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Liu C, Li X. Role of leptin and adiponectin in immune response and inflammation. Int Immunopharmacol 2025; 161:115082. [PMID: 40516255 DOI: 10.1016/j.intimp.2025.115082] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2025] [Revised: 05/29/2025] [Accepted: 06/09/2025] [Indexed: 06/16/2025]
Abstract
Adipose tissue has gained significant attention for its role in immune response and inflammation through the secretion of adipokines. Adipokines, such as leptin and adiponectin, are secreted by adipose tissue and have been implicated in various physiological processes, with a focus on their role in modulating immune responses and inflammation. Leptin and adiponectin are the most abundant adipokines in human, playing a crucial role in regulating functions of the heart, skeletal muscle, growth, and inflammation. Leptin, a pro-inflammatory adipokine, is involved in controlling food intake and energy expenditure, and it influences immune cell activation and cytokine production. In contrast, adiponectin, an anti-inflammatory adipokine, circulates at high levels in the plasma and modulates immune cell functions, counteracting the effects of leptin. Here we provided an overview of the role of adipokines in immune response and inflammation. In addition，The leptin-adiponectin ratio (Adpn/Lep) has emerged as a significant indicator of various metabolic diseases and conditions. Further research is needed to fully elucidate the mechanisms by which adipokines influence immune responses and to identify potential therapeutic targets for inflammatory and metabolic disorders.
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Affiliation(s)
- Chang Liu
- Department of Clinical Laboratory, Gongli Hospital of Shanghai Pudong, Shanghai 200120, China.
| | - Xiaojiao Li
- BioBank, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China.
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2
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Schimmer S, Kerkmann L, Kahlert N, Jubeh SA, Werner T, Corkish C, Prendeville H, Finlay DK, Sutter K, Dittmer U, Littwitz-Salomon E. Dietary lipid overload creates a suppressive environment that impedes the antiviral functions of NK cells. iScience 2025; 28:112396. [PMID: 40352719 PMCID: PMC12063142 DOI: 10.1016/j.isci.2025.112396] [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: 10/21/2024] [Revised: 02/03/2025] [Accepted: 04/07/2025] [Indexed: 05/14/2025] Open
Abstract
Natural killer (NK) cells are innate immune cells able to recognize and eliminate virus-infected cells. NK cell activity strongly correlates with a metabolic reprogramming and breakdown of fatty acids by β-oxidation during virus infections. However, there is limited knowledge regarding the impact of obesity on antiviral NK cell functions. Here, employing the Friend retrovirus mouse model, we show that the cytotoxicity and cytokine production of NK cells was impaired in obesity, leading to higher viral loads. NK cells suppression in obesity was mediated by activated Tregs. Furthermore, obese mice that were switched back to a regular diet showed complete recovery of the NK cell activity. Interestingly, feeding mice with a high-fat diet (HFD) for just ten days caused NK cell dysfunction and increased retroviral burden. This study is the first to link the detrimental impact of an obesity-induced immunosuppressive microenvironment with NK cell dysfunction during an acute retroviral infection.
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Affiliation(s)
- Simone Schimmer
- Institute for Virology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Leonie Kerkmann
- Institute for the Research on HIV and AIDS-associated Diseases, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Nele Kahlert
- Institute for the Research on HIV and AIDS-associated Diseases, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Shahd al Jubeh
- Institute for the Research on HIV and AIDS-associated Diseases, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Tanja Werner
- Institute for Virology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Carrie Corkish
- School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, 152-160 Pearse Street, Dublin 2, Ireland
| | - Hannah Prendeville
- Biomedical Engineering, School of Engineering, College of Science and Engineering, University of Galway, Galway, Ireland
| | - David K. Finlay
- School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, 152-160 Pearse Street, Dublin 2, Ireland
- School of Pharmacy and Pharmaceutical Sciences, Trinity Biomedical Sciences Institute, Trinity College Dublin, 152-160 Pearse Street, Dublin 2, Ireland
| | - Kathrin Sutter
- Institute for Virology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
- Institute for the Research on HIV and AIDS-associated Diseases, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Ulf Dittmer
- Institute for Virology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Elisabeth Littwitz-Salomon
- Institute for Virology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
- Institute for the Research on HIV and AIDS-associated Diseases, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
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3
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de Andrade AG, Vanderley SER, de Farias Marques L, Almeida FS, Cavalcante-Silva LHA, Keesen TSL. Leptin, NK cells, and the weight of immunity: Insights into obesity. Int Immunopharmacol 2025; 147:113992. [PMID: 39755107 DOI: 10.1016/j.intimp.2024.113992] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2024] [Revised: 12/28/2024] [Accepted: 12/29/2024] [Indexed: 01/06/2025]
Abstract
Obesity is a chronic inflammatory disease that affects more than 1 billion people worldwide and is associated with various metabolic and physiological dysfunctions, directly impacting the dynamics of the immune response, partly due to elevated leptin levels. Leptin is an important peptide hormone that regulates neuroendocrine function and energy homeostasis, with its blood levels reflecting energy reserves, fat mass, or energy deprivation. This hormone also plays a fundamental role in regulating immune function, including the activity of NK cells, which are essential components in antiviral and antitumor activity. In obese individuals, leptin resistance is commonly established, however, NK cells and other immune components remain responsive to this hormone. So far, leptin has demonstrated paradoxical activities of these cells, often associated with a dysfunctional profile when associated with obesity. The excessive fat is usually related to metabolic remodeling in NK cells, resulting in compromised antitumor responses due to reduced cytotoxic capacity and decreased expression of cytokines important for these defense mechanisms, such as IFN-γ. Therefore, this review approaches a better understanding of the immunoendocrine interactions between leptin and NK cells in the context of obesity.
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Affiliation(s)
- Arthur Gomes de Andrade
- Immunology Laboratory of Infectious Diseases, Department of Cellular and Molecular Biology, Federal University of Paraiba, João Pessoa, Paraíba 58051-900, Brazil
| | - Shayenne Eduarda Ramos Vanderley
- Immunology Laboratory of Infectious Diseases, Department of Cellular and Molecular Biology, Federal University of Paraiba, João Pessoa, Paraíba 58051-900, Brazil
| | - Lorrane de Farias Marques
- Immunology Laboratory of Infectious Diseases, Department of Cellular and Molecular Biology, Federal University of Paraiba, João Pessoa, Paraíba 58051-900, Brazil
| | - Fernanda Silva Almeida
- Immunology Laboratory of Infectious Diseases, Department of Cellular and Molecular Biology, Federal University of Paraiba, João Pessoa, Paraíba 58051-900, Brazil
| | | | - Tatjana Souza Lima Keesen
- Immunology Laboratory of Infectious Diseases, Department of Cellular and Molecular Biology, Federal University of Paraiba, João Pessoa, Paraíba 58051-900, Brazil.
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4
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Griesler B, Hölzel M, Oswald J, Fänder J, Fischer T, Büttner M, Quandt D, Bähr I, Jasinski-Bergner S, Bazwinsky-Wutschke I, Kielstein H. Impact of siRNA-Mediated Cofilin-1 Knockdown and Obesity Associated Microenvironment on the Motility of Natural Killer Cells. Immunol Invest 2024; 53:713-729. [PMID: 38721960 DOI: 10.1080/08820139.2024.2327327] [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: 06/21/2024]
Abstract
The anti-tumor capacity of natural killer (NK) cells heavily relies on their ability to migrate towards their target cells. This process is based on dynamic actinrearrangement, so-called actin treadmilling, andis tightly regulated by proteins such as cofilin-1. The aim of the present study was to identify the role of cofilin-1 (CFL-1) in the migratory behavior of NK cells and to investigate a possible impact of an obesity-associated micromilieu on these cells, as it is known that obesity correlates with various impaired NK cell functions. CFL-1 was knocked-down via transfection of NK-92 cells with respective siRNAs. Obesity associated micromilieu was mimicked by incubation of NK-92 cells with adipocyte-conditioned medium from human preadipocyte SGBS cells or leptin. Effects on CFL-1 levels, the degree of phosphorylation to the inactive pCFL-1 as well as NK-92 cell motility were analyzed. Surprisingly, siRNA-mediated CFL-1 knockdown led to a significant increase of migration, as determined by enhanced velocity and accumulated distance of migration. No effect on CFL-1 nor pCFL-1 expression levels, proportion of phosphorylation and cell migratory behavior could be demonstrated under the influence of an obesity-associated microenvironment. In conclusion, the results indicate a significant effect of a CFL-1 knockdown on NK cell motility.
