to their high expression of CD1d, enabling direct interactions with iNKT cells. This interaction has significant implications for humoral immunity, influencing B cell activation, class-switch recombination (CSR), germinal center formation, and memory B cell differentiation, thus expanding the conventional paradigm of T cell-B cell interactions. While the influence of iNKT cells on B cell biology and humoral responses is well-supported, many aspects of their interaction remain unresolved. Key questions include the roles of different iNKT cell subsets, the diversity of APCs, the spatiotemporal dynamics of these interactions, especially during early activation, and the potential for distinct glycolipid ligands to modulate immune outcomes. Understanding these factors could provide valuable insights into how iNKT cells regulate B cell-mediated immunity and offer opportunities to harness these interactions in immunotherapeutic applications, such as vaccine development. In this review, we examine these unresolved aspects and propose a novel perspective on the regulatory potential of iNKT cells in humoral immunity, emphasizing their promise as a target for innovative vaccine strategies.
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Affiliation(s)
- Pablo A. Palacios
- Millennium Institute on Immunology and Immunotherapy, Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago, Chile
| | - Álvaro Santibañez
- Millennium Institute on Immunology and Immunotherapy, Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago, Chile
| | - Fernanda Aguirre-Muñoz
- Millennium Institute on Immunology and Immunotherapy, Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago, Chile
| | - Cristián Gutiérrez-Vera
- Millennium Institute on Immunology and Immunotherapy, Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago, Chile
| | - Valentina Niño de Zepeda-Carrizo
- Millennium Institute on Immunology and Immunotherapy, Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago, Chile
| | - Martín Góngora-Pimentel
- Millennium Institute on Immunology and Immunotherapy, Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago, Chile
| | - Marioly Müller
- Departamento de Tecnología Médica, Facultad de Medicina, Universidad de Chile, Santiago, Chile
| | - Mónica Cáceres
- Millennium Institute on Immunology and Immunotherapy, Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago, Chile
| | - Alexis M. Kalergis
- Millennium Institute on Immunology and Immunotherapy, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Leandro J. Carreño
- Millennium Institute on Immunology and Immunotherapy, Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago, Chile
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9
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Xie G, Chen X, Gao Y, Yang M, Zhou S, Lu L, Wu H, Lu Q. Age-Associated B Cells in Autoimmune Diseases: Pathogenesis and Clinical Implications. Clin Rev Allergy Immunol 2025; 68:18. [PMID: 39960645 PMCID: PMC11832777 DOI: 10.1007/s12016-025-09021-w] [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] [Accepted: 01/07/2025] [Indexed: 02/20/2025]
Abstract
As a heterogeneous B cell subset, age-associated B cells (ABCs) exhibit distinct transcription profiles, extrafollicular differentiation processes, and multiple functions in autoimmunity. TLR7 and TLR9 signals, along with IFN-γ and IL-21 stimulation, are both essential for ABC differentiation, which is also regulated by chemokine receptors including CXCR3 and CCR2 and integrins including CD11b and CD11c. Given their functions in antigen uptake and presentation, autoantibody and proinflammatory cytokine secretion, and T helper cell activation, ABCs display potential in the prognosis, diagnosis, and therapy for autoimmune diseases, including systemic lupus erythematosus, rheumatoid arthritis, Sjögren's syndrome, multiple sclerosis, neuromyelitis optica spectrum disorders, and ankylosing spondylitis. Specifically targeting ABCs by inhibiting T-bet and CD11c and activating CD11b and ARA2 represents potential therapeutic strategies for SLE and RA. Although single-cell sequencing technologies have recently revealed the heterogeneous characteristics of ABCs, further investigations to explore and validate ABC-target therapies are still warranted.
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Affiliation(s)
- Guangyang Xie
- Department of Dermatology, the Second Xiangya Hospital, Hunan Key Laboratory of Medical Epigenomics, Central South University, Changsha, Hunan, China
| | - Xiaojing Chen
- Department of Dermatology, the Second Xiangya Hospital, Hunan Key Laboratory of Medical Epigenomics, Central South University, Changsha, Hunan, China
| | - Yixia Gao
- Department of Dermatology, the Second Xiangya Hospital, Hunan Key Laboratory of Medical Epigenomics, Central South University, Changsha, Hunan, China
| | - Ming Yang
- Department of Dermatology, the Second Xiangya Hospital, Hunan Key Laboratory of Medical Epigenomics, Central South University, Changsha, Hunan, China
| | - Suqing Zhou
- Department of Dermatology, the Second Xiangya Hospital, Hunan Key Laboratory of Medical Epigenomics, Central South University, Changsha, Hunan, China
| | - Liwei Lu
- Department of Pathology and Shenzhen Institute of Research and Innovation, The University of Hong Kong, Hong Kong, China.
- Centre for Oncology and Immunology, Hong Kong Science Park, Hong Kong, China.
| | - Haijing Wu
- Department of Dermatology, the Second Xiangya Hospital, Hunan Key Laboratory of Medical Epigenomics, Central South University, Changsha, Hunan, China.
- FuRong Laboratory, Changsha, China.
| | - Qianjin Lu
- Department of Dermatology, the Second Xiangya Hospital, Hunan Key Laboratory of Medical Epigenomics, Central South University, Changsha, Hunan, China.
- Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing, Jiangsu, China.
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10
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Samiea A, Celis G, Yadav R, Rodda LB, Moreau JM. B cells in non-lymphoid tissues. Nat Rev Immunol 2025:10.1038/s41577-025-01137-6. [PMID: 39910240 DOI: 10.1038/s41577-025-01137-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/16/2025] [Indexed: 02/07/2025]
Abstract
B cells have long been understood to be drivers of both humoral and cellular immunity. Recent advances underscore this importance but also indicate that in infection, inflammatory disease and cancer, B cells function directly at sites of inflammation and form tissue-resident memory populations. The spatial organization and cellular niches of tissue B cells have profound effects on their function and on disease outcome, as well as on patient response to therapy. Here we review the role of B cells in peripheral tissues in homeostasis and disease, and discuss the newly identified cellular and molecular signals that are involved in regulating their activity. We integrate emerging data from multi-omic human studies with experimental models to propose a framework for B cell function in tissue inflammation and homeostasis.
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Affiliation(s)
- Abrar Samiea
- Department of Cell, Developmental and Cancer Biology, Oregon Health & Science University, Portland, OR, USA
- Cancer Early Detection Advanced Research Center, Oregon Health & Science University, Portland, OR, USA
| | - George Celis
- Department of Molecular Microbiology and Immunology, Oregon Health & Science University, Portland, OR, USA
| | - Rashi Yadav
- Cancer Early Detection Advanced Research Center, Oregon Health & Science University, Portland, OR, USA
| | - Lauren B Rodda
- Department of Molecular Microbiology and Immunology, Oregon Health & Science University, Portland, OR, USA.
| | - Joshua M Moreau
- Department of Cell, Developmental and Cancer Biology, Oregon Health & Science University, Portland, OR, USA.
- Cancer Early Detection Advanced Research Center, Oregon Health & Science University, Portland, OR, USA.
- Department of Dermatology, Oregon Health & Science University, Portland, OR, USA.
- Division of Oncological Sciences, Oregon Health & Science University, Portland, OR, USA.
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11
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Liu Y, Zhao Y, Zhou C, Zhu H, Pan J, Fu J, Huang H, Lin H, Jin L. Immune imbalance in the pre-ovulatory follicular microenvironment of overweight and obese women during IVF. J Ovarian Res 2025; 18:23. [PMID: 39910676 PMCID: PMC11796254 DOI: 10.1186/s13048-025-01606-5] [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: 11/27/2024] [Accepted: 01/22/2025] [Indexed: 02/07/2025] Open
Abstract
BACKGROUND Overweight and obesity can induce an inflammatory milieu in the oocyte microenvironment and are closely associated with reduced assisted reproductive outcomes. OBJECTIVE How are immune cells, cytokines and lipid profiles altered in the pre-ovulatory microenvironment of overweight and obese women? METHODS 32 women undergoing in vitro fertilization (IVF) were included, with 14 overweight or obese (OW) and 18 normal weight (NW) participants. Serum was collected before ovulation induction, follicular fluid (FF) and aspirates were obtained during oocyte retrieval for flow cytometry, cytokines, hormone, and lipid profiles measurement. Clinical outcomes were recorded through a one-year follow-up. RESULTS The percentage of T cells in the pre-ovulatory follicular microenvironment, especially CD4+ T cells, increased significantly in the OW group, which positively related with BMI. Notably, type 2 cytokine IL4 and IL13 transcription level in OW group had significantly increased, while the type 1 cytokine IFNG only showed a non-statistically significant upward trend. Lipid profiles were screened, revealing no difference between the two groups, however, levels were higher in serum compared to FF. Additionally, the concentration gradient of TG between serum and FF was 22-fold in OW group (2.92 ± 3.66 vs. 0.13 ± 0.03), which was significantly higher than the 12-fold gradient observed in NW group (1.72 ± 0.95 vs. 0.14 ± 0.08). Furthermore, day 3 high quality embryos rate is negatively associated with BMI and exhibits a decreasing trend in OW group. CONCLUSION Overweight and obesity can disrupt immune hemostasis in the pre-ovulatory follicular microenvironment, potentially leading to adverse effects on assisted reproductive outcomes.
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Affiliation(s)
- Yang Liu
- Obstetrics and Gynecology Hospital, Institute of Reproduction and Development, Fudan University, Shanghai, 200011, China
| | - Yiran Zhao
- Obstetrics and Gynecology Hospital, Institute of Reproduction and Development, Fudan University, Shanghai, 200011, China
| | - Chengliang Zhou
- International Peace Maternity and Child Health Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200003, China
| | - Hong Zhu
- Obstetrics and Gynecology Hospital, Institute of Reproduction and Development, Fudan University, Shanghai, 200011, China
| | - Jiexue Pan
- Obstetrics and Gynecology Hospital, Institute of Reproduction and Development, Fudan University, Shanghai, 200011, China
| | - Jing Fu
- Shanghai JiAi Genetics and IVF Institute, Obstetrics and Gynecology Hospital, Fudan University, Shanghai, 200011, China
| | - Hefeng Huang
- Obstetrics and Gynecology Hospital, Institute of Reproduction and Development, Fudan University, Shanghai, 200011, China
- Shanghai Key Laboratory of Embryo Original Diseases, Shanghai, 200030, China
- Research Units of Embryo Original Diseases, Chinese Academy of Medical Sciences, (No. 2019RU056), Shanghai, 200030, China
- Key Laboratory of Reproductive Genetics (Ministry of Education), Department of Reproductive Endocrinology, Women's Hospital, Zhejiang University School of Medicine, Hangzhou, 311399, China
| | - Hui Lin
- Obstetrics and Gynecology Hospital, Institute of Reproduction and Development, Fudan University, Shanghai, 200011, China.
| | - Li Jin
- Obstetrics and Gynecology Hospital, Institute of Reproduction and Development, Fudan University, Shanghai, 200011, China.
- Shanghai JiAi Genetics and IVF Institute, Obstetrics and Gynecology Hospital, Fudan University, Shanghai, 200011, China.
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12
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Garcia JN, Cottam MA, Rodriguez AS, Agha AFH, Winn NC, Hasty AH. Interrupting T cell memory ameliorates exaggerated metabolic response to weight cycling. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.01.17.633599. [PMID: 39896598 PMCID: PMC11785015 DOI: 10.1101/2025.01.17.633599] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 02/04/2025]
Abstract
People frequently experience cycles of weight gain and loss. This weight cycling has been demonstrated, in humans and animal models, to increase cardiometabolic disease and disrupt glucose homeostasis. Obesity itself - and to an even greater extent weight regain - causes adipose tissue inflammation, resulting in metabolic dysfunction. Studies show that even after weight loss, increased numbers of lipid associated macrophages and memory T cells persist in adipose tissue and become more inflammatory upon weight regain. These findings suggest that the immune system retains a "memory" of obesity, which may contribute to the elevated inflammation and metabolic dysfunction associated with weight cycling. Here, we show that blocking the CD70-CD27 axis, critical for formation of immunological memory, decreases the number of memory T cells and reduces T cell clonality within adipose tissue after weight loss and weight cycling. Furthermore, while mice with impaired ability to create obesogenic immune memory have similar metabolic responses as wildtype mice to stable obesity, they are protected from the worsened glucose tolerance associated with weight cycling. Our data are the first to target metabolic consequences of weight cycling through an immunomodulatory mechanism. Thus, we propose a new avenue of therapeutic intervention by which targeting memory T cells can be leveraged to minimize the adverse consequences of weight cycling. These findings are particularly timely given the increasing use of efficacious weight loss drugs, which will likely lead to more instances of human weight cycling.