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Affiliation(s)
- Bruno Griesler
- Institute of Anatomy and Cell Biology, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany
- Department of Internal Medicine IV, University Medicine, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany
| | - Marijke Hölzel
- Institute of Anatomy and Cell Biology, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany
| | - Jana Oswald
- Institute of Anatomy and Cell Biology, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany
| | - Johannes Fänder
- Institute of Anatomy and Cell Biology, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany
- Department of Pediatrics I, University Medicine, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany
| | - Trutz Fischer
- Institute of Anatomy and Cell Biology, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany
- Department of Internal Medicine I, University Medicine, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany
| | - Maximilian Büttner
- Institute of Anatomy and Cell Biology, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany
| | - Dagmar Quandt
- Institute of Anatomy and Cell Biology, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany
| | - Ina Bähr
- Institute of Anatomy and Cell Biology, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany
| | - Simon Jasinski-Bergner
- Institute of Anatomy and Cell Biology, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany
- Institute for Medical Immunology, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany
| | - Ivonne Bazwinsky-Wutschke
- Institute of Anatomy and Cell Biology, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany
| | - Heike Kielstein
- Institute of Anatomy and Cell Biology, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany
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Liu M, Li C, Qu J, Sun S, Zhao Z, Wang W, Lv W, Zhang Y, Cai Y, Zhao F, Wu F, Zhang S, Zhao X. Baicalein enhances immune response in TNBC by inhibiting leptin expression of adipocytes. Cancer Sci 2023; 114:3834-3847. [PMID: 37489486 PMCID: PMC10551602 DOI: 10.1111/cas.15916] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2023] [Revised: 07/04/2023] [Accepted: 07/10/2023] [Indexed: 07/26/2023] Open
Abstract
Triple-negative breast cancer (TNBC) is a special pathological type of breast cancer (BC) with poor prognosis. Obesity is shown to be involved in TNBC tumor progression. The interaction between obesity and BC has generated great attention in recent years, however, the mechanism is still unclear. Here, we showed that leptin secreted by adipocytes upregulated PD-L1 expression in TNBC through the p-STAT3 signaling pathway and that baicalein inhibited PD-L1 expression in tumor microenvironment by suppressing leptin transcription of adipocytes. Collectively, our findings suggest that leptin may be the key factor participating in obesity-related tumor progression and that baicalein can break through the dilemma to boost the anti-tumor immune response.
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Affiliation(s)
- Mengjie Liu
- Department of OncologyThe Second Affiliated Hospital of Xi'an Jiaotong UniversityXi'anChina
| | - Chaofan Li
- Department of OncologyThe Second Affiliated Hospital of Xi'an Jiaotong UniversityXi'anChina
| | - Jingkun Qu
- Department of OncologyThe Second Affiliated Hospital of Xi'an Jiaotong UniversityXi'anChina
| | - Shiyu Sun
- Department of OncologyThe Second Affiliated Hospital of Xi'an Jiaotong UniversityXi'anChina
| | - Zitong Zhao
- Department of OncologyThe Second Affiliated Hospital of Xi'an Jiaotong UniversityXi'anChina
| | - Weiwei Wang
- Department of OncologyThe Second Affiliated Hospital of Xi'an Jiaotong UniversityXi'anChina
| | - Wei Lv
- Department of OncologyThe Second Affiliated Hospital of Xi'an Jiaotong UniversityXi'anChina
| | - Yu Zhang
- Department of OncologyThe Second Affiliated Hospital of Xi'an Jiaotong UniversityXi'anChina
| | - Yifan Cai
- Department of OncologyThe Second Affiliated Hospital of Xi'an Jiaotong UniversityXi'anChina
| | - Fang Zhao
- Department of OncologyThe Second Affiliated Hospital of Xi'an Jiaotong UniversityXi'anChina
| | - Fei Wu
- Department of OncologyThe Second Affiliated Hospital of Xi'an Jiaotong UniversityXi'anChina
| | - Shuqun Zhang
- Department of OncologyThe Second Affiliated Hospital of Xi'an Jiaotong UniversityXi'anChina
| | - Xixi Zhao
- Department of OncologyThe Second Affiliated Hospital of Xi'an Jiaotong UniversityXi'anChina
- Department of Radiation OncologyThe Second Affiliated Hospital of Xi'an Jiaotong UniversityXi'anChina
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6
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Vick LV, Canter RJ, Monjazeb AM, Murphy WJ. Multifaceted effects of obesity on cancer immunotherapies: Bridging preclinical models and clinical data. Semin Cancer Biol 2023; 95:88-102. [PMID: 37499846 PMCID: PMC10836337 DOI: 10.1016/j.semcancer.2023.07.004] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2023] [Revised: 07/04/2023] [Accepted: 07/24/2023] [Indexed: 07/29/2023]
Abstract
Obesity, defined by excessive body fat, is a highly complex condition affecting numerous physiological processes, such as metabolism, proliferation, and cellular homeostasis. These multifaceted effects impact cells and tissues throughout the host, including immune cells as well as cancer biology. Because of the multifaceted nature of obesity, common parameters used to define it (such as body mass index in humans) can be problematic, and more nuanced methods are needed to characterize the pleiotropic metabolic effects of obesity. Obesity is well-accepted as an overall negative prognostic factor for cancer incidence, progression, and outcome. This is in part due to the meta-inflammatory and immunosuppressive effects of obesity. Immunotherapy is increasingly used in cancer therapy, and there are many different types of immunotherapy approaches. The effects of obesity on immunotherapy have only recently been studied with the demonstration of an "obesity paradox", in which some immune therapies have been demonstrated to result in greater efficacy in obese subjects despite the direct adverse effects of obesity and excess body fat acting on the cancer itself. The multifactorial characteristics that influence the effects of obesity (age, sex, lean muscle mass, underlying metabolic conditions and drugs) further confound interpretation of clinical data and necessitate the use of more relevant preclinical models mirroring these variables in the human scenario. Such models will allow for more nuanced mechanistic assessment of how obesity can impact, both positively and negatively, cancer biology, host metabolism, immune regulation, and how these intersecting processes impact the delivery and outcome of cancer immunotherapy.
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Affiliation(s)
- Logan V Vick
- Department of Dermatology, University of California Davis School of Medicine, Sacramento, CA, USA
| | - Robert J Canter
- Department of Surgery, Division of Surgical Oncology, University of California Davis Comprehensive Cancer Center, University of California Davis School of Medicine, Sacramento, CA, USA
| | - Arta M Monjazeb
- Department of Radiation Oncology, University of California Davis Comprehensive Cancer Center, University of California School of Medicine, Sacramento, CA, USA
| | - William J Murphy
- Department of Dermatology, University of California Davis School of Medicine, Sacramento, CA, USA; Department of Internal Medicine, Division of Malignant Hematology, Cellular Therapy and Transplantation, University of California Davis School of Medicine, Sacramento, CA, USA.
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7
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De Barra C, O'Shea D, Hogan AE. NK cells vs. obesity: A tale of dysfunction & redemption. Clin Immunol 2023; 255:109744. [PMID: 37604354 DOI: 10.1016/j.clim.2023.109744] [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: 06/01/2023] [Revised: 08/08/2023] [Accepted: 08/15/2023] [Indexed: 08/23/2023]
Abstract
Natural killer (NK) cells are critical in protecting the body against infection and cancer. NK cells can rapidly respond to these threats by directly targeting the infected or transformed cell using their cytotoxic machinery or by initiating and amplifying the immune response via their production of cytokines. Additionally, NK cells are resident across many tissues including adipose, were their role extends from host protection to tissue homeostasis. Adipose resident NK cells can control macrophage polarization via cytokine production, whilst also regulating stressed adipocyte fate using their cytotoxic machinery. Obesity is strongly associated with increased rates of cancer and a heightened susceptibility to severe infections. This is in part due to significant obesity-related immune dysregulation, including defects in both peripheral and adipose tissue NK cells. In this review, we detail the literature to date on NK cells in the setting of obesity - outlining the consequences, mechanisms and therapeutic interventions.
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Affiliation(s)
- Conor De Barra
- Kathleen Lonsdale Institute for Human Health Research, Maynooth University, Maynooth, Co Kildare, Ireland
| | - Donal O'Shea
- Obesity Immunology Group, Education and Research Centre, St Vincent's University Hospital, University College, Dublin 4, Ireland
| | - Andrew E Hogan
- Kathleen Lonsdale Institute for Human Health Research, Maynooth University, Maynooth, Co Kildare, Ireland; National Children's Research Centre, Dublin 12, Ireland.
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8
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Cho AR, Suh E, Oh H, Cho BH, Gil M, Lee YK. Low Muscle and High Fat Percentages Are Associated with Low Natural Killer Cell Activity: A Cross-Sectional Study. Int J Mol Sci 2023; 24:12505. [PMID: 37569879 PMCID: PMC10419953 DOI: 10.3390/ijms241512505] [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: 07/07/2023] [Revised: 08/02/2023] [Accepted: 08/04/2023] [Indexed: 08/13/2023] Open
Abstract
This study aimed to investigate whether body fat and muscle percentages are associated with natural killer cell activity (NKA). This was a cross-sectional study, conducted on 8058 subjects in a medical center in Korea. The association between the muscle and fat percentage tertiles and a low NKA, defined as an interferon-gamma level lower than 500 pg/mL, was assessed. In both men and women, the muscle mass and muscle percentage were significantly low in participants with a low NKA, whereas the fat percentage, white blood cell count, and C-reactive protein (CRP) level were significantly high in those with a low NKA. Compared with the lowest muscle percentage tertile as a reference, the fully adjusted odd ratios (ORs) (95% confidence intervals (CIs)) for a low NKA were significantly lower in T2 (OR: 0.69; 95% CI: 0.55-0.86) and T3 (OR: 0.74; 95% CI: 0.57-0.95) of men, and T3 (OR: 0.76; 95% CI: 0.59-0.99) of women. Compared with the lowest fat percentage tertile as a reference, the fully adjusted OR was significantly higher in T3 of men (OR: 1.31; 95% CI: 1.01-1.69). A high muscle percentage was significantly inversely associated with a low NKA in men and women, whereas a high fat percentage was significantly associated with a low NKA in men.
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Affiliation(s)
- A-Ra Cho
- Department of Family Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul 06273, Republic of Korea;
| | - Eunkyung Suh
- Chaum Life Center, CHA University, Seoul 06062, Republic of Korea; (E.S.); (H.O.)
| | - Hyoju Oh
- Chaum Life Center, CHA University, Seoul 06062, Republic of Korea; (E.S.); (H.O.)
| | - Baek Hwan Cho
- Department of Biomedical Informatics, CHA University School of Medicine, CHA University, Seongnam 13488, Republic of Korea;
| | - Minchan Gil
- NKMAX Co., Ltd., Seongnam 13605, Republic of Korea;
| | - Yun-Kyong Lee
- Chaum Life Center, CHA University, Seoul 06062, Republic of Korea; (E.S.); (H.O.)
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9
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Abdalla MMI. Serum resistin and the risk for hepatocellular carcinoma in diabetic patients. World J Gastroenterol 2023; 29:4271-4288. [PMID: 37545641 PMCID: PMC10401662 DOI: 10.3748/wjg.v29.i27.4271] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/26/2023] [Revised: 06/11/2023] [Accepted: 06/27/2023] [Indexed: 07/13/2023] Open
Abstract
Hepatocellular carcinoma (HCC), the predominant type of liver cancer, is a major contributor to cancer-related fatalities across the globe. Diabetes has been identified as a significant risk factor for HCC, with recent research indicating that the hormone resistin could be involved in the onset and advancement of HCC in diabetic individuals. Resistin is a hormone that is known to be involved in inflammation and insulin resistance. Patients with HCC have been observed to exhibit increased resistin levels, which could be correlated with more severe disease stages and unfavourable prognoses. Nevertheless, the exact processes through which resistin influences the development and progression of HCC in diabetic patients remain unclear. This article aims to examine the existing literature on the possible use of resistin levels as a biomarker for HCC development and monitoring. Furthermore, it reviews the possible pathways of HCC initiation due to elevated resistin and offers new perspectives on comprehending the fundamental mechanisms of HCC in diabetic patients. Gaining a better understanding of these processes may yield valuable insights into HCC’s development and progression, as well as identify possible avenues for prevention and therapy.
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Affiliation(s)
- Mona Mohamed Ibrahim Abdalla
- Department of Human Biology, School of Medicine, International Medical University, Bukit Jalil 57000, Kuala Lumpur, Malaysia
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van der Woude H, Hally KE, Currie MJ, Gasser O, Henry CE. Importance of the endometrial immune environment in endometrial cancer and associated therapies. Front Oncol 2022; 12:975201. [PMID: 36072799 PMCID: PMC9441707 DOI: 10.3389/fonc.2022.975201] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2022] [Accepted: 08/04/2022] [Indexed: 11/13/2022] Open
Abstract
Endometrial cancer is rising in prevalence. The standard treatment modality of hysterectomy is becoming increasingly inadequate due primarily to the direct link between endometrial cancer and high BMI which increases surgical risks. This is an immunogenic cancer, with unique molecular subtypes associated with differential immune infiltration. Despite the immunogenicity of endometrial cancer, there is limited pre-clinical and clinical evidence of the function of immune cells in both the normal and cancerous endometrium. Immune checkpoint inhibitors for endometrial cancer are the most well studied type of immune therapy but these are not currently used as standard-of-care and importantly, they represent only one method of immune manipulation. There is limited evidence regarding the use of other immunotherapies as surgical adjuvants or alternatives. Levonorgestrel-loaded intra-uterine systems can also be effective for early-stage disease, but with varying success. There is currently no known reason as to what predisposes some patients to respond while others do not. As hormones can directly influence immune cell function, it is worth investigating the immune compartment in this context. This review assesses the immunological components of the endometrium and describes how the immune microenvironment changes with hormones, obesity, and in progression to malignancy. It also describes the importance of investigating novel pathways for immunotherapy.
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Affiliation(s)
- Hannah van der Woude
- Department of Obstetrics, Gynaecology and Women’s Health, University of Otago, Wellington, New Zealand
| | | | - Margaret Jane Currie
- Department of Pathology and Biomedical Science, University of Otago, Christchurch, New Zealand
| | - Olivier Gasser
- Malaghan Institute of Medical Research, Wellington, New Zealand
| | - Claire Elizabeth Henry
- Department of Obstetrics, Gynaecology and Women’s Health, University of Otago, Wellington, New Zealand
- *Correspondence: Claire Elizabeth Henry,
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11
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Wu J, Wang M, Han L, Zhang H, Lei S, Zhang Y, Mo X. RNA modification-related variants in genomic loci associated with body mass index. Hum Genomics 2022; 16:25. [PMID: 35879730 PMCID: PMC9316745 DOI: 10.1186/s40246-022-00403-1] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2022] [Accepted: 07/16/2022] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Genome-wide association studies (GWASs) have identified hundreds of loci for body mass index (BMI), but functional variants in these loci are less known. The purpose of this study was to identify RNA modification-related SNPs (RNAm-SNPs) for BMI in GWAS loci. BMI-associated RNAm-SNPs were identified in a GWAS of approximately 700,000 individuals. Gene expression and circulating protein levels affected by the RNAm-SNPs were identified by QTL analyses. Mendelian randomization (MR) methods were applied to test whether the gene expression and protein levels were associated with BMI. RESULTS A total of 78 RNAm-SNPs associated with BMI (P < 5.0 × 10-8) were identified, including 65 m6A-, 10 m1A-, 3 m7G- and 1 A-to-I-related SNPs. Two functional loss, high confidence level m6A-SNPs, rs6713978 (P = 6.4 × 10-60) and rs13410999 (P = 8.2 × 10-59), in the intron of ADCY3 were the top significant SNPs. These two RNAm-SNPs were associated with ADCY3 gene expression in adipose tissues, whole blood cells, the tibial nerve, the tibial artery and lymphocytes, and the expression levels in these tissues were associated with BMI. Proteins enriched in specific KEGG pathways, such as natural killer cell-mediated cytotoxicity, the Rap1 signaling pathway and the Ras signaling pathway, were affected by the RNAm-SNPs, and circulating levels of some of these proteins (ADH1B, DOCK9, MICB, PRDM1, STOM, TMPRSS11D and TXNDC12) were associated with BMI in MR analyses. CONCLUSIONS Our study identified RNAm-SNPs in BMI-related genomic loci and suggested that RNA modification may affect BMI by affecting the expression levels of corresponding genes and proteins.
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Affiliation(s)
- Jingyun Wu
- Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Department of Epidemiology, School of Public Health, Soochow University, 199 Renai Road, Suzhou, 215123, Jiangsu, People's Republic of China.,Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Center for Genetic Epidemiology and Genomics, School of Public Health, Soochow University, Suzhou, China
| | - Mimi Wang
- Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Department of Epidemiology, School of Public Health, Soochow University, 199 Renai Road, Suzhou, 215123, Jiangsu, People's Republic of China.,Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Center for Genetic Epidemiology and Genomics, School of Public Health, Soochow University, Suzhou, China
| | - Limin Han
- Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Department of Epidemiology, School of Public Health, Soochow University, 199 Renai Road, Suzhou, 215123, Jiangsu, People's Republic of China.,Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Center for Genetic Epidemiology and Genomics, School of Public Health, Soochow University, Suzhou, China
| | - Huan Zhang
- Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Department of Epidemiology, School of Public Health, Soochow University, 199 Renai Road, Suzhou, 215123, Jiangsu, People's Republic of China
| | - Shufeng Lei
- Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Department of Epidemiology, School of Public Health, Soochow University, 199 Renai Road, Suzhou, 215123, Jiangsu, People's Republic of China.,Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Center for Genetic Epidemiology and Genomics, School of Public Health, Soochow University, Suzhou, China
| | - Yonghong Zhang
- Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Department of Epidemiology, School of Public Health, Soochow University, 199 Renai Road, Suzhou, 215123, Jiangsu, People's Republic of China
| | - Xingbo Mo
- Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Department of Epidemiology, School of Public Health, Soochow University, 199 Renai Road, Suzhou, 215123, Jiangsu, People's Republic of China. .,Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Center for Genetic Epidemiology and Genomics, School of Public Health, Soochow University, Suzhou, China.