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Affiliation(s)
- Jamie N. Garcia
- Department of Molecular Physiology & Biophysics, Vanderbilt University, Nashville, Tennessee, USA
- VA Tennessee Valley Healthcare System, Nashville, Tennessee, USA
| | - Matthew A. Cottam
- Department of Molecular Physiology & Biophysics, Vanderbilt University, Nashville, Tennessee, USA
- Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Alec S. Rodriguez
- Department of Molecular Physiology & Biophysics, Vanderbilt University, Nashville, Tennessee, USA
| | - Anwar F. Hussein Agha
- Department of Molecular Physiology & Biophysics, Vanderbilt University, Nashville, Tennessee, USA
| | - Nathan C. Winn
- Department of Molecular Physiology & Biophysics, Vanderbilt University, Nashville, Tennessee, USA
- Division of Gastroenterology, Hepatology, & Nutrition, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Alyssa H. Hasty
- Department of Molecular Physiology & Biophysics, Vanderbilt University, Nashville, Tennessee, USA
- VA Tennessee Valley Healthcare System, Nashville, Tennessee, USA
- University of Texas Southwestern, Dallas, Texas, USA
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13
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Zhu Y, Shrestha A. Metabolic syndrome and its effect on immune cells in apical periodontitis- a narrative review. Clin Oral Investig 2025; 29:67. [PMID: 39825203 DOI: 10.1007/s00784-025-06161-3] [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: 11/07/2024] [Accepted: 01/11/2025] [Indexed: 01/20/2025]
Abstract
OBJECTIVES Apical periodontitis (AP) is an inflammatory immune response in periapical tissues caused by microbial infections. Failure of root canal treatment or delayed healing is often due to intracanal or extra-radicular bacteria. However, beyond microbial factors, the patient's systemic health can significantly influence the progression and healing of AP. Metabolic syndrome is a risk factor and it is characterized by a cluster of interconnected metabolic risk factors, including abdominal obesity, hyperlipidemia, hypertension, and hyperglycemia. MATERIALS AND METHODS A comprehensive literature review was conducted on apical periodontitis and metabolic syndrome, and their impact on the roles of different immune cell populations. RESULTS Both AP and metabolic syndrome are inflammatory diseases that involve complex and interwoven immune responses. The affected immune cells are categorized into the innate (neutrophils, macrophages, and dendritic cells) and adaptive immune systems (T cells and B cells). CONCLUSIONS Metabolic diseases and AP are closely correlated, possibly intertwined in a two-way relationship driven by a shared dysregulated immune response. CLINICAL RELEVANCE Understanding the pathophysiology and immune mechanisms underlying the two-way relationship between metabolic syndrome and AP can help improve treatment outcomes and enhance the overall well-being of patients with endodontic disease complicated by metabolic syndrome.
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Affiliation(s)
- Yi Zhu
- Faculty of Dentistry, University of Toronto, 124 Edward Street, Toronto, ON, M5G 1G6, Canada
| | - Annie Shrestha
- Faculty of Dentistry, University of Toronto, 124 Edward Street, Toronto, ON, M5G 1G6, Canada.
- Department of Laboratory Medicine and Pathobiology, University of Toronto, 1 King's College Circle, Toronto, ON, M5S 1A8, Canada.
- Department of Dentistry, Mt. Sinai Hospital, Toronto 412-600 University Avenue, Toronto, ON, M5G 1X5, Canada.
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14
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Liu Y, Shen Y, Ding H, He D, Cheng P, Wu X, Xiang Z, Shen L, Bian Y, Zhu Q. T-bet +ILC3 in peripheral blood is increased in the ankylosing spondylitis with high disease activity. Heliyon 2025; 11:e41678. [PMID: 39866450 PMCID: PMC11757778 DOI: 10.1016/j.heliyon.2025.e41678] [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: 09/23/2024] [Revised: 12/29/2024] [Accepted: 01/02/2025] [Indexed: 01/28/2025] Open
Abstract
Objective Ankylosing spondylitis (AS) is a chronic autoimmune disease characterized by systemic inflammation, often resulting in fusion of the spine and peripheral joints. This study aimed to investigate the role of innate lymphoid cells (ILCs) in AS patients with high disease activity. Methods Blood samples were collected from healthy controls and AS patients categorized by high or low disease activity. Systemic inflammation was quantified through C-reactive protein (CRP) levels and erythrocyte sedimentation rate (ESR), alongside disease activity scores such as Ankylosing Spondylitis Disease Activity Score(ASDAS) and Bath Ankylosing Spondylitis Disease Activity Index(BASDAI). The levels of different ILC subsets and the expression of T-box transcription factor 21 (T-bet) and retinoic-acid-receptor-related orphan receptor gamma (RORγt) in peripheral blood were analyzed via flow cytometry. Additionally, 24 cytokines in plasma were measured using a Luminex liquid suspension chip. Results The proportion of total ILCs and the distribution of ILC subsets in peripheral blood varied with AS disease activity scores. Specifically, the frequencies of total ILCs and ILC3s were significantly elevated in AS patients with high disease activity (AS-HA). The frequency and absolute number of ILC3s showed a positively correlation with disease severity scores. Furthermore, T-bet+ILC3s were significantly increased in the AS-HA group. Plasma levels of IL-17A and IFN-γ were positively correlated with the frequency of circulating-ILC3 in AS patients. Conclusions These findings highlight the critical role of T-bet+ILC3s in the inflammatory process of AS, suggesting their potential as a therapeutic target for managing AS disease.
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Affiliation(s)
- Yang Liu
- Department of Rheumatology, Shanghai Guanghua Hospital of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 200052, China
- Department of Traditional Chinese Medicine, PengPu Town No.2 Community Healthcare Center, Shanghai, 200436, China
| | - Yi Shen
- Department of Rheumatology, Shanghai Guanghua Hospital of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 200052, China
- Institute of Arthritis Research in Integrative Medicine, Shanghai Academy of Traditional Chinese Medicine, Shanghai, 200052, China
| | - Hongbai Ding
- Department of Rheumatology, Shanghai Guanghua Hospital of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 200052, China
| | - Dongyi He
- Department of Rheumatology, Shanghai Guanghua Hospital of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 200052, China
- Institute of Arthritis Research in Integrative Medicine, Shanghai Academy of Traditional Chinese Medicine, Shanghai, 200052, China
| | - Peng Cheng
- Department of Rheumatology, Shanghai Guanghua Hospital of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 200052, China
| | - Xinyao Wu
- Department of Rheumatology, Shanghai Guanghua Hospital of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 200052, China
| | - Zheng Xiang
- Institute of Arthritis Research in Integrative Medicine, Shanghai Academy of Traditional Chinese Medicine, Shanghai, 200052, China
| | - Lei Shen
- Shanghai Institute of Immunology, Department of Immunology and Microbiology, and Key Laboratory of Cell Differentiation and Apoptosis of the Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Yanqin Bian
- Institute of Arthritis Research in Integrative Medicine, Shanghai Academy of Traditional Chinese Medicine, Shanghai, 200052, China
| | - Qi Zhu
- Department of Rheumatology, Shanghai Guanghua Hospital of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 200052, China
- Institute of Arthritis Research in Integrative Medicine, Shanghai Academy of Traditional Chinese Medicine, Shanghai, 200052, China
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15
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Soták M, Clark M, Suur BE, Börgeson E. Inflammation and resolution in obesity. Nat Rev Endocrinol 2025; 21:45-61. [PMID: 39448830 DOI: 10.1038/s41574-024-01047-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 09/30/2024] [Indexed: 10/26/2024]
Abstract
Inflammation is an essential physiological defence mechanism, but prolonged or excessive inflammation can cause disease. Indeed, unresolved systemic and adipose tissue inflammation drives obesity-related cardiovascular disease and type 2 diabetes mellitus. Drugs targeting pro-inflammatory cytokine pathways or inflammasome activation have been approved for clinical use for the past two decades. However, potentially serious adverse effects, such as drug-induced weight gain and increased susceptibility to infections, prevented their wider clinical implementation. Furthermore, these drugs do not modulate the resolution phase of inflammation. This phase is an active process orchestrated by specialized pro-resolving mediators, such as lipoxins, and other endogenous resolution mechanisms. Pro-resolving mediators mitigate inflammation and development of obesity-related disease, for instance, alleviating insulin resistance and atherosclerosis in experimental disease models, so mechanisms to modulate their activity are, therefore, of great therapeutic interest. Here, we review current clinical attempts to either target pro-inflammatory mediators (IL-1β, NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome, tumour necrosis factor (TNF) and IL-6) or utilize endogenous resolution pathways to reduce obesity-related inflammation and improve cardiometabolic outcomes. A remaining challenge in the field is to establish more precise biomarkers that can differentiate between acute and chronic inflammation and to assess the functionality of individual leukocyte populations. Such advancements would improve the monitoring of drug effects and support personalized treatment strategies that battle obesity-related inflammation and cardiometabolic disease.
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Affiliation(s)
- Matúš Soták
- Department of Clinical Immunology and Transfusion Medicine, Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Madison Clark
- Steno Diabetes Center Aarhus, Aarhus University Hospital, Aarhus, Denmark
- Department of Biomedicine, Aarhus University, Aarhus, Denmark
| | - Bianca E Suur
- Steno Diabetes Center Aarhus, Aarhus University Hospital, Aarhus, Denmark
- Department of Biomedicine, Aarhus University, Aarhus, Denmark
| | - Emma Börgeson
- Department of Clinical Immunology and Transfusion Medicine, Sahlgrenska University Hospital, Gothenburg, Sweden.
- Steno Diabetes Center Aarhus, Aarhus University Hospital, Aarhus, Denmark.
- Department of Biomedicine, Aarhus University, Aarhus, Denmark.
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16
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Steffen TL, Stafford JD, Samson WK, Yosten GLC. Nesfatin-1 is a regulator of inflammation with implications during obesity and metabolic syndrome. Appetite 2024; 203:107669. [PMID: 39251090 DOI: 10.1016/j.appet.2024.107669] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2024] [Revised: 08/19/2024] [Accepted: 09/06/2024] [Indexed: 09/11/2024]
Abstract
Nesfatin-1, derived from the nucleobindin 2 (NUCB2) precursor, is a potent anorexigenic peptide that was discovered in 2006. Since its identification in the hypothalamus, it has been shown to have wide ranging actions within and outside of the central nervous system. One of these actions is the regulation of inflammation, which could potentially be exploited therapeutically in the context of obesity-associated inflammation in adipose tissue. Here, we review recent advances in our knowledge about the ability of nesfatin-1 to control inflammation by regulating NFκB signaling, which likely attenuates pro-inflammatory cytokine production and inhibits apoptosis.
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Affiliation(s)
- Tara L Steffen
- Saint Louis University School of Medicine, Department of Pharmacology and Physiology, St. Louis, MO, USA.
| | - Joshua D Stafford
- Saint Louis University School of Medicine, Department of Pharmacology and Physiology, St. Louis, MO, USA
| | - Willis K Samson
- Saint Louis University School of Medicine, Department of Pharmacology and Physiology, St. Louis, MO, USA
| | - Gina L C Yosten
- Saint Louis University School of Medicine, Department of Pharmacology and Physiology, St. Louis, MO, USA
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17
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Yang Y, Huang B, Qin Y, Wang D, Jin Y, Su L, Wang Q, Pan Y, Zhang Y, Shen Y, Hu W, Cao Z, Jin L, Zhang F. Adipocyte microRNA-802 promotes adipose tissue inflammation and insulin resistance by modulating macrophages in obesity. eLife 2024; 13:e99162. [PMID: 39589393 DOI: 10.7554/elife.99162] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2024] [Accepted: 11/22/2024] [Indexed: 11/27/2024] Open
Abstract
Adipose tissue inflammation is now considered to be a key process underlying metabolic diseases in obese individuals. However, it remains unclear how adipose inflammation is initiated and maintained or the mechanism by which inflammation develops. We found that microRNA-802 (Mir802) expression in adipose tissue is progressively increased with the development of dietary obesity in obese mice and humans. The increasing trend of Mir802 preceded the accumulation of macrophages. Adipose tissue-specific knockout of Mir802 lowered macrophage infiltration and ameliorated systemic insulin resistance. Conversely, the specific overexpression of Mir802 in adipose tissue aggravated adipose inflammation in mice fed a high-fat diet. Mechanistically, Mir802 activates noncanonical and canonical NF-κB pathways by targeting its negative regulator, TRAF3. Next, NF-κB orchestrated the expression of chemokines and SREBP1, leading to strong recruitment and M1-like polarization of macrophages. Our findings indicate that Mir802 endows adipose tissue with the ability to recruit and polarize macrophages, which underscores Mir802 as an innovative and attractive candidate for miRNA-based immune therapy for adipose inflammation.