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12
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Boland L, Bitterlich LM, Hogan AE, Ankrum JA, English K. Translating MSC Therapy in the Age of Obesity. Front Immunol 2022; 13:943333. [PMID: 35860241 PMCID: PMC9289617 DOI: 10.3389/fimmu.2022.943333] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2022] [Accepted: 06/10/2022] [Indexed: 12/19/2022] Open
Abstract
Mesenchymal stromal cell (MSC) therapy has seen increased attention as a possible option to treat a number of inflammatory conditions including COVID-19 acute respiratory distress syndrome (ARDS). As rates of obesity and metabolic disease continue to rise worldwide, increasing proportions of patients treated with MSC therapy will be living with obesity. The obese environment poses critical challenges for immunomodulatory therapies that should be accounted for during development and testing of MSCs. In this review, we look to cancer immunotherapy as a model for the challenges MSCs may face in obese environments. We then outline current evidence that obesity alters MSC immunomodulatory function, drastically modifies the host immune system, and therefore reshapes interactions between MSCs and immune cells. Finally, we argue that obese environments may alter essential features of allogeneic MSCs and offer potential strategies for licensing of MSCs to enhance their efficacy in the obese microenvironment. Our aim is to combine insights from basic research in MSC biology and clinical trials to inform new strategies to ensure MSC therapy is effective for a broad range of patients.
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Affiliation(s)
- Lauren Boland
- Roy J. Carver Department of Biomedical Engineering, University of Iowa, Iowa City, IA, United States
- Fraternal Order of Eagles Diabetes Research Center, University of Iowa, Iowa City, IA, United States
| | - Laura Melanie Bitterlich
- Biology Department, Maynooth University, Maynooth, Ireland
- Kathleen Lonsdale Institute for Human Health Research, Maynooth, Ireland
| | - Andrew E. Hogan
- Biology Department, Maynooth University, Maynooth, Ireland
- Kathleen Lonsdale Institute for Human Health Research, Maynooth, Ireland
| | - James A. Ankrum
- Roy J. Carver Department of Biomedical Engineering, University of Iowa, Iowa City, IA, United States
- Fraternal Order of Eagles Diabetes Research Center, University of Iowa, Iowa City, IA, United States
- *Correspondence: James A. Ankrum, ; Karen English,
| | - Karen English
- Biology Department, Maynooth University, Maynooth, Ireland
- Kathleen Lonsdale Institute for Human Health Research, Maynooth, Ireland
- *Correspondence: James A. Ankrum, ; Karen English,
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13
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NK and cells with NK-like activities in cancer immunotherapy-clinical perspectives. Med Oncol 2022; 39:131. [PMID: 35716327 DOI: 10.1007/s12032-022-01735-7] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2022] [Accepted: 04/13/2022] [Indexed: 01/10/2023]
Abstract
Natural killer (NK) cells are lymphoid cells of innate immunity that take important roles in immune surveillance. NK cells are considered as a bridge between innate and adaptive immunity, and their infiltration into tumor area is related positively with prolonged patient survival. They are defined as CD16+ CD56+ CD3- cells in clinic. NK cells promote cytolytic effects on target cells and induce their apoptosis. Loss of NK cell cytotoxic activity and reduction in the number of activating receptors are the current issues for application of such cells in cellular immunotherapy, which resulted in the diminished long-term effects. The focus of this review is to discuss about the activity of NK cells and cells with NK-like activity including natural killer T (NKT), cytokine-induced killer (CIK) and lymphokine-activated killer (LAK) cells in immunotherapy of human solid cancers.
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14
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Exercise suppresses tumor growth independent of high fat food intake and associated immune dysfunction. Sci Rep 2022; 12:5476. [PMID: 35361802 PMCID: PMC8971502 DOI: 10.1038/s41598-022-08850-5] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2019] [Accepted: 03/11/2022] [Indexed: 11/24/2022] Open
Abstract
Epidemiological data suggest that exercise training protects from cancer independent of BMI. Here, we aimed to elucidate mechanisms involved in voluntary wheel running-dependent control of tumor growth across chow and high-fat diets. Access to running wheels decreased tumor growth in B16F10 tumor-bearing on chow (− 50%) or high-fat diets (− 75%, p < 0.001), however, tumor growth was augmented in high-fat fed mice (+ 53%, p < 0.001). Tumor growth correlated with serum glucose (p < 0.01), leptin (p < 0.01), and ghrelin levels (p < 0.01), but not with serum insulin levels. Voluntary wheel running increased immune recognition of tumors as determined by microarray analysis and gene expression analysis of markers of macrophages, NK and T cells, but the induction of markers of macrophages and NK cells was attenuated with high-fat feeding. Moreover, we found that the regulator of innate immunity, ZBP1, was induced by wheel running, attenuated by high-fat feeding and associated with innate immune recognition in the B16F10 tumors. We observed no effects of ZBP1 on cell cycle arrest, or exercise-regulated necrosis in the tumors of running mice. Taken together, our data support epidemiological findings showing that exercise suppresses tumor growth independent of BMI, however, our data suggest that high-fat feeding attenuates exercise-mediated immune recognition of tumors.
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15
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Keilen J, Gar C, Rottenkolber M, Fueessl L, Joseph AT, Draenert R, Seissler J, Lechner A. No association of natural killer cell number and function in peripheral blood with overweight/obesity and metabolic syndrome in a cohort of young women. Physiol Rep 2022; 10:e15148. [PMID: 35179822 PMCID: PMC8855889 DOI: 10.14814/phy2.15148] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2021] [Revised: 11/28/2021] [Accepted: 11/30/2021] [Indexed: 06/14/2023] Open
Abstract
AIM To reexamine the associations of NK cell number and function in the peripheral blood with overweight/obesity and the metabolic syndrome in a large, well-phenotyped human cohort. METHODS Cross-sectional analysis of 273 women in the PPSDiab Study; measurement of absolute and relative number of NK cells in peripheral blood, and of functional parameters CD69 positivity and cytotoxicity against K562 cells; group comparison of NK cell characteristics between lean, overweight, and obese participants, as well as metabolic syndrome scores of 0, 1, 2, and ≥3; Spearman correlation analyses to clinical parameters related to the metabolic syndrome. RESULTS We found no differences in NK cell number and function between lean, overweight, and obese women (relative NK cell number (median (Q1-Q3), [%]) 5.1(2.6-9.4) vs. 4.8 (2.9-8.4) vs. 3.8 (1.7-7.8), p = 0.187; absolute NK cell number [106 /L]: 86.9 (44.6-188.8) vs. 92.6 (52.5-154.6) vs. 85.9 (44-153.8), p = 0.632; CD69+ [%]: 27.2 (12.9-44.3) vs. 37.6 (13.2-52.8) vs. 33.6 (16.3-45), p = 0.136; cytotoxicity [%]: 11.0 (7.1-14.5) vs. 8.5 (6.4-13.2) vs. 11.3 (8.7-14.2), p = 0.094), as well as between different metabolic syndrome scores. Nonesterified fatty acids correlated with absolute and relative NK cell number and cytotoxicity (ρ [p-value]: 0.142 [0.021], 0.119 [0.049], and 0.131 [0.035], respectively). Relative NK cell number further correlated with high-density lipoprotein cholesterol (0.144 [0.018]) and cytotoxicity with 2 h glucose in oral glucose tolerance testing (0.132 [0.034]). CD69 positivity correlated with body fat (0.141 [0.021]), triglycerides (0.129 [0.033]), and plasma leptin (0.155 [0.010]). After correction for multiple testing, none of the associations remained significant. CONCLUSION In the present study, we observed no associations of NK cell number and function in the peripheral blood with overweight/obesity and the metabolic syndrome. Extreme phenotypes of obesity and the metabolic syndrome might have caused differing results in previous studies. Further analyses with a focus on compartments other than peripheral blood may help to clarify the relation between NK cells and metabolic diseases.
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Affiliation(s)
- Julia Keilen
- Diabetes Research GroupDepartment of Medicine IVUniversity HospitalLMU MunichMunichGermany
- Clinical Cooperation Group DiabetesLudwig‐Maximilians‐Universität München and Helmholtz Zentrum MünchenMunichGermany
- German Center for Diabetes Research (DZD)München‐NeuherbergGermany
| | - Christina Gar
- Diabetes Research GroupDepartment of Medicine IVUniversity HospitalLMU MunichMunichGermany
- Clinical Cooperation Group DiabetesLudwig‐Maximilians‐Universität München and Helmholtz Zentrum MünchenMunichGermany
- German Center for Diabetes Research (DZD)München‐NeuherbergGermany
| | - Marietta Rottenkolber
- Diabetes Research GroupDepartment of Medicine IVUniversity HospitalLMU MunichMunichGermany
- Clinical Cooperation Group DiabetesLudwig‐Maximilians‐Universität München and Helmholtz Zentrum MünchenMunichGermany
- German Center for Diabetes Research (DZD)München‐NeuherbergGermany
| | - Louise U. Fueessl
- Diabetes Research GroupDepartment of Medicine IVUniversity HospitalLMU MunichMunichGermany
- Clinical Cooperation Group DiabetesLudwig‐Maximilians‐Universität München and Helmholtz Zentrum MünchenMunichGermany
- German Center for Diabetes Research (DZD)München‐NeuherbergGermany
| | - Anna T. Joseph
- Diabetes Research GroupDepartment of Medicine IVUniversity HospitalLMU MunichMunichGermany
- Clinical Cooperation Group DiabetesLudwig‐Maximilians‐Universität München and Helmholtz Zentrum MünchenMunichGermany
- German Center for Diabetes Research (DZD)München‐NeuherbergGermany
| | - Rika Draenert
- Stabsstelle Antibiotic StewardshipLMU Klinikum MunichMunichGermany
| | - Jochen Seissler
- Diabetes Research GroupDepartment of Medicine IVUniversity HospitalLMU MunichMunichGermany
- Clinical Cooperation Group DiabetesLudwig‐Maximilians‐Universität München and Helmholtz Zentrum MünchenMunichGermany
- German Center for Diabetes Research (DZD)München‐NeuherbergGermany
| | - Andreas Lechner
- Diabetes Research GroupDepartment of Medicine IVUniversity HospitalLMU MunichMunichGermany
- Clinical Cooperation Group DiabetesLudwig‐Maximilians‐Universität München and Helmholtz Zentrum MünchenMunichGermany
- German Center for Diabetes Research (DZD)München‐NeuherbergGermany
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16
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Bähr I, Jaeschke L, Nimptsch K, Janke J, Herrmann P, Kobelt D, Kielstein H, Pischon T, Stein U. Obesity, colorectal cancer and MACC1 expression: A possible novel molecular association. Int J Oncol 2022; 60:17. [PMID: 35014688 PMCID: PMC8776326 DOI: 10.3892/ijo.2022.5307] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2021] [Accepted: 12/06/2021] [Indexed: 11/23/2022] Open
Abstract
Obesity is a major and increasing public health concern, associated with an increased risk of and mortality from several types of cancer including colorectal cancer (CRC), being associated with cancer progression, metastasis and resistance to therapy. It was hypothesized that the expression of cancer/metastasis-inducing gene metastasis-associated in colon cancer 1 (MACC1) is increased in obesity, which may constitute a link to obesity-induced cancer. The present study thus analyzed circulating cell-free plasma MACC1 expression levels in human obese (vs. normal weight) adult individuals from independent studies, namely the Martin Luther University (MLU) study (n=32) and the Metabolic syndrome study (MetScan, Berlin) (n=191). Higher plasma MACC1 levels were found in obese individuals, increasing with a greater body fat mass and body mass index; these levels were predominantly observed in male and to a lesser extent in female individuals, although the results were not significant. A reduction in body fat mass following dietary intervention and physical exercise decreased the MACC1 expression levels in the MLU study. Furthermore, Wistar rats with diet-induced obesity exhibited slightly increased plasma MACC1 levels compared with rats of normal weight. The obese Wistar rats exposed to azoxymethane to induce colon cancer exhibited a more severe colon tumor outcome, which was associated with significantly increased MACC1 levels compared with their non-obese littermates. On the whole, the findings of the present study suggest an association between MACC1 and obesity, as well as with obesity-induced CRC.
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Affiliation(s)
- Ina Bähr
- Institute of Anatomy and Cell Biology, Medical Faculty of Martin Luther University Halle‑Wittenberg, D‑06108 Halle (Saale), Germany
| | - Lina Jaeschke
- Max‑Delbrück‑Center for Molecular Medicine in The Helmholtz Association, Molecular Epidemiology Research Group, D‑13125 Berlin, Germany
| | - Katharina Nimptsch
- Max‑Delbrück‑Center for Molecular Medicine in The Helmholtz Association, Molecular Epidemiology Research Group, D‑13125 Berlin, Germany
| | - Jürgen Janke
- Max‑Delbrück‑Center for Molecular Medicine in The Helmholtz Association, Molecular Epidemiology Research Group, D‑13125 Berlin, Germany
| | - Pia Herrmann
- Translational Oncology of Solid Tumors, Experimental and Clinical Research Center, Charité‑Universitätsmedizin Berlin and Max‑Delbrück‑Center for Molecular Medicine in The Helmholtz Association, D‑13125 Berlin, Germany
| | - Dennis Kobelt
- Translational Oncology of Solid Tumors, Experimental and Clinical Research Center, Charité‑Universitätsmedizin Berlin and Max‑Delbrück‑Center for Molecular Medicine in The Helmholtz Association, D‑13125 Berlin, Germany
| | - Heike Kielstein
- Institute of Anatomy and Cell Biology, Medical Faculty of Martin Luther University Halle‑Wittenberg, D‑06108 Halle (Saale), Germany
| | - Tobias Pischon
- Max‑Delbrück‑Center for Molecular Medicine in The Helmholtz Association, Molecular Epidemiology Research Group, D‑13125 Berlin, Germany
| | - Ulrike Stein
- Translational Oncology of Solid Tumors, Experimental and Clinical Research Center, Charité‑Universitätsmedizin Berlin and Max‑Delbrück‑Center for Molecular Medicine in The Helmholtz Association, D‑13125 Berlin, Germany
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Saitoh S, Van Wijk K, Nakajima O. Crosstalk between Metabolic Disorders and Immune Cells. Int J Mol Sci 2021; 22:ijms221810017. [PMID: 34576181 PMCID: PMC8469678 DOI: 10.3390/ijms221810017] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2021] [Revised: 09/08/2021] [Accepted: 09/15/2021] [Indexed: 12/22/2022] Open
Abstract
Metabolic syndrome results from multiple risk factors that arise from insulin resistance induced by abnormal fat deposition. Chronic inflammation owing to obesity primarily results from the recruitment of pro-inflammatory M1 macrophages into the adipose tissue stroma, as the adipocytes within become hypertrophied. During obesity-induced inflammation in adipose tissue, pro-inflammatory cytokines are produced by macrophages and recruit further pro-inflammatory immune cells into the adipose tissue to boost the immune response. Here, we provide an overview of the biology of macrophages in adipose tissue and the relationship between other immune cells, such as CD4+ T cells, natural killer cells, and innate lymphoid cells, and obesity and type 2 diabetes. Finally, we discuss the link between the human pathology and immune response and metabolism and further highlight potential therapeutic targets for the treatment of metabolic disorders.
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Affiliation(s)
- Shinichi Saitoh
- Department of Immunology, Yamagata University Faculty of Medicine, Yamagata 990-9585, Japan;
| | - Koen Van Wijk
- Research Center for Molecular Genetics, Institute for Promotion of Medical Science Research, Yamagata University Faculty of Medicine, Yamagata 990-9585, Japan;
| | - Osamu Nakajima
- Research Center for Molecular Genetics, Institute for Promotion of Medical Science Research, Yamagata University Faculty of Medicine, Yamagata 990-9585, Japan;
- Correspondence:
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18
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Han S, Jung M, Kim AS, Lee DY, Cha BH, Putnam CW, Lim KS, Bull DA, Won YW. Peptide Adjuvant to Invigorate Cytolytic Activity of NK Cells in an Obese Mouse Cancer Model. Pharmaceutics 2021; 13:pharmaceutics13081279. [PMID: 34452238 PMCID: PMC8401452 DOI: 10.3390/pharmaceutics13081279] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2021] [Revised: 07/08/2021] [Accepted: 07/09/2021] [Indexed: 11/24/2022] Open
Abstract
Cancer patients who are overweight compared to those with normal body weight have obesity-associated alterations of natural killer (NK) cells, characterized by poor cytotoxicity, slow proliferation, and inadequate anti-cancer activity. Concomitantly, prohibitin overexpressed by cancer cells elevates glucose metabolism, rendering the tumor microenvironment (TME) more tumor-favorable, and leading to malfunction of immune cells present in the TME. These changes cause vicious cycles of tumor growth. Adoptive immunotherapy has emerged as a promising option for cancer patients; however, obesity-related alterations in the TME allow the tumor to bypass immune surveillance and to down-regulate the activity of adoptively transferred NK cells. We hypothesized that inhibiting the prohibitin signaling pathway in an obese model would reduce glucose metabolism of cancer cells, thereby changing the TME to a pro-immune microenvironment and restoring the cytolytic activity of NK cells. Priming tumor cells with an inhibitory the prohibitin-binding peptide (PBP) enhances cytokine secretion and augments the cytolytic activity of adoptively transferred NK cells. NK cells harvested from the PBP-primed tumors exhibit multiple markers associated with the effector function of active NK cells. Our findings suggest that PBP has the potential as an adjuvant to enhance the cytolytic activity of adoptively transferred NK cells in cancer patients with obesity.