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Affiliation(s)
- Yue Yang
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, School of life Science and Technology, China Pharmaceutical University, Nanjing, China
| | - Bin Huang
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, School of life Science and Technology, China Pharmaceutical University, Nanjing, China
| | - Yimeng Qin
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, School of life Science and Technology, China Pharmaceutical University, Nanjing, China
| | - Danwei Wang
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, School of life Science and Technology, China Pharmaceutical University, Nanjing, China
| | - Yinuo Jin
- NanJing HanKai Academy, Nanjing, China
| | - Linmin Su
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, School of life Science and Technology, China Pharmaceutical University, Nanjing, China
| | - Qingxin Wang
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, School of life Science and Technology, China Pharmaceutical University, Nanjing, China
| | - Yi Pan
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, School of life Science and Technology, China Pharmaceutical University, Nanjing, China
| | - Yanfeng Zhang
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, School of life Science and Technology, China Pharmaceutical University, Nanjing, China
| | - Yumeng Shen
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China
| | - Wenjun Hu
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, School of life Science and Technology, China Pharmaceutical University, Nanjing, China
| | - Zhengyu Cao
- Jiangsu Key Laboratory of TCM Evaluation and Translational Research, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Liang Jin
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, School of life Science and Technology, China Pharmaceutical University, Nanjing, China
| | - Fangfang Zhang
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, School of life Science and Technology, China Pharmaceutical University, Nanjing, China
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18
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Li X, Yang W, Ma K, Zheng Z, Liu X, Hu B, Liu H, Zhao Q, Han Y, Xiao Z, Chen R, Li H, Huang S, Liu J, Wang C, Yin L, Meng Y. Circulating B Cell-Derived Small RNA Delivered by Extracellular Vesicles: A Dialogue Mechanism for Long-Range Targeted Renal Mitochondrial Injury in Obesity. SMALL (WEINHEIM AN DER BERGSTRASSE, GERMANY) 2024; 20:e2402526. [PMID: 38958071 DOI: 10.1002/smll.202402526] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/29/2024] [Revised: 05/24/2024] [Indexed: 07/04/2024]
Abstract
The intricate processes that govern the interactions between peripatetic immune cells and distal renal injury in obesity are not fully understood. Employing transcriptomic analysis of circulating extracellular vesicles (EVs), a marked amplification of small RNA (miR-3960) is discerned within CD3-CD19+ B cells. This RNA is found to be preferentially augmented in kidney tissues, contrasting with its subdued expression in other organs. By synthesizing dual-luciferase reporter assay with co-immunoprecipitation analysis, it is pinpointed that miR-3960 specifically targets the nuclear gene TRMT5, a pivotal actor in the methylation of mitochondrial tRNA. This liaison instigates aberrations in the post-transcriptional modifications of mitochondrial tRNA, engendering deficiencies within the electron respiratory chain, primarily attributable to the diminution of the mitochondrial bioenergetic compound (NDUFA7) complex I. Such perturbations lead to a compromised mitochondrial respiratory capacity in renal tubular cells, thereby exacerbating tubular injury. In contrast, EV blockade or miR-3960 depletion markedly alleviates renal tubular injury in obesity. This investigation unveils a hitherto unexplored pathway by which obesity-induced circulating immune cells remotely manipulate mitochondrial metabolism in target organs. The strategic targeting of obese EVs or infiltrative immune cells and their specifically secreted RNAs emerges as a promising therapeutic avenue to forestall obesity-related renal afflictions.
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Affiliation(s)
- Xiaqing Li
- Institute of Nephrology and Blood Purification, The First Affiliated Hospital of Jinan University, Jinan University, Guangzhou, Guangdong, 510632, China
- Nephrology department, The Fifth Affiliated Hospital (Heyuan Shenhe People's Hospital), Jinan University, Heyuan, Guangdong, 517000, China
| | - Wah Yang
- Department of Obesity and Metabolic Disorders, The First Affiliated Hospital of Jinan University, Jinan University, Guangzhou, Guangdong, 510632, China
- Institute of Obesity and Metabolic Disorders, Jinan University, Guangzhou, Guangdong, 510632, China
| | - Ke Ma
- Institute of Nephrology and Blood Purification, The First Affiliated Hospital of Jinan University, Jinan University, Guangzhou, Guangdong, 510632, China
- Nephrology department, The Fifth Affiliated Hospital (Heyuan Shenhe People's Hospital), Jinan University, Heyuan, Guangdong, 517000, China
| | - Zirun Zheng
- Institute of Nephrology and Blood Purification, The First Affiliated Hospital of Jinan University, Jinan University, Guangzhou, Guangdong, 510632, China
- Nephrology department, The Fifth Affiliated Hospital (Heyuan Shenhe People's Hospital), Jinan University, Heyuan, Guangdong, 517000, China
| | - Xiayun Liu
- Institute of Nephrology and Blood Purification, The First Affiliated Hospital of Jinan University, Jinan University, Guangzhou, Guangdong, 510632, China
- Nephrology department, The Fifth Affiliated Hospital (Heyuan Shenhe People's Hospital), Jinan University, Heyuan, Guangdong, 517000, China
| | - Bo Hu
- Institute of Nephrology and Blood Purification, The First Affiliated Hospital of Jinan University, Jinan University, Guangzhou, Guangdong, 510632, China
| | - Huanhuan Liu
- Institute of Nephrology and Blood Purification, The First Affiliated Hospital of Jinan University, Jinan University, Guangzhou, Guangdong, 510632, China
| | - Qian Zhao
- Department of Infectious Diseases and Hepatology Center, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, 510400, China
| | - Yi Han
- Traditional Chinese Medicine Department, People's Hospital of Yanjiang District, Ziyang, Sichuan, 641300, China
| | - Zhangzhang Xiao
- Institute of Nephrology and Blood Purification, The First Affiliated Hospital of Jinan University, Jinan University, Guangzhou, Guangdong, 510632, China
- Department of Nephrology, Houjie Hospital of Dongguan, Dongguan, Guangdong, 523945, China
| | - Ruichang Chen
- Department of Emergency Medicine, The First Affiliated Hospital of Jinan University, Jinan University, Guangzhou, Guangdong, 510632, China
| | - Hongyue Li
- Institute of Nephrology and Blood Purification, The First Affiliated Hospital of Jinan University, Jinan University, Guangzhou, Guangdong, 510632, China
- Nephrology department, The Fifth Affiliated Hospital (Heyuan Shenhe People's Hospital), Jinan University, Heyuan, Guangdong, 517000, China
| | - Sibo Huang
- Health Management Center, The First Affiliated Hospital of Jinan University, Jinan University, Guangzhou, Guangdong, 510632, China
| | - Jinfeng Liu
- Department of Gastroenterology, Binhaiwan Central Hospital of Dongguan, Dongguan, Guangdong, 523000, China
| | - Cunchuan Wang
- Department of Obesity and Metabolic Disorders, The First Affiliated Hospital of Jinan University, Jinan University, Guangzhou, Guangdong, 510632, China
- Institute of Obesity and Metabolic Disorders, Jinan University, Guangzhou, Guangdong, 510632, China
| | - Lianghong Yin
- Institute of Nephrology and Blood Purification, The First Affiliated Hospital of Jinan University, Jinan University, Guangzhou, Guangdong, 510632, China
- Huangpu Institute of Materials, Guangzhou, Guangdong, 510663, China
| | - Yu Meng
- Institute of Nephrology and Blood Purification, The First Affiliated Hospital of Jinan University, Jinan University, Guangzhou, Guangdong, 510632, China
- Nephrology department, The Fifth Affiliated Hospital (Heyuan Shenhe People's Hospital), Jinan University, Heyuan, Guangdong, 517000, China
- Nephrology Department and Guangdong Provincial Key Laboratory of Spine and Spinal Cord Reconstruction, The Fifth Affiliated Hospital (Heyuan Shenhe People's Hospital), Jinan University, Heyuan, Guangdong, 517000, China
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19
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Roessner PM, Seufert I, Chapaprieta V, Jayabalan R, Briesch H, Massoni-Badosa R, Boskovic P, Benckendorff J, Roider T, Arseni L, Coelho M, Chakraborty S, Vaca AM, Sivina M, Muckenhuber M, Rodriguez-Rodriguez S, Bonato A, Herbst SA, Zapatka M, Sun C, Kretzmer H, Naake T, Bruch PM, Czernilofsky F, ten Hacken E, Schneider M, Helm D, Yosifov DY, Kauer J, Danilov AV, Bewarder M, Heyne K, Schneider C, Stilgenbauer S, Wiestner A, Mallm JP, Burger JA, Efremov DG, Lichter P, Dietrich S, Martin-Subero JI, Rippe K, Seiffert M. T-bet suppresses proliferation of malignant B cells in chronic lymphocytic leukemia. Blood 2024; 144:510-524. [PMID: 38684038 PMCID: PMC11307267 DOI: 10.1182/blood.2023021990] [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: 07/31/2023] [Revised: 03/28/2024] [Accepted: 04/13/2024] [Indexed: 05/02/2024] Open
Abstract
ABSTRACT The T-box transcription factor T-bet is known as a master regulator of the T-cell response but its role in malignant B cells has not been sufficiently explored. Here, we conducted single-cell resolved multi-omics analyses of malignant B cells from patients with chronic lymphocytic leukemia (CLL) and studied a CLL mouse model with a genetic knockout of Tbx21. We found that T-bet acts as a tumor suppressor in malignant B cells by decreasing their proliferation rate. NF-κB activity, induced by inflammatory signals provided by the microenvironment, triggered T-bet expression, which affected promoter-proximal and distal chromatin coaccessibility and controlled a specific gene signature by mainly suppressing transcription. Gene set enrichment analysis identified a positive regulation of interferon signaling and negative control of proliferation by T-bet. In line, we showed that T-bet represses cell cycling and is associated with longer overall survival of patients with CLL. Our study uncovered a novel tumor suppressive role of T-bet in malignant B cells via its regulation of inflammatory processes and cell cycling, which has implications for the stratification and therapy of patients with CLL. Linking T-bet activity to inflammation explains the good prognostic role of genetic alterations in the inflammatory signaling pathways in CLL.