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Affiliation(s)
- Seungmin Han
- Division of Cardiothoracic Surgery, Department of Surgery, University of Arizona College of Medicine—Tucson, Tucson, AZ 85724, USA; (S.H.); (M.J.); (A.S.K.); (D.Y.L.); (B.-H.C.); (C.W.P.); (D.A.B.)
| | - Minjin Jung
- Division of Cardiothoracic Surgery, Department of Surgery, University of Arizona College of Medicine—Tucson, Tucson, AZ 85724, USA; (S.H.); (M.J.); (A.S.K.); (D.Y.L.); (B.-H.C.); (C.W.P.); (D.A.B.)
| | - Angela S. Kim
- Division of Cardiothoracic Surgery, Department of Surgery, University of Arizona College of Medicine—Tucson, Tucson, AZ 85724, USA; (S.H.); (M.J.); (A.S.K.); (D.Y.L.); (B.-H.C.); (C.W.P.); (D.A.B.)
| | - Daniel Y. Lee
- Division of Cardiothoracic Surgery, Department of Surgery, University of Arizona College of Medicine—Tucson, Tucson, AZ 85724, USA; (S.H.); (M.J.); (A.S.K.); (D.Y.L.); (B.-H.C.); (C.W.P.); (D.A.B.)
| | - Byung-Hyun Cha
- Division of Cardiothoracic Surgery, Department of Surgery, University of Arizona College of Medicine—Tucson, Tucson, AZ 85724, USA; (S.H.); (M.J.); (A.S.K.); (D.Y.L.); (B.-H.C.); (C.W.P.); (D.A.B.)
| | - Charles W. Putnam
- Division of Cardiothoracic Surgery, Department of Surgery, University of Arizona College of Medicine—Tucson, Tucson, AZ 85724, USA; (S.H.); (M.J.); (A.S.K.); (D.Y.L.); (B.-H.C.); (C.W.P.); (D.A.B.)
| | - Kwang Suk Lim
- Interdisciplinary Program in Biohealth-Machinery Convergence Engineering, Department of Biotechnology and Bioengineering, College of Art, Culture and Engineering, Kangwon National University, Chuncheon 24341, Korea;
| | - David A. Bull
- Division of Cardiothoracic Surgery, Department of Surgery, University of Arizona College of Medicine—Tucson, Tucson, AZ 85724, USA; (S.H.); (M.J.); (A.S.K.); (D.Y.L.); (B.-H.C.); (C.W.P.); (D.A.B.)
| | - Young-Wook Won
- Division of Cardiothoracic Surgery, Department of Surgery, University of Arizona College of Medicine—Tucson, Tucson, AZ 85724, USA; (S.H.); (M.J.); (A.S.K.); (D.Y.L.); (B.-H.C.); (C.W.P.); (D.A.B.)
- Correspondence:
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19
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Elaraby E, Malek AI, Abdullah HW, Elemam NM, Saber-Ayad M, Talaat IM. Natural Killer Cell Dysfunction in Obese Patients with Breast Cancer: A Review of a Triad and Its Implications. J Immunol Res 2021; 2021:9972927. [PMID: 34212054 PMCID: PMC8205589 DOI: 10.1155/2021/9972927] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2021] [Revised: 05/04/2021] [Accepted: 05/19/2021] [Indexed: 12/11/2022] Open
Abstract
Natural killer cells (NK cells) are a crucial constituent of the innate immune system as they mediate immunity against viruses, bacteria, parasites, and most importantly, tumor cells. The exact mechanism of how the innate immune system and specifically NK cells interact with cancer cells is complex and is yet to be understood. Several factors that constitute the tumor microenvironment (TME) such as hypoxia and TGF-β are believed to play a role in the complex physiological reaction of NK cells to tumor cells. On the other hand, several risk factors are implicated in the development and progression of breast cancer, most importantly: obesity. Cytokines released from adipose tissue such as adipokines, leptin, and resistin, among others, are also believed to facilitate tumor progression. In this study, we aimed to build a triad of breast cancer, obesity, and NK cell dysfunction to elucidate a link between these pillars on a cellular level. Directing efforts towards solidifying the link between these factors will help in designing a targeted immunotherapy with a low side-effect profile that can revolutionize breast cancer treatment and improve survival in obese patients.
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Affiliation(s)
- Esraa Elaraby
- College of Medicine, University of Sharjah, Sharjah, UAE
| | | | | | - Noha Mousaad Elemam
- College of Medicine, University of Sharjah, Sharjah, UAE
- Sharjah Institute for Medical Research, University of Sharjah, Sharjah, UAE
| | - Maha Saber-Ayad
- College of Medicine, University of Sharjah, Sharjah, UAE
- Sharjah Institute for Medical Research, University of Sharjah, Sharjah, UAE
- Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Iman M. Talaat
- College of Medicine, University of Sharjah, Sharjah, UAE
- Sharjah Institute for Medical Research, University of Sharjah, Sharjah, UAE
- Faculty of Medicine, Alexandria University, Alexandria, Egypt
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20
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Immunosurveillance of Cancer and Viral Infections with Regard to Alterations of Human NK Cells Originating from Lifestyle and Aging. Biomedicines 2021; 9:biomedicines9050557. [PMID: 34067700 PMCID: PMC8156987 DOI: 10.3390/biomedicines9050557] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2021] [Revised: 04/29/2021] [Accepted: 05/14/2021] [Indexed: 01/22/2023] Open
Abstract
Natural killer (NK) cells are cytotoxic immune cells with an innate capacity for eliminating cancer cells and virus- infected cells. NK cells are critical effector cells in the immunosurveillance of cancer and viral infections. Patients with low NK cell activity or NK cell deficiencies are predisposed to increased risks of cancer and severe viral infections. However, functional alterations of human NK cells are associated with lifestyles and aging. Personal lifestyles, such as cigarette smoking, alcohol consumption, stress, obesity, and aging are correlated with NK cell dysfunction, whereas adequate sleep, moderate exercise, forest bathing, and listening to music are associated with functional healthy NK cells. Therefore, adherence to a healthy lifestyle is essential and will be favorable for immunosurveillance of cancer and viral infections with healthy NK cells.
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21
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Jacquelot N, Belz GT, Seillet C. Neuroimmune Interactions and Rhythmic Regulation of Innate Lymphoid Cells. Front Neurosci 2021; 15:657081. [PMID: 33994930 PMCID: PMC8116950 DOI: 10.3389/fnins.2021.657081] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2021] [Accepted: 03/29/2021] [Indexed: 01/21/2023] Open
Abstract
The Earth’s rotation around its axis, is one of the parameters that never changed since life emerged. Therefore, most of the organisms from the cyanobacteria to humans have conserved natural oscillations to regulate their physiology. These daily oscillations define the circadian rhythms that set the biological clock for almost all physiological processes of an organism. They allow the organisms to anticipate and respond behaviorally and physiologically to changes imposed by the day/night cycle. As other physiological systems, the immune system is also regulated by circadian rhythms and while diurnal variation in host immune responses to lethal infection have been observed for many decades, the underlying mechanisms that affect immune function and health have only just started to emerge. These oscillations are generated by the central clock in our brain, but neuroendocrine signals allow the synchronization of the clocks in peripheral tissues. In this review, we discuss how the neuroimmune interactions create a rhythmic activity of the innate lymphoid cells. We highlight how the disruption of these rhythmic regulations of immune cells can disturb homeostasis and lead to the development of chronic inflammation in murine models.
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Affiliation(s)
- Nicolas Jacquelot
- Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia.,Department of Medical Biology, University of Melbourne, Parkville, VIC, Australia
| | - Gabrielle T Belz
- Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia.,Department of Medical Biology, University of Melbourne, Parkville, VIC, Australia.,Diamantina Institute, The University of Queensland, Woolloongabba, QLD, Australia
| | - Cyril Seillet
- Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia.,Department of Medical Biology, University of Melbourne, Parkville, VIC, Australia
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22
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Andrade FB, Gualberto A, Rezende C, Percegoni N, Gameiro J, Hottz ED. The Weight of Obesity in Immunity from Influenza to COVID-19. Front Cell Infect Microbiol 2021; 11:638852. [PMID: 33816341 PMCID: PMC8011498 DOI: 10.3389/fcimb.2021.638852] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2020] [Accepted: 02/19/2021] [Indexed: 12/15/2022] Open
Abstract
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has emerged in December 2019 and rapidly outspread worldwide endangering human health. The coronavirus disease 2019 (COVID-19) manifests itself through a wide spectrum of symptoms that can evolve to severe presentations as pneumonia and several non-respiratory complications. Increased susceptibility to COVID-19 hospitalization and mortality have been linked to associated comorbidities as diabetes, hypertension, cardiovascular diseases and, recently, to obesity. Similarly, individuals living with obesity are at greater risk to develop clinical complications and to have poor prognosis in severe influenza pneumonia. Immune and metabolic dysfunctions associated with the increased susceptibility to influenza infection are linked to obesity-associated low-grade inflammation, compromised immune and endocrine systems, and to high cardiovascular risk. These preexisting conditions may favor virological persistence, amplify immunopathological responses and worsen hemodynamic instability in severe COVID-19 as well. In this review we highlight the main factors and the current state of the art on obesity as risk factor for influenza and COVID-19 hospitalization, severe respiratory manifestations, extrapulmonary complications and even death. Finally, immunoregulatory mechanisms of severe influenza pneumonia in individuals with obesity are addressed as likely factors involved in COVID-19 pathophysiology.