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MESH Headings
- Leukemia, Lymphocytic, Chronic, B-Cell/pathology
- Leukemia, Lymphocytic, Chronic, B-Cell/genetics
- Leukemia, Lymphocytic, Chronic, B-Cell/immunology
- Leukemia, Lymphocytic, Chronic, B-Cell/metabolism
- T-Box Domain Proteins/genetics
- T-Box Domain Proteins/metabolism
- Animals
- Humans
- Cell Proliferation
- Mice
- B-Lymphocytes/pathology
- B-Lymphocytes/metabolism
- B-Lymphocytes/immunology
- Mice, Knockout
- Gene Expression Regulation, Leukemic
- NF-kappa B/metabolism
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Affiliation(s)
- Philipp M. Roessner
- Division of Molecular Genetics, German Cancer Research Center, Heidelberg, Germany
| | - Isabelle Seufert
- Division of Chromatin Networks, German Cancer Research Center and BioQuant, Heidelberg, Germany
- Faculty of Biosciences, University of Heidelberg, Heidelberg, Germany
| | | | - Ruparoshni Jayabalan
- Division of Molecular Genetics, German Cancer Research Center, Heidelberg, Germany
- Faculty of Biosciences, University of Heidelberg, Heidelberg, Germany
| | - Hannah Briesch
- Division of Molecular Genetics, German Cancer Research Center, Heidelberg, Germany
- Faculty of Biosciences, University of Heidelberg, Heidelberg, Germany
| | - Ramon Massoni-Badosa
- Division of Molecular Genetics, German Cancer Research Center, Heidelberg, Germany
- Single Cell Genomics, Centre for Genomic Regulation, Barcelona Institute of Science and Technology, Barcelona, Spain
| | - Pavle Boskovic
- Division of Molecular Genetics, German Cancer Research Center, Heidelberg, Germany
- Faculty of Biosciences, University of Heidelberg, Heidelberg, Germany
| | | | - Tobias Roider
- Department of Medicine V, Heidelberg University Hospital, Heidelberg, Germany
- Molecular Medicine Partnership Unit, Heidelberg, Germany
| | - Lavinia Arseni
- Division of Molecular Genetics, German Cancer Research Center, Heidelberg, Germany
| | - Mariana Coelho
- Division of Molecular Genetics, German Cancer Research Center, Heidelberg, Germany
- Faculty of Biosciences, University of Heidelberg, Heidelberg, Germany
| | - Supriya Chakraborty
- Molecular Hematology, International Centre for Genetic Engineering and Biotechnology, Trieste, Italy
| | - Alicia M. Vaca
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Mariela Sivina
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Markus Muckenhuber
- Division of Chromatin Networks, German Cancer Research Center and BioQuant, Heidelberg, Germany
| | | | - Alice Bonato
- Molecular Hematology, International Centre for Genetic Engineering and Biotechnology, Trieste, Italy
| | - Sophie A. Herbst
- Department of Medicine V, Heidelberg University Hospital, Heidelberg, Germany
- Molecular Medicine Partnership Unit, Heidelberg, Germany
| | - Marc Zapatka
- Division of Molecular Genetics, German Cancer Research Center, Heidelberg, Germany
| | - Clare Sun
- Laboratory of Lymphoid Malignancies, Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD
| | - Helene Kretzmer
- Department of Genome Regulation, Max Planck Institute for Molecular Genetics, Berlin, Germany
| | - Thomas Naake
- Genome Biology Unit, European Molecular Biology Laboratory, Heidelberg, Germany
| | - Peter-Martin Bruch
- Department of Medicine V, Heidelberg University Hospital, Heidelberg, Germany
- Molecular Medicine Partnership Unit, Heidelberg, Germany
- Department of Hematology, Oncology and Clinical Immunology, University Hospital Düsseldorf, Düsseldorf, Germany
| | - Felix Czernilofsky
- Department of Medicine V, Heidelberg University Hospital, Heidelberg, Germany
- Molecular Medicine Partnership Unit, Heidelberg, Germany
| | | | - Martin Schneider
- Proteomics Core Facility, German Cancer Research Center, Heidelberg, Germany
| | - Dominic Helm
- Proteomics Core Facility, German Cancer Research Center, Heidelberg, Germany
| | - Deyan Y. Yosifov
- Division of Chronic Lymphocytic Leukemia, Department of Internal Medicine III, Ulm University, Ulm, Germany
- Cooperation Unit Mechanisms of Leukemogenesis, German Cancer Research Center, Heidelberg, Germany
| | - Joseph Kauer
- Department of Medicine V, Heidelberg University Hospital, Heidelberg, Germany
- Molecular Medicine Partnership Unit, Heidelberg, Germany
| | - Alexey V. Danilov
- Department of Hematology, City of Hope National Medical Center, Duarte, CA
| | - Moritz Bewarder
- José Carreras Center for Immuno- and Gene Therapy and Internal Medicine I, Saarland University Medical School, Homburg/Saar, Germany
| | - Kristina Heyne
- José Carreras Center for Immuno- and Gene Therapy and Internal Medicine I, Saarland University Medical School, Homburg/Saar, Germany
| | - Christof Schneider
- Division of Chronic Lymphocytic Leukemia, Department of Internal Medicine III, Ulm University, Ulm, Germany
| | - Stephan Stilgenbauer
- Division of Chronic Lymphocytic Leukemia, Department of Internal Medicine III, Ulm University, Ulm, Germany
| | - Adrian Wiestner
- Laboratory of Lymphoid Malignancies, Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD
| | - Jan-Philipp Mallm
- Division of Chromatin Networks, German Cancer Research Center and BioQuant, Heidelberg, Germany
| | - Jan A. Burger
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Dimitar G. Efremov
- Molecular Hematology, International Centre for Genetic Engineering and Biotechnology, Trieste, Italy
| | - Peter Lichter
- Division of Molecular Genetics, German Cancer Research Center, Heidelberg, Germany
| | - Sascha Dietrich
- Department of Medicine V, Heidelberg University Hospital, Heidelberg, Germany
- Molecular Medicine Partnership Unit, Heidelberg, Germany
- Department of Hematology, Oncology and Clinical Immunology, University Hospital Düsseldorf, Düsseldorf, Germany
| | - José I. Martin-Subero
- Institut d’Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain
- Institució Catalana de Recerca i Estudis Avançats, Barcelona, Spain
| | - Karsten Rippe
- Division of Chromatin Networks, German Cancer Research Center and BioQuant, Heidelberg, Germany
| | - Martina Seiffert
- Division of Molecular Genetics, German Cancer Research Center, Heidelberg, Germany
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20
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Chen Y, Ji X, Ge Y, Niu H, Zhang X, Jiang F, Wu C. B-cell hub genes play a cardiovascular pathogenic role of in childhood obesity and Kawasaki disease as revealed by transcriptomics-based analyses. Sci Rep 2024; 14:15671. [PMID: 38977728 PMCID: PMC11231228 DOI: 10.1038/s41598-024-65865-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2024] [Accepted: 06/25/2024] [Indexed: 07/10/2024] Open
Abstract
The study aims to explore the central genes that Kawasaki disease (KD) and Obesity (OB) may jointly contribute to coronary artery disease. Investigating single-cell datasets (GSE168732 and GSE163830) from a comprehensive gene expression database, we identified characteristic immune cell subpopulations in KD and OB. B cells emerged as the common immune cell characteristic subgroup in both conditions. Subsequently, we analyzed RNA sequencing datasets (GSE18606 and GSE87493) to identify genes associated with B-cell subpopulations in KD and OB. Lastly, a genome-wide association study and Mendelian randomization were conducted to substantiate the causal impact of these core genes on myocardial infarction. Quantitative real-time PCR (qRT-PCR) to validate the expression levels of hub genes in KD and OB. The overlapping characteristic genes of B cell clusters in both KD and OB yielded 70 shared characteristic genes. PPI analysis led to the discovery of eleven key genes that significantly contribute to the crosstalk. Employing receiver operating characteristic analysis, we evaluated the specificity and sensitivity of these core genes and scored them using Cytoscape software. The inverse variance weighting analysis suggested an association between TNFRSF17 and myocardial infarction risk, with an odds ratio of 0.9995 (95% CI = 0.9990-1.0000, p = 0.049). By employing a single-cell combined transcriptome data analysis, we successfully pinpointed central genes associated with both KD and OB. The implications of these findings extend to shedding light on the increased risk of coronary artery disease resulting from the co-occurrence of OB and KD.
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Affiliation(s)
- Yuan Chen
- Department of Rehabilitation Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China
| | - Xiaoyi Ji
- Department of Pediatrics, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yao Ge
- Department of Rehabilitation Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China
| | - Huimin Niu
- Department of Rehabilitation Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China
| | - Xinyi Zhang
- Department of Rehabilitation Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China
| | - Feng Jiang
- Department of Neonatology, Obstetrics and Gynecology Hospital of Fudan University, Shanghai, 200011, China.
| | - Chuyan Wu
- Department of Rehabilitation Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China.
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21
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Daley AD, Bénézech C. Fat-associated lymphoid clusters: Supporting visceral adipose tissue B cell function in immunity and metabolism. Immunol Rev 2024; 324:78-94. [PMID: 38717136 DOI: 10.1111/imr.13339] [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: 12/22/2023] [Accepted: 04/09/2024] [Indexed: 07/23/2024]
Abstract
It is now widely understood that visceral adipose tissue (VAT) is a highly active and dynamic organ, with many functions beyond lipid accumulation and storage. In this review, we discuss the immunological role of this tissue, underpinned by the presence of fat-associated lymphoid clusters (FALCs). FALC's distinctive structure and stromal cell composition support a very different immune cell mix to that found in classical secondary lymphoid organs, which underlies their unique functions of filtration, surveillance, innate-like immune responses, and adaptive immunity within the serous cavities. FALCs are important B cell hubs providing B1 cell-mediated frontline protection against infection and supporting B2 cell-adaptative immune responses. Beyond these beneficial immune responses orchestrated by FALCs, immune cells within VAT play important homeostatic role. Dysregulation of immune cells during obesity and aging leads to chronic pathological "metabolic inflammation", which contributes to the development of cardiometabolic diseases. Here, we examine the emerging and complex functions of B cells in VAT homeostasis and the metabolic complications of obesity, highlighting the potential role that FALCs play and emphasize the areas where further research is needed.
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Affiliation(s)
- Alexander D Daley
- Centre for Cardiovascular Science, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK
| | - Cécile Bénézech
- Centre for Cardiovascular Science, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK
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22
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Yang Z, Chen F, Zhang Y, Ou M, Tan P, Xu X, Li Q, Zhou S. Therapeutic targeting of white adipose tissue metabolic dysfunction in obesity: mechanisms and opportunities. MedComm (Beijing) 2024; 5:e560. [PMID: 38812572 PMCID: PMC11134193 DOI: 10.1002/mco2.560] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2023] [Revised: 04/09/2024] [Accepted: 04/14/2024] [Indexed: 05/31/2024] Open
Abstract
White adipose tissue is not only a highly heterogeneous organ containing various cells, such as adipocytes, adipose stem and progenitor cells, and immune cells, but also an endocrine organ that is highly important for regulating metabolic and immune homeostasis. In individuals with obesity, dynamic cellular changes in adipose tissue result in phenotypic switching and adipose tissue dysfunction, including pathological expansion, WAT fibrosis, immune cell infiltration, endoplasmic reticulum stress, and ectopic lipid accumulation, ultimately leading to chronic low-grade inflammation and insulin resistance. Recently, many distinct subpopulations of adipose tissue have been identified, providing new insights into the potential mechanisms of adipose dysfunction in individuals with obesity. Therefore, targeting white adipose tissue as a therapeutic agent for treating obesity and obesity-related metabolic diseases is of great scientific interest. Here, we provide an overview of white adipose tissue remodeling in individuals with obesity including cellular changes and discuss the underlying regulatory mechanisms of white adipose tissue metabolic dysfunction. Currently, various studies have uncovered promising targets and strategies for obesity treatment. We also outline the potential therapeutic signaling pathways of targeting adipose tissue and summarize existing therapeutic strategies for antiobesity treatment including pharmacological approaches, lifestyle interventions, and novel therapies.
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Affiliation(s)
- Zi‐Han Yang
- Department of Plastic and Burn SurgeryWest China Hospital of Sichuan UniversityChengduChina
- Department of Plastic & Reconstructive SurgeryShanghai Ninth People's HospitalShanghai Jiao Tong University School of MedicineShanghaiChina
| | - Fang‐Zhou Chen
- Department of Plastic & Reconstructive SurgeryShanghai Ninth People's HospitalShanghai Jiao Tong University School of MedicineShanghaiChina
| | - Yi‐Xiang Zhang
- Department of Plastic & Reconstructive SurgeryShanghai Ninth People's HospitalShanghai Jiao Tong University School of MedicineShanghaiChina
| | - Min‐Yi Ou
- Department of Plastic & Reconstructive SurgeryShanghai Ninth People's HospitalShanghai Jiao Tong University School of MedicineShanghaiChina
| | - Poh‐Ching Tan
- Department of Plastic & Reconstructive SurgeryShanghai Ninth People's HospitalShanghai Jiao Tong University School of MedicineShanghaiChina
| | - Xue‐Wen Xu
- Department of Plastic and Burn SurgeryWest China Hospital of Sichuan UniversityChengduChina
| | - Qing‐Feng Li
- Department of Plastic & Reconstructive SurgeryShanghai Ninth People's HospitalShanghai Jiao Tong University School of MedicineShanghaiChina
| | - Shuang‐Bai Zhou
- Department of Plastic & Reconstructive SurgeryShanghai Ninth People's HospitalShanghai Jiao Tong University School of MedicineShanghaiChina
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23
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Meliopoulos V, Honce R, Livingston B, Hargest V, Freiden P, Lazure L, Brigleb PH, Karlsson E, Sheppard H, Allen EK, Boyd D, Thomas PG, Schultz-Cherry S. Diet-induced obesity affects influenza disease severity and transmission dynamics in ferrets. SCIENCE ADVANCES 2024; 10:eadk9137. [PMID: 38728395 PMCID: PMC11086619 DOI: 10.1126/sciadv.adk9137] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/18/2023] [Accepted: 04/08/2024] [Indexed: 05/12/2024]
Abstract
Obesity, and the associated metabolic syndrome, is a risk factor for increased disease severity with a variety of infectious agents, including influenza virus. Yet, the mechanisms are only partially understood. As the number of people, particularly children, living with obesity continues to rise, it is critical to understand the role of host status on disease pathogenesis. In these studies, we use a diet-induced obese ferret model and tools to demonstrate that, like humans, obesity resulted in notable changes to the lung microenvironment, leading to increased clinical disease and viral spread to the lower respiratory tract. The decreased antiviral responses also resulted in obese animals shedding higher infectious virus for a longer period, making them more likely to transmit to contacts. These data suggest that the obese ferret model may be crucial to understanding obesity's impact on influenza disease severity and community transmission and a key tool for therapeutic and intervention development for this high-risk population.
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Affiliation(s)
- Victoria Meliopoulos
- Department of Host-Microbe Interactions, St. Jude Children’s Research Hospital, Memphis, TN, USA
| | - Rebekah Honce
- Department of Host-Microbe Interactions, St. Jude Children’s Research Hospital, Memphis, TN, USA
| | - Brandi Livingston
- Department of Host-Microbe Interactions, St. Jude Children’s Research Hospital, Memphis, TN, USA
| | - Virginia Hargest
- Department of Host-Microbe Interactions, St. Jude Children’s Research Hospital, Memphis, TN, USA
| | - Pamela Freiden
- Department of Host-Microbe Interactions, St. Jude Children’s Research Hospital, Memphis, TN, USA
| | - Lauren Lazure
- Department of Host-Microbe Interactions, St. Jude Children’s Research Hospital, Memphis, TN, USA
| | - Pamela H. Brigleb
- Department of Host-Microbe Interactions, St. Jude Children’s Research Hospital, Memphis, TN, USA
| | - Erik Karlsson
- Department of Host-Microbe Interactions, St. Jude Children’s Research Hospital, Memphis, TN, USA
| | - Heather Sheppard
- Veterinary Pathology Core, St. Jude Children’s Research Hospital, Memphis, TN, USA
| | - E. Kaity Allen
- Department of Immunology, St. Jude Children’s Research Hospital, Memphis, TN, USA
| | - David Boyd
- Department of Immunology, St. Jude Children’s Research Hospital, Memphis, TN, USA
| | - Paul G. Thomas
- Department of Immunology, St. Jude Children’s Research Hospital, Memphis, TN, USA
| | - Stacey Schultz-Cherry
- Department of Host-Microbe Interactions, St. Jude Children’s Research Hospital, Memphis, TN, USA
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24
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Knox JJ, Cancro MP. ABCs begin with ZEB2. Immunol Cell Biol 2024; 102:229-231. [PMID: 38525813 DOI: 10.1111/imcb.12744] [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] [Indexed: 03/26/2024]
Abstract
Age-associated B cells (ABCs) are a stable subset of memory B lymphocytes that develop during microbial infections and in autoimmune diseases. Despite growing appreciation of their phenotypic and functional characteristics, the transcriptional networks involved in ABC fate commitment and maintenance have remained elusive. In their recent publication, Dai et al. tackle this problem, leveraging both mouse models and human diseases to reveal zinc finger E-box-binding homeobox 2 (ZEB2) as a key transcriptional regulator of ABC lineage specification. In aggregate, their results show that ZEB2, a member of the zinc finger E homeobox binding family, promotes ABC differentiation by repressing alternative differentiative fates and targeting genes important for ABC character and function. Moreover, their results strengthen the case for causal links between ABC fate and function in autoimmune pathologies.
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Affiliation(s)
- James J Knox
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
| | - Michael P Cancro
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
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25
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Carey A, Nguyen K, Kandikonda P, Kruglov V, Bradley C, Dahlquist KJV, Cholensky S, Swanson W, Badovinac VP, Griffith TS, Camell CD. Age-associated accumulation of B cells promotes macrophage inflammation and inhibits lipolysis in adipose tissue during sepsis. Cell Rep 2024; 43:113967. [PMID: 38492219 PMCID: PMC11014686 DOI: 10.1016/j.celrep.2024.113967] [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: 09/26/2023] [Revised: 02/14/2024] [Accepted: 02/29/2024] [Indexed: 03/18/2024] Open
Abstract
Non-canonical lipolysis induced by inflammatory cytokines or Toll-like receptor ligands is required for the regulation of inflammation during endotoxemia and sepsis. Canonical lipolysis induced by catecholamines declines during aging due to factors including an expansion of lymphocytes, pro-inflammatory macrophage polarization, and an increase in chronic low-grade inflammation; however, the extent to which the non-canonical pathway of lipolysis is active and impacted by immune cells during aging remains unclear. Therefore, we aimed to define the extent to which immune cells from old mice influence non-canonical lipolysis during sepsis. We identified age-associated impairments of non-canonical lipolysis and an accumulation of dysfunctional B1 B cells in the visceral white adipose tissue (vWAT) of old mice. Lifelong deficiency of B cells results in restored non-canonical lipolysis and reductions in pro-inflammatory macrophage populations. Our study suggests that targeting the B cell-macrophage signaling axis may resolve metabolic dysfunction in aged vWAT and attenuate septic severity in older individuals.
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Affiliation(s)
- Anna Carey
- Molecular Pharmacology and Therapeutics Graduate Program, Department of Pharmacology, University of Minnesota, Minneapolis, MN 55455, USA; Institute on the Biology of Aging and Metabolism, Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, MN 55455, USA; Center for Immunology, University of Minnesota, Minneapolis, MN 55455, USA
| | - Katie Nguyen
- Institute on the Biology of Aging and Metabolism, Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, MN 55455, USA; Center for Immunology, University of Minnesota, Minneapolis, MN 55455, USA
| | - Pranathi Kandikonda
- Institute on the Biology of Aging and Metabolism, Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, MN 55455, USA; Center for Immunology, University of Minnesota, Minneapolis, MN 55455, USA
| | - Victor Kruglov
- Institute on the Biology of Aging and Metabolism, Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, MN 55455, USA; Center for Immunology, University of Minnesota, Minneapolis, MN 55455, USA
| | - Claire Bradley
- Institute on the Biology of Aging and Metabolism, Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, MN 55455, USA; Center for Immunology, University of Minnesota, Minneapolis, MN 55455, USA
| | - Korbyn J V Dahlquist
- Institute on the Biology of Aging and Metabolism, Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, MN 55455, USA; Center for Immunology, University of Minnesota, Minneapolis, MN 55455, USA
| | - Stephanie Cholensky
- Institute on the Biology of Aging and Metabolism, Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, MN 55455, USA; Center for Immunology, University of Minnesota, Minneapolis, MN 55455, USA
| | - Whitney Swanson
- Center for Immunology, University of Minnesota, Minneapolis, MN 55455, USA; Department of Urology, University of Minnesota, Minneapolis, MN 55455, USA
| | | | - Thomas S Griffith
- Center for Immunology, University of Minnesota, Minneapolis, MN 55455, USA; Department of Urology, University of Minnesota, Minneapolis, MN 55455, USA; Minneapolis VA Health Care System, Minneapolis, MN 55417, USA
| | - Christina D Camell
- Molecular Pharmacology and Therapeutics Graduate Program, Department of Pharmacology, University of Minnesota, Minneapolis, MN 55455, USA; Institute on the Biology of Aging and Metabolism, Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, MN 55455, USA; Center for Immunology, University of Minnesota, Minneapolis, MN 55455, USA.
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26
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Nichols JM, Pham HV, Lee EF, Mahalingam R, Shepherd AJ. Single-cell analysis of age-related changes in leukocytes of diabetic mouse hindpaws. Cell Mol Life Sci 2024; 81:146. [PMID: 38502310 PMCID: PMC10951029 DOI: 10.1007/s00018-024-05128-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2023] [Revised: 12/28/2023] [Accepted: 01/13/2024] [Indexed: 03/21/2024]
Abstract
Complications associated with Type 1 and Type 2 diabetes, such as diabetic peripheral neuropathy and diabetic foot ulcers, are a growing health-care concern. In addition, this concern increases as diabetic patients age due to their increased susceptibility to complications. To address this growing problem, it is important to understand fluctuations in physiology which lead to pathological changes associated with the metabolic disturbances of diabetes. Our study explores dysregulation of immune cell populations in the hindpaws of healthy and diabetic mice at 12 and 21 weeks of age using single-cell RNA sequencing to provide insight into immune disruptions occurring in the distal limb during chronic diabetes. In 21-week-old Leprdb/db mice, increases were seen in mast cells/basophils, dermal γδ T cells, heterogeneous T cells, and Type 2 innate lymphoid cells. In addition, macrophages represented the largest cluster of immune cells and showed the greatest increase in genes associated with immune-specific pathways. Sub-clustering of macrophages revealed a bias toward angiogenic Lyve1+MHCIIlo macrophages in the hindpaws of 21-week-old diabetic mice, which corresponded to an increase in Lyve1+ macrophages in the hindpaws of 21-week-old diabetic mice on histology. Our results show that in Type 2 diabetes, the immunological function and phenotype of multiple immune cell types shift not only with metabolic disturbance, but also with duration of disease, which may explain the increased susceptibility to pathologies of the distal limb in patients with more chronic diabetes.
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Affiliation(s)
- James M Nichols
- The MD Anderson Pain Research Consortium and the Laboratories of Neuroimmunology, Department of Symptom Research, Division of Internal Medicine, The University of Texas MD Anderson Cancer Center, Unit 1055, 6565 MD Anderson Boulevard, Houston, TX, 77030, USA
| | - Hoang Vu Pham
- The MD Anderson Pain Research Consortium and the Laboratories of Neuroimmunology, Department of Symptom Research, Division of Internal Medicine, The University of Texas MD Anderson Cancer Center, Unit 1055, 6565 MD Anderson Boulevard, Houston, TX, 77030, USA
| | - Eric F Lee
- The MD Anderson Pain Research Consortium and the Laboratories of Neuroimmunology, Department of Symptom Research, Division of Internal Medicine, The University of Texas MD Anderson Cancer Center, Unit 1055, 6565 MD Anderson Boulevard, Houston, TX, 77030, USA
| | - Rajasekaran Mahalingam
- The MD Anderson Pain Research Consortium and the Laboratories of Neuroimmunology, Department of Symptom Research, Division of Internal Medicine, The University of Texas MD Anderson Cancer Center, Unit 1055, 6565 MD Anderson Boulevard, Houston, TX, 77030, USA.
| | - Andrew J Shepherd
- The MD Anderson Pain Research Consortium and the Laboratories of Neuroimmunology, Department of Symptom Research, Division of Internal Medicine, The University of Texas MD Anderson Cancer Center, Unit 1055, 6565 MD Anderson Boulevard, Houston, TX, 77030, USA.
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27
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Conte C, Cipponeri E, Roden M. Diabetes Mellitus, Energy Metabolism, and COVID-19. Endocr Rev 2024; 45:281-308. [PMID: 37934800 PMCID: PMC10911957 DOI: 10.1210/endrev/bnad032] [Citation(s) in RCA: 8] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/10/2023] [Revised: 08/30/2023] [Accepted: 11/01/2023] [Indexed: 11/09/2023]
Abstract
Obesity, diabetes mellitus (mostly type 2), and COVID-19 show mutual interactions because they are not only risk factors for both acute and chronic COVID-19 manifestations, but also because COVID-19 alters energy metabolism. Such metabolic alterations can lead to dysglycemia and long-lasting effects. Thus, the COVID-19 pandemic has the potential for a further rise of the diabetes pandemic. This review outlines how preexisting metabolic alterations spanning from excess visceral adipose tissue to hyperglycemia and overt diabetes may exacerbate COVID-19 severity. We also summarize the different effects of SARS-CoV-2 infection on the key organs and tissues orchestrating energy metabolism, including adipose tissue, liver, skeletal muscle, and pancreas. Last, we provide an integrative view of the metabolic derangements that occur during COVID-19. Altogether, this review allows for better understanding of the metabolic derangements occurring when a fire starts from a small flame, and thereby help reducing the impact of the COVID-19 pandemic.