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Affiliation(s)
- Fernanda B. Andrade
- Laboratory of Immunothrombosis, Department of Biochemistry, Institute of Biological Sciences, Federal University of Juiz de Fora, Juiz de Fora, Brazil
| | - Ana Gualberto
- Laboratory of Immunology, Obesity and Infectious Diseases, Department of Parasitology, Microbiology and Immunology, Institute of Biological Sciences, Federal University of Juiz de Fora, Juiz de Fora, Brazil
| | - Camila Rezende
- Department of Nutrition, Institute of Biological Sciences, Federal University of Juiz de Fora, Juiz de Fora, Brazil
| | - Nathércia Percegoni
- Department of Nutrition, Institute of Biological Sciences, Federal University of Juiz de Fora, Juiz de Fora, Brazil
| | - Jacy Gameiro
- Laboratory of Immunology, Obesity and Infectious Diseases, Department of Parasitology, Microbiology and Immunology, Institute of Biological Sciences, Federal University of Juiz de Fora, Juiz de Fora, Brazil
| | - Eugenio D. Hottz
- Laboratory of Immunothrombosis, Department of Biochemistry, Institute of Biological Sciences, Federal University of Juiz de Fora, Juiz de Fora, Brazil
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23
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Li Y, Wang F, Imani S, Tao L, Deng Y, Cai Y. Natural Killer Cells: Friend or Foe in Metabolic Diseases? Front Immunol 2021; 12:614429. [PMID: 33717101 PMCID: PMC7943437 DOI: 10.3389/fimmu.2021.614429] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2020] [Accepted: 01/12/2021] [Indexed: 12/12/2022] Open
Abstract
The worldwide epidemic of metabolic diseases, especially obesity and other diseases caused by it, has shown a dramatic increase in incidence. A great deal of attention has been focused on the underlying mechanisms of these pathological processes and potential strategies to solve these problems. Chronic inflammation initiated by abdominal adipose tissues and immune cell activation in obesity is the major cause of the consequent development of complications. In addition to adipocytes, macrophages and monocytes, natural killer (NK) cells have been verified to be vital components involved in shaping the inflammatory microenvironment, thereby leading to various obesity-related metabolic diseases. Here, we provide an overview of the roles of NK cells and the interactions of these cells with other immune and nonimmune cells in the pathological processes of metabolic diseases. Finally, we also discuss potential therapeutic strategies targeting NK cells to treat metabolic diseases.
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Affiliation(s)
- Yi Li
- Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, China.,Student Brigade, Preclinical School of Medicine, The Fourth Military Medical University, Xi'an, China.,Department of Anesthesiology and Perioperative Medicine, Xijing Hospital, The Fourth Military Medical University, Xi'an, China
| | - Fangjie Wang
- State Key Laboratory of Trauma, Burns and Combined Injury, Department of Wound Infection and Drug, Daping Hospital, Army Medical University (Third Military Medical University), Chongqing, China
| | - Saber Imani
- Department of Oncology, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Ling Tao
- Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, China
| | - Youcai Deng
- Institute of Materia Medica, College of Pharmacy, Army Medical University (Third Military Medical University), Chongqing, China
| | - Yue Cai
- Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, China
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24
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Yoon KJ, Ahn A, Park SH, Kwak SH, Kwak SE, Lee W, Yang YR, Kim M, Shin HM, Kim HR, Moon HY. Exercise reduces metabolic burden while altering the immune system in aged mice. Aging (Albany NY) 2021; 13:1294-1313. [PMID: 33406502 PMCID: PMC7834985 DOI: 10.18632/aging.202312] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2020] [Accepted: 11/13/2020] [Indexed: 02/06/2023]
Abstract
Although several evidence has suggested the impact of exercise on the prevention of aging phenotypes, few studies have been conducted on the mechanism by which exercise alters the immune-cell profile, thereby improving metabolism in senile obesity. In this study, we confirmed that 4-week treadmill exercise sufficiently improved metabolic function, including increased lean mass and decreased fat mass, in 88-week-old mice. The expression level of the senescence marker p16 in the white adipose tissue (WAT) was decreased after 4-weeks of exercise. Exercise induced changes in the profiles of immune-cell subsets, including natural killer (NK) cells, central memory CD8+ T cells, eosinophils, and neutrophils, in the stromal vascular fraction of WAT. In addition, it has been shown through transcriptome analysis of WAT that exercise can activate pathways involved in the interaction between WAT and immune cells, in particular NK cells, in aged mice. These results suggest that exercise has a profound effect on changes in immune-cell distribution and senescent-cell scavenging in WAT of aged mice, eventually affecting overall energy metabolism toward a more youthful state.
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Affiliation(s)
- Kyeong Jin Yoon
- Department of Physical Education, Seoul National University, Gwanak-ro, Gwanak-gu, Seoul, Republic of Korea.,Institute of Sport Science, Seoul National University, Gwanak-ro, Gwanak-gu, Seoul, Republic of Korea
| | - Aram Ahn
- Department of Kinesiology, University of Connecticut, Storrs, CT 06269,USA
| | - Soo Hong Park
- Department of Physical Education, Seoul National University, Gwanak-ro, Gwanak-gu, Seoul, Republic of Korea.,Institute of Sport Science, Seoul National University, Gwanak-ro, Gwanak-gu, Seoul, Republic of Korea
| | - Seung Hee Kwak
- Department of Physical Education, Seoul National University, Gwanak-ro, Gwanak-gu, Seoul, Republic of Korea.,Institute of Sport Science, Seoul National University, Gwanak-ro, Gwanak-gu, Seoul, Republic of Korea
| | - Seong Eun Kwak
- Department of Physical Education, Seoul National University, Gwanak-ro, Gwanak-gu, Seoul, Republic of Korea.,School of Kinesiology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Wonsang Lee
- Department of Physical Education, Seoul National University, Gwanak-ro, Gwanak-gu, Seoul, Republic of Korea.,Institute of Sport Science, Seoul National University, Gwanak-ro, Gwanak-gu, Seoul, Republic of Korea
| | - Yong Ryoul Yang
- Aging Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Republic of Korea
| | - Minji Kim
- Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea.,Wide River Institute of Immunology, Seoul National University, Hongcheon, Republic of Korea
| | - Hyun Mu Shin
- Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea.,Wide River Institute of Immunology, Seoul National University, Hongcheon, Republic of Korea
| | - Hang-Rae Kim
- Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea.,BK21Plus Biomedical Science Project, Seoul National University College of Medicine, Seoul, Republic of Korea.,Medical Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea.,Wide River Institute of Immunology, Seoul National University, Hongcheon, Republic of Korea
| | - Hyo Youl Moon
- Department of Physical Education, Seoul National University, Gwanak-ro, Gwanak-gu, Seoul, Republic of Korea.,Institute of Sport Science, Seoul National University, Gwanak-ro, Gwanak-gu, Seoul, Republic of Korea.,Institute on Aging, Seoul National University, Gwanak-ro, Gwanak-gu, Seoul, Republic of Korea
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25
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Lipid Metabolism in Tumor-Associated Natural Killer Cells. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2021; 1316:71-85. [PMID: 33740244 DOI: 10.1007/978-981-33-6785-2_5] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Accumulative data demonstrate that during the initiation and progression of tumors, several types of cellular components in tumor microenvironment, including tumor cells and immune cells, exhibit malfunctions in cellular energy metabolism. For instance, lipid metabolism impairments in immune cells are crucial in coordinating immunosuppression and tumor immune escape. In particular, excessive lipids have been shown to exhibit negative effects on innate immunity. Previous studies on lipid metabolism in immune cells are mainly focused on macrophages and T lymphocytes. Although natural killer (NK) cells are major players in the innate elimination of virus, bacteria, and tumor cells, available literature reports related with lipid metabolism in NK cells and tumor-associated NK (TANK) cells are very sparse. Despite these, the importance and clinical relevance of the crosstalk among lipid metabolism, NK/TANK cells, and tumors have been clearly indicated. In this chapter, following a general description of NK and TANK cells, our knowledge on the regulation of lipid metabolism in NK cells is reviewed, with an emphasis on the roles of mTOR and SREBP signaling. Then the interactions between lipid metabolism and NK/TANK cells under pathological conditions, e.g., obesity and cancer, were carefully introduced. As there is an urgent need to reveal more regulators and to clarify detailed molecular mechanisms by which lipid metabolism interacts with NK/TANK cells, several categories of potential regulators/pathways, as well as the challenges and perspectives in this emerging field, are discussed.