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Affiliation(s)
- Caterina Conte
- Department of Human Sciences and Promotion of the Quality of Life, San Raffaele Roma Open University, Rome 00166, Italy
- Department of Endocrinology, Nutrition and Metabolic Diseases, IRCCS MultiMedica, Milan 20099, Italy
| | - Elisa Cipponeri
- Department of Endocrinology, Nutrition and Metabolic Diseases, IRCCS MultiMedica, Milan 20099, Italy
| | - Michael Roden
- Department of Endocrinology and Diabetology, Medical Faculty and University Hospital Düsseldorf, Heinrich-Heine-University Düsseldorf, Düsseldorf 40225, Germany
- Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich-Heine-University Düsseldorf, Düsseldorf 40225, Germany
- German Center for Diabetes Research, Partner Düsseldorf, Neuherberg 85764, Germany
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28
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Bradley D, Deng T, Shantaram D, Hsueh WA. Orchestration of the Adipose Tissue Immune Landscape by Adipocytes. Annu Rev Physiol 2024; 86:199-223. [PMID: 38345903 DOI: 10.1146/annurev-physiol-042222-024353] [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] [Indexed: 02/15/2024]
Abstract
Obesity is epidemic and of great concern because of its comorbid and costly inflammatory-driven complications. Extensive investigations in mice have elucidated highly coordinated, well-balanced interactions between adipocytes and immune cells in adipose tissue that maintain normal systemic metabolism in the lean state, while in obesity, proinflammatory changes occur in nearly all adipose tissue immune cells. Many of these changes are instigated by adipocytes. However, less is known about obesity-induced adipose-tissue immune cell alterations in humans. Upon high-fat diet feeding, the adipocyte changes its well-known function as a metabolic cell to assume the role of an immune cell, orchestrating proinflammatory changes that escalate inflammation and progress during obesity. This transformation is particularly prominent in humans. In this review, we (a) highlight a leading and early role for adipocytes in promulgating inflammation, (b) discuss immune cell changes and the time course of these changes (comparing humans and mice when possible), and (c) note how reversing proinflammatory changes in most types of immune cells, including adipocytes, rescues adipose tissue from inflammation and obese mice from insulin resistance.
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Affiliation(s)
- David Bradley
- Diabetes and Metabolism Research Center, Division of Endocrinology, Diabetes and Metabolism, Department of Internal Medicine, The Ohio State University, Columbus, Ohio, USA;
- Division of Endocrinology, Diabetes and Metabolism, Department of Internal Medicine, Pennsylvania State Health Milton S. Hershey Medical Center, Hershey, Pennsylvania, USA;
| | - Tuo Deng
- Second Xiangya Hospital, Central South University, Changsha, China
| | - Dharti Shantaram
- Diabetes and Metabolism Research Center, Division of Endocrinology, Diabetes and Metabolism, Department of Internal Medicine, The Ohio State University, Columbus, Ohio, USA;
| | - Willa A Hsueh
- Diabetes and Metabolism Research Center, Division of Endocrinology, Diabetes and Metabolism, Department of Internal Medicine, The Ohio State University, Columbus, Ohio, USA;
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29
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Apaza CJ, Días M, García Tejedor A, Boscá L, Laparra Llopis JM. Contribution of Nucleotide-Binding Oligomerization Domain-like (NOD) Receptors to the Immune and Metabolic Health. Biomedicines 2024; 12:341. [PMID: 38397943 PMCID: PMC10886542 DOI: 10.3390/biomedicines12020341] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2024] [Revised: 01/24/2024] [Accepted: 01/30/2024] [Indexed: 02/25/2024] Open
Abstract
Nucleotide-binding oligomerization domain-like (NOD) receptors rely on the interface between immunity and metabolism. Dietary factors constitute critical players in the activation of innate immunity and modulation of the gut microbiota. The latter have been involved in worsening or improving the control and promotion of diseases such as obesity, type 2 diabetes, metabolic syndrome, diseases known as non-communicable metabolic diseases (NCDs), and the risk of developing cancer. Intracellular NODs play key coordinated actions with innate immune 'Toll-like' receptors leading to a diverse array of gene expressions that initiate inflammatory and immune responses. There has been an improvement in the understanding of the molecular and genetic implications of these receptors in, among others, such aspects as resting energy expenditure, insulin resistance, and cell proliferation. Genetic factors and polymorphisms of the receptors are determinants of the risk and severity of NCDs and cancer, and it is conceivable that dietary factors may have significant differential consequences depending on them. Host factors are difficult to influence, while environmental factors are predominant and approachable with a preventive and/or therapeutic intention in obesity, T2D, and cancer. However, beyond the recognition of the activation of NODs by peptidoglycan as its prototypical agonist, the underlying molecular response(s) and its consequences on these diseases remain ill-defined. Metabolic (re)programming is a hallmark of NCDs and cancer in which nutritional strategies might play a key role in preventing the unprecedented expansion of these diseases. A better understanding of the participation and effects of immunonutritional dietary ingredients can boost integrative knowledge fostering interdisciplinary science between nutritional precision and personalized medicine against cancer. This review summarizes the current evidence concerning the relationship(s) and consequences of NODs on immune and metabolic health.
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Affiliation(s)
- César Jeri Apaza
- Molecular Immunonutrition Group, Madrid Institute for Advanced Studies in Food (IMDEA Food), Ctra Cantoblanco, 8, 28049 Madrid, Spain;
| | - Marisol Días
- Center of Biological Enginneering (CEB), Iberian Nantotechnology Laboratory (INL), University of Minho, 4715-330 Braga, Portugal;
| | - Aurora García Tejedor
- Bioactivity and Nutritional Immunology Group (BIOINUT), Faculty of Health Sciences, Universidad Internacional de Valencia (VIU), Pintor Sorolla 21, 46002 Valencia, Spain;
| | - Lisardo Boscá
- Instituto de Investigaciones Biomédicas Alberto Sols-Morreale (CSIC-UAM), Arturo Duperier 4, 28029 Madrid, Spain;
- Centro de Investigación Biomédica en Red en Enfermedades Cardiovasculares (CIBERCV), Melchor Fernández Almagro 6, 28029 Madrid, Spain
| | - José Moisés Laparra Llopis
- Molecular Immunonutrition Group, Madrid Institute for Advanced Studies in Food (IMDEA Food), Ctra Cantoblanco, 8, 28049 Madrid, Spain;
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Gao F, Litchfield B, Wu H. Adipose tissue lymphocytes and obesity. THE JOURNAL OF CARDIOVASCULAR AGING 2024; 4:5. [PMID: 38455510 PMCID: PMC10919906 DOI: 10.20517/jca.2023.38] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Indexed: 03/09/2024]
Abstract
Obesity is associated with chronic inflammation in adipose tissue (AT), mainly evidenced by infiltration and phenotypic changes of various types of immune cells. Macrophages are the major innate immune cells and represent the predominant immune cell population within AT. Lymphocytes, including T cells and B cells, are adaptive immune cells and constitute another important immune cell population in AT. In obesity, CD8+ effector memory T cells, CD4+ Th1 cells, and B2 cells are increased in AT and promote AT inflammation, while regulatory T cells and Th2 cells, which usually function as immune regulatory or type 2 inflammatory cells, are reduced in AT. Immune cells may regulate the metabolism of adipocytes and other cells through various mechanisms, contributing to the development of metabolic diseases, including insulin resistance and type 2 diabetes. Efforts targeting immune cells and inflammation to prevent and treat obesity-linked metabolic disease have been explored, but have not yielded significant success in clinical studies. This review provides a concise overview of the changes in lymphocyte populations within AT and their potential role in AT inflammation and the regulation of metabolic functions in the context of obesity.
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Affiliation(s)
- Feng Gao
- Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA
| | | | - Huaizhu Wu
- Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA
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Olivieri G, Cotugno N, Palma P. Emerging insights into atypical B cells in pediatric chronic infectious diseases and immune system disorders: T(o)-bet on control of B-cell immune activation. J Allergy Clin Immunol 2024; 153:12-27. [PMID: 37890706 PMCID: PMC10842362 DOI: 10.1016/j.jaci.2023.10.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2023] [Revised: 10/13/2023] [Accepted: 10/13/2023] [Indexed: 10/29/2023]
Abstract
Repetitive or persistent cellular stimulation in vivo has been associated with the development of a heterogeneous B-cell population that exhibits a distinctive phenotype and, in addition to classical B-cell markers, often expresses the transcription factor T-bet and myeloid marker CD11c. Research suggests that this atypical population consists of B cells with distinct B-cell receptor specificities capable of binding the antigens responsible for their development. The expansion of this population occurs in the presence of chronic inflammatory conditions and autoimmune diseases where different nomenclatures have been used to describe them. However, as a result of the diverse contexts in which they have been investigated, these cells have remained largely enigmatic, with much ambiguity remaining regarding their phenotype and function in humoral immune response as well as their role in autoimmunity. Atypical B cells have garnered considerable interest because of their ability to produce specific antibodies and/or autoantibodies and because of their association with key disease manifestations. Although they have been widely described in the context of adults, little information is present for children. Therefore, the aim of this narrative review is to describe the characteristics of this population, suggest their function in pediatric immune-related diseases and chronic infections, and explore their potential therapeutic avenues.
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Affiliation(s)
- Giulio Olivieri
- Research Unit of Clinical Immunology and Vaccinology, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy; PhD Program in Immunology, Molecular Medicine and Applied Biotechnology, University of Rome Tor Vergata, Rome, Italy
| | - Nicola Cotugno
- Research Unit of Clinical Immunology and Vaccinology, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy; Department of Systems Medicine, Molecular Medicine, and Applied Biotechnology, University of Rome Tor Vergata, Rome, Italy
| | - Paolo Palma
- Research Unit of Clinical Immunology and Vaccinology, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy; Department of Systems Medicine, Molecular Medicine, and Applied Biotechnology, University of Rome Tor Vergata, Rome, Italy.
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Pal A, Lin CT, Boykov I, Benson E, Kidd G, Fisher-Wellman KH, Neufer PD, Shaikh SR. High Fat Diet-Induced Obesity Dysregulates Splenic B Cell Mitochondrial Activity. Nutrients 2023; 15:4807. [PMID: 38004202 PMCID: PMC10675399 DOI: 10.3390/nu15224807] [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: 10/16/2023] [Revised: 11/07/2023] [Accepted: 11/14/2023] [Indexed: 11/26/2023] Open
Abstract
Diet-induced obesity impairs mitochondrial respiratory responses in tissues that are highly metabolically active, such as the heart. However, less is known about the impact of obesity on the respiratory activity of specific cell types, such as splenic B cells. B cells are of relevance, as they play functional roles in obesity-induced insulin resistance, inflammation, and responses to infection. Here, we tested the hypothesis that high-fat-diet (HFD)-induced obesity could impair the mitochondrial respiration of intact and permeabilized splenic CD19+ B cells isolated from C57BL/6J mice and activated ex vivo with lipopolysaccharide (LPS). High-resolution respirometry was used with intact and permeabilized cells. To reveal potential mechanistic targets by which HFD-induced obesity dysregulates B cell mitochondria, we conducted proteomic analyses and 3D serial block face scanning electron microscopy (SBFEM). High-resolution respirometry revealed that intact LPS-stimulated B cells of obese mice, relative to controls, displayed lower ATP-linked, as well as maximal uncoupled, respiration. To directly investigate mitochondrial function, we used permeabilized LPS-stimulated B cells, which displayed increased H2O2 emission and production with obesity. We also examined oxidative phosphorylation efficiency simultaneously, which revealed that oxygen consumption and ATP production were decreased in LPS-stimulated B cells with obesity relative to controls. Despite minimal changes in total respiratory complex abundance, in LPS-stimulated B cells of obese mice, three of the top ten most downregulated proteins were all accessory subunits of respiratory complex I. SBFEM showed that B cells of obese mice, compared to controls, underwent no change in mitochondrial cristae integrity but displayed increased mitochondrial volume that was linked to bioenergetic function. Collectively, these results establish a proof of concept that HFD-induced obesity dysregulates the mitochondrial bioenergetic metabolism of activated splenic B cells.
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Affiliation(s)
- Anandita Pal
- Department of Nutrition, Gillings School of Global Public Health and School of Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA;
| | - Chien-Te Lin
- East Carolina Diabetes and Obesity Institute, Brody School of Medicine, East Carolina University, Greenville, NC 27834, USA; (C.-T.L.); (I.B.); (K.H.F.-W.)
- Department of Physiology, Brody School of Medicine, East Carolina University, Greenville, NC 27834, USA
| | - Ilya Boykov
- East Carolina Diabetes and Obesity Institute, Brody School of Medicine, East Carolina University, Greenville, NC 27834, USA; (C.-T.L.); (I.B.); (K.H.F.-W.)
- Department of Physiology, Brody School of Medicine, East Carolina University, Greenville, NC 27834, USA
| | - Emily Benson
- 3D-EM Ultrastructural Imaging and Computation Core, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44106, USA; (E.B.); (G.K.)
| | - Grahame Kidd
- 3D-EM Ultrastructural Imaging and Computation Core, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44106, USA; (E.B.); (G.K.)
| | - Kelsey H. Fisher-Wellman
- East Carolina Diabetes and Obesity Institute, Brody School of Medicine, East Carolina University, Greenville, NC 27834, USA; (C.-T.L.); (I.B.); (K.H.F.-W.)
- Department of Physiology, Brody School of Medicine, East Carolina University, Greenville, NC 27834, USA
| | - P. Darrell Neufer
- East Carolina Diabetes and Obesity Institute, Brody School of Medicine, East Carolina University, Greenville, NC 27834, USA; (C.-T.L.); (I.B.); (K.H.F.-W.)
- Department of Physiology, Brody School of Medicine, East Carolina University, Greenville, NC 27834, USA
- Department of Biochemistry and Molecular Biology, Brody School of Medicine, East Carolina University, Greenville, NC 27834, USA
| | - Saame Raza Shaikh
- Department of Nutrition, Gillings School of Global Public Health and School of Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA;
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Meliopoulos V, Honce R, Livingston B, Hargest V, Freiden P, Lazure L, Brigleb PH, Karlsson E, Tillman H, Allen EK, Boyd D, Thomas PG, Schultz-Cherry S. Diet-induced obesity impacts influenza disease severity and transmission dynamics in ferrets. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.09.26.558609. [PMID: 37808835 PMCID: PMC10557597 DOI: 10.1101/2023.09.26.558609] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/10/2023]
Abstract
Obesity, and the associated metabolic syndrome, is a risk factor for increased disease severity with a variety of infectious agents, including influenza virus. Yet the mechanisms are only partially understood. As the number of people, particularly children, living with obesity continues to rise, it is critical to understand the role of host status on disease pathogenesis. In these studies, we use a novel diet-induced obese ferret model and new tools to demonstrate that like humans, obesity resulted in significant changes to the lung microenvironment leading to increased clinical disease and viral spread to the lower respiratory tract. The decreased antiviral responses also resulted in obese animals shedding higher infectious virus for longer making them more likely to transmit to contacts. These data suggest the obese ferret model may be crucial to understanding obesity's impact on influenza disease severity and community transmission, and a key tool for therapeutic and intervention development for this high-risk population. Teaser A new ferret model and tools to explore obesity's impact on respiratory virus infection, susceptibility, and community transmission.
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Prechtl P, Schmitz T, Pochert N, Traidl-Hoffmann C, Linseisen J, Meisinger C, Freuer D. Association between body fat distribution and B-lymphocyte subsets in peripheral blood. Immun Ageing 2023; 20:47. [PMID: 37705078 PMCID: PMC10498588 DOI: 10.1186/s12979-023-00372-6] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2023] [Accepted: 09/06/2023] [Indexed: 09/15/2023]
Abstract
BACKGROUND Obesity is associated with chronic low-grade inflammation, which is underpinned by the presence of elevated levels of circulating proinflammatory cytokines in obese individuals. Due to the close relationship between adipose tissue and the immune system, it can be speculated that the accumulation of fat may influence the frequency and phenotype of lymphocyte populations. The aim of our study was to investigate whether body fat distribution is associated with B lymphocyte composition in peripheral blood. We examined the association between visceral (VAT) and total body fat (TBF) and the frequencies of B-cell subsets in 238 subjects over a period of up to one year using random intercept models. B lymphocyte subsets were determined by fluorescence-based flow cytometry. RESULTS Inverse associations were found between body fat measurements and plasma blasts, memory B cells, and IgM-IgD- cells. VAT, but not TBF, was positively associated with naive CD19 cells. In our analyses, both VAT and TBF showed positive associations with IgD only B cells. CONCLUSIONS In conclusion, body fat accumulation seems to be associated with a lower proportion of antibody-secreting plasma blasts and memory cells and an increasing amount of partially anergic, naive CD19 cells.
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Affiliation(s)
- Pia Prechtl
- Epidemiology, Medical Faculty, University of Augsburg, Augsburg, Germany
- Institute for Medical Information Processing, Biometry and Epidemiology - IBE, LMU, Munich, Munich, Germany
| | - Timo Schmitz
- Epidemiology, Medical Faculty, University of Augsburg, Augsburg, Germany
| | - Nicole Pochert
- Institute of Environmental Medicine, Helmholtz Munich, Munich, Germany
- Department of Obstetrics and Gynecology, University Hospital of Augsburg, Augsburg, Germany
| | - Claudia Traidl-Hoffmann
- Institute of Environmental Medicine, Helmholtz Munich, Munich, Germany
- Environmental Medicine, Faculty of Medicine, University of Augsburg, Augsburg, Germany
| | - Jakob Linseisen
- Epidemiology, Medical Faculty, University of Augsburg, Augsburg, Germany
- Institute for Medical Information Processing, Biometry and Epidemiology - IBE, LMU, Munich, Munich, Germany
| | - Christa Meisinger
- Epidemiology, Medical Faculty, University of Augsburg, Augsburg, Germany
| | - Dennis Freuer
- Epidemiology, Medical Faculty, University of Augsburg, Augsburg, Germany.
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Ramirez De Oleo I, Kim V, Atisha-Fregoso Y, Shih AJ, Lee K, Diamond B, Kim SJ. Phenotypic and functional characteristics of murine CD11c+ B cells which is suppressed by metformin. Front Immunol 2023; 14:1241531. [PMID: 37744368 PMCID: PMC10512061 DOI: 10.3389/fimmu.2023.1241531] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2023] [Accepted: 08/21/2023] [Indexed: 09/26/2023] Open
Abstract
Since the description of age-associated or autoimmune-associated B cells (ABCs), there has been a growing interest in the role of these cells in autoimmunity. ABCs are differently defined depending on the research group and are heterogenous subsets. Here, we sought to characterize ABCs in Sle1/2/3 triple congenic (TC) mice, which is a well accepted mouse model of lupus. Compared to follicular (FO) B cells, ABCs have many distinct functional properties, including antigen presentation. They express key costimulatory molecules for T cell activation and a distinct profile of cytokines. Moreover, they exhibit an increased capacity for antigen uptake. ABCs were also compared with germinal center (GC) B cells, which are antigen activated B cell population. There are several phenotypic similarities between ABCs and GC B cells, but GC B cells do not produce proinflammatory cytokines or take up antigen. While T cell proliferation and activation is induced by both FO B and ABCs in an antigen-dependent manner, ABCs induce stronger T cell receptor signaling in naïve CD4+ T cells and preferentially induce differentiation of T follicular helper (Tfh) cells. We found that ABCs exhibit a distinct transcriptomic profile which is focused on metabolism, cytokine signaling and antigen uptake and processing. ABCs exhibit an increase in both glycolysis and oxidative phosphorylation compared to FO B cells. Treatment of ABCs with metformin suppresses antigen presentation by decreasing antigen uptake, resulting in decreased Tfh differentiation. Taken together, these findings define a fundamental connection between metabolism and function within ABCs.
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Affiliation(s)
- Ivan Ramirez De Oleo
- Center for Autoimmune, Musculoskeletal and Hematopoietic Diseases, The Feinstein Institutes for Medical Research, Manhasset, NY, United States
| | - Vera Kim
- Center for Autoimmune, Musculoskeletal and Hematopoietic Diseases, The Feinstein Institutes for Medical Research, Manhasset, NY, United States
| | - Yemil Atisha-Fregoso
- Center for Autoimmune, Musculoskeletal and Hematopoietic Diseases, The Feinstein Institutes for Medical Research, Manhasset, NY, United States
| | - Andrew J. Shih
- Center for Genomics and Human Genetics, The Feinstein Institutes for Medical Research, Manhasset, NY, United States
| | - Kyungwoo Lee
- Center for Autoimmune, Musculoskeletal and Hematopoietic Diseases, The Feinstein Institutes for Medical Research, Manhasset, NY, United States
- Department of Biology at Hofstra University, Hempstead, NY, United States
| | - Betty Diamond
- Center for Autoimmune, Musculoskeletal and Hematopoietic Diseases, The Feinstein Institutes for Medical Research, Manhasset, NY, United States
- Department of Molecular Medicine, Donald and Barbara Zucker School of Medicine at Hofstra University/Northwell, Hempstead, NY, United States
| | - Sun Jung Kim
- Center for Autoimmune, Musculoskeletal and Hematopoietic Diseases, The Feinstein Institutes for Medical Research, Manhasset, NY, United States
- Department of Molecular Medicine, Donald and Barbara Zucker School of Medicine at Hofstra University/Northwell, Hempstead, NY, United States
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Abstract
In this review, we provide a brief synopsis of the connections between adipose tissue and metabolic health and highlight some recent developments in understanding and exploiting adipocyte biology. Adipose tissue plays critical roles in the regulation of systemic glucose and lipid metabolism and secretes bioactive molecules possessing endocrine, paracrine, and autocrine functions. Dysfunctional adipose tissue has a detrimental impact on metabolic health and is intimately involved in key aspects of metabolic diseases such as insulin resistance, lipid overload, inflammation, and organelle stress. Differences in the distribution of fat depots and adipose characteristics relate to divergent degrees of metabolic dysfunction found in metabolically healthy and unhealthy obese individuals. Thermogenic adipocytes increase energy expenditure via mitochondrial uncoupling or adenosine triphosphate-consuming futile substrate cycles, while functioning as a metabolic sink and participating in crosstalk with other metabolic organs. Manipulation of adipose tissue provides a wealth of opportunities to intervene and combat the progression of associated metabolic diseases. We discuss current treatment modalities for obesity including incretin hormone analogs and touch upon emerging strategies with therapeutic potential including exosome-based therapy, pharmacological activation of brown and beige adipocyte thermogenesis, and administration or inhibition of adipocyte-derived factors.
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Affiliation(s)
- Sung-Min An
- Division of Endocrinology, Department of Internal Medicine, University of California Davis School of Medicine, Davis, CA, USA
| | - Seung-Hee Cho
- Division of Endocrinology, Department of Internal Medicine, University of California Davis School of Medicine, Davis, CA, USA
| | - John C. Yoon
- Division of Endocrinology, Department of Internal Medicine, University of California Davis School of Medicine, Davis, CA, USA
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Wang HW, Tang J, Sun L, Li Z, Deng M, Dai Z. Mechanism of immune attack in the progression of obesity-related type 2 diabetes. World J Diabetes 2023; 14:494-511. [PMID: 37273249 PMCID: PMC10236992 DOI: 10.4239/wjd.v14.i5.494] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/28/2022] [Revised: 03/06/2023] [Accepted: 03/30/2023] [Indexed: 05/15/2023] Open
Abstract
Obesity and overweight are widespread issues in adults, children, and adolescents globally, and have caused a noticeable rise in obesity-related complications such as type 2 diabetes mellitus (T2DM). Chronic low-grade inflammation is an important promotor of the pathogenesis of obesity-related T2DM. This proinflammatory activation occurs in multiple organs and tissues. Immune cell-mediated systemic attack is considered to contribute strongly to impaired insulin secretion, insulin resistance, and other metabolic disorders. This review focused on highlighting recent advances and underlying mechanisms of immune cell infiltration and inflammatory responses in the gut, islet, and insulin-targeting organs (adipose tissue, liver, skeletal muscle) in obesity-related T2DM. There is current evidence that both the innate and adaptive immune systems contribute to the development of obesity and T2DM.
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Affiliation(s)
- Hua-Wei Wang
- Department of Endocrinology, Zhongnan Hospital of Wuhan University, Wuhan 430071, Hubei Province, China
| | - Jun Tang
- Department of Endocrinology, Zhongnan Hospital of Wuhan University, Wuhan 430071, Hubei Province, China
| | - Li Sun
- Department of Endocrinology, Zhongnan Hospital of Wuhan University, Wuhan 430071, Hubei Province, China
| | - Zhen Li
- Department of Hepatobiliary and Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Wuhan 430071, Hubei Province, China
| | - Ming Deng
- Department of Radiology, Zhongnan Hospital of Wuhan University, Wuhan 430071, Hubei Province, China
| | - Zhe Dai
- Department of Endocrinology, Zhongnan Hospital of Wuhan University, Wuhan 430071, Hubei Province, China
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T-bet highCD21 low B cells: the need to unify our understanding of a distinct B cell population in health and disease. Curr Opin Immunol 2023; 82:102300. [PMID: 36931129 DOI: 10.1016/j.coi.2023.102300] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2022] [Revised: 02/13/2023] [Accepted: 02/14/2023] [Indexed: 03/17/2023]
Abstract
After many years of a niche research in a few laboratories of the world, T-bethighCD21low B cells have entered the limelight during the last years after the discovery of T-bet as common transcription factor of this unconventional B cell population and the increasing awareness of the expansion of these cells in autoimmune and infectious diseases. This population consists of different subsets which share large parts of their transcriptome, essential phenotypic markers, and reduced B cell receptor (BCR) signaling capacity. Inborn errors of immunity have helped to delineate essential signals for their differentiation. While our comprehension of their origin has improved, future research will hopefully profit from a common definition of the different T-bethighCD21low subpopulations in order to better define their specific roles during normal and aberrant immune responses.
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Abstract
Single-cell mapping of human and mouse white adipose tissue across different depots and body masses revealed cellular heterogeneity, and identified distinct subpopulations of adipocytes, adipose progenitors and immune cells across species and types of diet2 . In obesity, T-bet+ B cells, which express the T helper 1-lineage transcription factor T-bet, accumulated in the adipose tissue of humans and mice, and activated T-bet+ B cells secreted the proinflammatory chemokine CXCL10 to exacerbate obesity-associated metabolic abnormalities5 . Extracellular vesicles (EVs) produced by dysfunctional adipose tissue could deliver microRNAs to the brain and cause synaptic damage in the hippocampus and cognitive impairments; targeting adipose tissue-derived EVs or microRNAs prevented cognitive defects in mice7 . Cold exposure inhibited tumour growth in mice carrying various xenografted solid tumours, an effect mediated via the activation of brown adipose tissue, leading to decreased circulating levels of glucose and attenuated glycolytic and lipid metabolism in tumours8 . SARS-CoV-2 directly infected human adipocytes and altered cell metabolism in a depot-specific and viral lineage-dependent fashion; visceral adipocytes were more susceptible to SARS-CoV-2 infection than subcutaneous adipocytes10 .
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Affiliation(s)
- Yu-Hua Tseng
- Section on Integrative Physiology and Metabolism, Joslin Diabetes Center and Department of Medicine, Harvard Medical School, Boston, MA, USA.
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Hong X, Zhou Y, Zhu Z, Li Y, Li Z, Zhang Y, Hu X, Zhu F, Wang Y, Fang M, Huang Y, Shen T. Environmental endocrine disruptor Bisphenol A induces metabolic derailment and obesity via upregulating IL-17A in adipocytes. ENVIRONMENT INTERNATIONAL 2023; 172:107759. [PMID: 36696794 DOI: 10.1016/j.envint.2023.107759] [Citation(s) in RCA: 35] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/21/2022] [Revised: 12/15/2022] [Accepted: 01/14/2023] [Indexed: 06/17/2023]
Abstract
BACKGROUND Bisphenol A (BPA), a ubiquitous environmental endocrine disruptor, has been extensively demonstrated to be associated with metabolic disorders, including obesity and type 2 diabetes mellitus. However, the underlying mechanism underpinning the environmental etiology of chronic metabolic disorders has not been sufficiently elucidated. OBJECTIVES This study is designed to explore the toxicological pathogenesis of chronic inflammation in BPA exposure during obesity. METHODS We investigated the role of IL-17A in the association of BPA exposure and obesity from human cross-sectional study to animal models, including genetically modified IL-17A-/- mice. RESULTS Here, our work started from case-control observation that BPA exposure was significantly associated with risk of obesity (odds ratio = 4.72, 95%CI: 3.18 - 11.18, P < 0.01), metabolic disorder and levels of interleukin-17A (IL-17A) in human adipose (estimated changes β = 0.46, 95%CI: 0.15 - 1.01, P < 0.01) with bariatric surgery. Animal model fed with high-fat diet (HFD) confirmed that BPA exposure aggravated body weight gain and insulin resistance, concurrent with much heightened inflammatory responses in the adipose tissue including increase in IL-17A and macrophage polarization towards M1 stage. Genetically modified IL-17A ablated mice (IL-17A-/-) showed reversed adipose tissue inflammation response, improved macrophage polarization homeostasis, along with insulin sensitivity in both HFD group alone or much more significantly the HFD + BPA group. Moreover, mediation analysis in human epidemiological investigation demonstrated that plasma IL-17A attributed up to 30.01% mediating role in the associations between BPA exposure and obesity risk. DISCUSSION This research paradigm from human to animal provides strong evidence for the elucidation of IL-17A moderating inflammation and insulin resistance in obesity. Such findings reiterate the obesogenic role of environmental endocrine disruptor BPA in metabolic disorders and unveils the potential toxicological mechanisms underpinning such effect.
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Affiliation(s)
- Xu Hong
- Department of Occupational Health and Environmental Health, School of Public Health, Anhui Medical University, Hefei 230032, Anhui, PR China
| | - Yi Zhou
- Department of Occupational Health and Environmental Health, School of Public Health, Anhui Medical University, Hefei 230032, Anhui, PR China
| | - Zhiyuan Zhu
- Department of Occupational Health and Environmental Health, School of Public Health, Anhui Medical University, Hefei 230032, Anhui, PR China
| | - Yuting Li
- Department of Occupational Health and Environmental Health, School of Public Health, Anhui Medical University, Hefei 230032, Anhui, PR China
| | - Zuo Li
- Department of Occupational Health and Environmental Health, School of Public Health, Anhui Medical University, Hefei 230032, Anhui, PR China
| | - Yuheng Zhang
- Department of Occupational Health and Environmental Health, School of Public Health, Anhui Medical University, Hefei 230032, Anhui, PR China
| | - Xinxin Hu
- Department of Occupational Health and Environmental Health, School of Public Health, Anhui Medical University, Hefei 230032, Anhui, PR China
| | - Fuhai Zhu
- Health Management Center, Second Affiliated Hospital, Anhui Medical University, Hefei 230032, Anhui, PR China
| | - Yong Wang
- Department of General Surgery, Second Affiliated Hospital, Anhui Medical University, Hefei 230032, Anhui, PR China
| | - Mingliang Fang
- Department of Environmental Science and Engineering, Fudan University, Shanghai 200433, China
| | - Yichao Huang
- Department of Toxicology, School of Public Health, Anhui Medical University, Hefei 230032, Anhui, PR China.
| | - Tong Shen
- Department of Occupational Health and Environmental Health, School of Public Health, Anhui Medical University, Hefei 230032, Anhui, PR China.
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Chen W, Meng F, Zeng X, Cao X, Bu G, Du X, Yu G, Kong F, Li Y, Gan T, Han X. Mechanic Insight into the Distinct and Common Roles of Ovariectomy Versus Adrenalectomy on Adipose Tissue Remodeling in Female Mice. Int J Mol Sci 2023; 24:ijms24032308. [PMID: 36768630 PMCID: PMC9916485 DOI: 10.3390/ijms24032308] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2023] [Revised: 01/15/2023] [Accepted: 01/17/2023] [Indexed: 01/26/2023] Open
Abstract
Dysfunctions of the ovaries and adrenal glands are both evidenced to cause aberrant adipose tissue (AT) remodeling and resultant metabolic disorders, but their distinct and common roles are poorly understood. In this study, through biochemical, histological and RNA-seq analyses, we comprehensively explored the mechanisms underpinning subcutaneous (SAT) and visceral adipose tissue (VAT) remodeling, in response to ovariectomy (OVX) versus adrenalectomy (ADX) in female mice. OVX promoted adipocyte differentiation and fat accumulation in both SAT and VAT, by potentiating the Pparg signaling, while ADX universally prevented the cell proliferation and extracellular matrix organization in both SAT and VAT, likely by inactivating the Nr3c1 signaling, thus causing lipoatrophy in females. ADX, but not OVX, exerted great effects on the intrinsic difference between SAT and VAT. Specifically, ADX reversed a large cluster of genes differentially expressed between SAT and VAT, by activating 12 key transcription factors, and thereby caused senescent cell accumulation, massive B cell infiltration and the development of selective inflammatory response in SAT. Commonly, both OVX and ADX enhance circadian rhythmicity in VAT, and impair cell proliferation, neurogenesis, tissue morphogenesis, as well as extracellular matrix organization in SAT, thus causing dysfunction of adipose tissues and concomitant metabolic disorders.
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Li ZY, Cai ML, Qin Y, Chen Z. Age/autoimmunity-associated B cells in inflammatory arthritis: An emerging therapeutic target. Front Immunol 2023; 14:1103307. [PMID: 36817481 PMCID: PMC9933781 DOI: 10.3389/fimmu.2023.1103307] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2022] [Accepted: 01/10/2023] [Indexed: 01/25/2023] Open
Abstract
Age/autoimmunity-associated B cells (ABCs) are a novel B cell subpopulation with a unique transcriptional signature and cell surface phenotype. They are not sensitive to BCR but rely on TLR7 or TLR9 in the context of T cell-derived cytokines for the differentiation. It has been established that aberrant expansion of ABCs is linked to the pathogenesis of systemic autoimmune diseases such as systemic lupus erythematosus. Recently, we and other groups have shown that increased ABCs is associated with rheumatoid arthritis (RA) disease activity and have demonstrated their pathogenic role in RA, indicating that targeting specific B cell subsets is a promising strategy for the treatment of inflammatory arthritis. In this review, we summarize the current knowledge of ABCs, focusing on their emerging role in the pathogenesis of inflammatory arthritis. A deep understanding of the biology of ABCs in the context of inflammatory settings in vivo will ultimately contribute to the development of novel targeted therapies for the treatment of inflammatory arthritis.
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Affiliation(s)
- Zhen-Yu Li
- Department of Rheumatology and Immunology, the First Affiliated Hospital of University of Science and Technology of China (USTC), Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Ming-Long Cai
- Department of Rheumatology and Immunology, the First Affiliated Hospital of University of Science and Technology of China (USTC), Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Yi Qin
- Department of Rheumatology and Immunology, the First Affiliated Hospital of University of Science and Technology of China (USTC), Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Zhu Chen
- Department of Rheumatology and Immunology, the First Affiliated Hospital of University of Science and Technology of China (USTC), Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
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Khan S, Winer DA. T-bet + B cells exacerbate obesity-related metabolic disease. Trends Immunol 2022; 43:855-857. [PMID: 36216716 DOI: 10.1016/j.it.2022.09.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2022] [Accepted: 09/23/2022] [Indexed: 01/12/2023]
Abstract
B cells are associated with the development of obesity-associated metabolic disease. Recently, Hägglöf, Vanz, et al. identified a novel obesity-related subset of B cells that are demarcated by the transcription factor T-bet and their pathogenic ability to worsen metabolic disease outcomes.
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Affiliation(s)
- Saad Khan
- Department of Immunology, University of Toronto, Toronto, ON M5S 1A8, Canada; Division of Cellular & Molecular Biology, Diabetes Research Group, Toronto General Hospital Research Institute (TGHRI), University Health Network, Toronto, ON M5G 1L7, Canada
| | - Daniel A Winer
- Department of Immunology, University of Toronto, Toronto, ON M5S 1A8, Canada; Division of Cellular & Molecular Biology, Diabetes Research Group, Toronto General Hospital Research Institute (TGHRI), University Health Network, Toronto, ON M5G 1L7, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, ON M5S 1A8, Canada; Buck Institute for Research on Aging, 8001 Redwood Boulevard, Novato, CA 94945, USA.
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Tysoe O. T-bet + B cells promote metabolic disease. Nat Rev Endocrinol 2022; 18:589. [PMID: 35970892 DOI: 10.1038/s41574-022-00736-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
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Cancro MP. T-bet B or not T-bet B, is that the question in obesity-related metabolic disease? Cell Metab 2022; 34:1081-1082. [PMID: 35921814 DOI: 10.1016/j.cmet.2022.07.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
Obesity is linked to inflammation and downstream metabolic dysregulation. In this issue of Cell Metabolism, Hägglöf et al. show that iNKT cells enable the accumulation of T-bet+ B cells in white adipose tissue, which in turn produce chemokine and antibody mediators that exacerbate the onset and severity of metabolic disease.
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Affiliation(s)
- Michael P Cancro
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
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