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26
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Spielmann J, Naujoks W, Emde M, Allweyer M, Kielstein H, Quandt D, Bähr I. High-Fat Diet and Feeding Regime Impairs Number, Phenotype, and Cytotoxicity of Natural Killer Cells in C57BL/6 Mice. Front Nutr 2020; 7:585693. [PMID: 33330585 PMCID: PMC7728990 DOI: 10.3389/fnut.2020.585693] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2020] [Accepted: 10/22/2020] [Indexed: 12/14/2022] Open
Abstract
Overweight and obesity are major public health challenges worldwide. Obesity is associated with a higher risk for the development of several cancer types, but specific mechanisms underlying the link of obesity and cancer are still unclear. Natural killer (NK) cells are circulating lymphoid cells promoting the elimination of virus-infected and tumor cells. Previous investigations demonstrated conflicting results concerning the influence of obesity on functional NK cell parameters in small animal models. The aim of the present study was to clarify potential obesity-associated alterations of murine NK cells in vivo, implementing different feeding regimes. Therefore, C57BL/6 mice were fed a normal-fat diet (NFD) or high-fat diet (HFD) under restrictive and ad libitum feeding regimes. Results showed diet and feeding-regime dependent differences in body weight, visceral fat mass and plasma cytokine concentrations. Flow cytometry analyses demonstrated significant changes in total cell counts as well as frequencies of immune cell populations in peripheral blood comparing mice fed NFD or HFD in an ad libitum or restrictive manner. Mice fed the HFD showed significantly decreased frequencies of total NK cells and the mature CD11b+CD27+ NK cell subset compared to mice fed the NFD. Feeding HFD resulted in significant changes in the expression of the maturation markers KLRG1 and CD127 in NK cells. Furthermore, real-time PCR analyses of NK-cell related functional parameters in adipose tissue revealed significant diet and feeding-regime dependent differences. Most notable, real-time cytotoxicity assays demonstrated an impaired cytolytic activity of splenic NK cells toward murine colon cancer cells in HFD-fed mice compared to NFD-fed mice. In conclusion, our data demonstrate that feeding a high-fat diet influences the frequency, phenotype and function of NK cells in C57BL/6 mice. Interestingly, restricted feeding of HFD compared to ad libitum feeding resulted in a partial prevention of the obesity-associated alterations on immune cells and especially on NK cells, nicely fitting with the current concept of an advantage for interval fasting for improved health.
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Affiliation(s)
- Julia Spielmann
- Institute of Anatomy and Cell Biology, Medical Faculty of Martin Luther University Halle-Wittenberg, Halle (Saale), Germany
| | - Wiebke Naujoks
- Institute of Anatomy and Cell Biology, Medical Faculty of Martin Luther University Halle-Wittenberg, Halle (Saale), Germany
| | - Matthias Emde
- Institute of Anatomy and Cell Biology, Medical Faculty of Martin Luther University Halle-Wittenberg, Halle (Saale), Germany
| | - Martin Allweyer
- Institute of Anatomy and Cell Biology, Medical Faculty of Martin Luther University Halle-Wittenberg, Halle (Saale), Germany
| | - Heike Kielstein
- Institute of Anatomy and Cell Biology, Medical Faculty of Martin Luther University Halle-Wittenberg, Halle (Saale), Germany
| | - Dagmar Quandt
- Institute of Anatomy and Cell Biology, Medical Faculty of Martin Luther University Halle-Wittenberg, Halle (Saale), Germany.,School of Medicine, College of Medicine, Nursing and Health Sciences, Regenerative Medicine Institute (REMEDI) at CÚRAM Centre for Research in Medical Devices, National University of Ireland Galway, Galway, Ireland
| | - Ina Bähr
- Institute of Anatomy and Cell Biology, Medical Faculty of Martin Luther University Halle-Wittenberg, Halle (Saale), Germany
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27
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Spielmann J, Mattheis L, Jung JS, Rauße H, Glaß M, Bähr I, Quandt D, Oswald J, Kielstein H. Effects of obesity on NK cells in a mouse model of postmenopausal breast cancer. Sci Rep 2020; 10:20606. [PMID: 33244094 PMCID: PMC7692502 DOI: 10.1038/s41598-020-76906-5] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2020] [Accepted: 11/03/2020] [Indexed: 02/07/2023] Open
Abstract
Obesity is a widely spread disease and a crucial risk factor for malign disorders, including breast cancer of women in the postmenopause. Studies demonstrated that in case of obesity crucial natural killer (NK) cell functions like combating tumor cells are affected. This study aims to analyze NK cells and NK cell receptor expression of obese mice in a model for postmenopausal breast cancer. Therefore, female BALB/c mice were fed either a high fat or a standard diet. Thereafter, ovaries were ectomized and a syngeneic and orthotopical injection of 4T1-luc2 mouse mammary tumor cells into the mammary adipose tissue pad was performed. Obese mice showed increased body weights and visceral fat mass as well as increased levels of leptin and IL-6 in plasma. Moreover, compared to the lean littermates, tumor growth was increased and the NKp46-expression on circulating NK cells was decreased. Furthermore, the activating NK cell receptor NKG2D ligand (MULT1) expression was enhanced in adipose tissue of obese tumor bearing mice. The present study gives novel insights into gene expression of NK cell receptors in obesity and aims to promote possible links of the obesity-impaired NK cell physiology and the elevated breast cancer risk in obese women.
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Affiliation(s)
- Julia Spielmann
- Institute of Anatomy and Cell Biology, Medical Faculty of Martin Luther University Halle-Wittenberg, Grosse Steinstrasse 52, 06108, Halle (Saale), Germany.
| | - Laura Mattheis
- Institute of Anatomy and Cell Biology, Medical Faculty of Martin Luther University Halle-Wittenberg, Grosse Steinstrasse 52, 06108, Halle (Saale), Germany
- Deptartment of Internal Medicine I, Medical Faculty of Martin Luther University Halle-Wittenberg, Halle (Saale), Germany
| | - Juliane-Susanne Jung
- Institute of Anatomy and Cell Biology, Medical Faculty of Martin Luther University Halle-Wittenberg, Grosse Steinstrasse 52, 06108, Halle (Saale), Germany
| | - Henrik Rauße
- Institute of Anatomy and Cell Biology, Medical Faculty of Martin Luther University Halle-Wittenberg, Grosse Steinstrasse 52, 06108, Halle (Saale), Germany
- Clinic for Psychosomatics and Psychotherapy, Landschaftsverband Westfalen-Lippe Clinic, Lengerich, Germany
| | - Markus Glaß
- Institute of Molecular Medicine, Charles Tanford Protein Center, Medical Faculty of Martin Luther University Halle-Wittenberg, Halle (Saale), Germany
| | - Ina Bähr
- Institute of Anatomy and Cell Biology, Medical Faculty of Martin Luther University Halle-Wittenberg, Grosse Steinstrasse 52, 06108, Halle (Saale), Germany
| | - Dagmar Quandt
- Institute of Anatomy and Cell Biology, Medical Faculty of Martin Luther University Halle-Wittenberg, Grosse Steinstrasse 52, 06108, Halle (Saale), Germany
- Regenerative Medicine Institute (REMEDI) at CÚRAM Centre for Research in Medical Devices, School of Medicine, College of Medicine, Nursing and Health Sciences, National University of Ireland, Galway, Ireland
| | - Jana Oswald
- Institute of Anatomy and Cell Biology, Medical Faculty of Martin Luther University Halle-Wittenberg, Grosse Steinstrasse 52, 06108, Halle (Saale), Germany
| | - Heike Kielstein
- Institute of Anatomy and Cell Biology, Medical Faculty of Martin Luther University Halle-Wittenberg, Grosse Steinstrasse 52, 06108, Halle (Saale), Germany
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28
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Naujoks W, Quandt D, Hauffe A, Kielstein H, Bähr I, Spielmann J. Characterization of Surface Receptor Expression and Cytotoxicity of Human NK Cells and NK Cell Subsets in Overweight and Obese Humans. Front Immunol 2020; 11:573200. [PMID: 33101297 PMCID: PMC7546782 DOI: 10.3389/fimmu.2020.573200] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2020] [Accepted: 08/17/2020] [Indexed: 12/14/2022] Open
Abstract
Obesity is associated with an increased risk for several cancer types and an altered phenotype and functionality of natural killer (NK) cells. This study aimed to investigate the association of overweight and obesity with NK cell functions and receptor expression profiles in humans. Therefore, peripheral blood mononuclear cells were isolated from normal weight, overweight, and obese healthy blood donors. In depth analysis of immune cell populations and 23 different surface markers, including NK cell receptors, NK-cell-related markers as well as functional intracellular markers on total NK cells and NK subgroups were performed by multicolor flow cytometry. The data revealed a decreased expression of the activating NK cell receptors KIR2DS4 and NKp46 as well as an increased expression of the inhibitory NK cell receptors NKG2A and Siglec-7 in overweight and obese compared to normal weight individuals. Additionally, the expression of the adhesion molecule CD62L and the maturation and differentiation marker CD27 was downregulated in NK cells of overweight and obese subjects. Furthermore, the cytotoxicity of NK cells against colorectal cancer cells was decreased in overweight and obese subjects. Investigations on underlying killing mechanisms demonstrated a reduced TRAIL expression on NK cells of obese subjects suggesting an impaired death receptor pathway in obesity. The present study gives new insights into an impaired functionality and phenotype of NK cells and NK cell subsets in overweight and obesity. These phenotypic alterations and dysfunction of NK cells might be an explanation for the increased cancer risk in obesity.
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Affiliation(s)
- Wiebke Naujoks
- Institute of Anatomy and Cell Biology, Medical Faculty of Martin Luther University Halle-Wittenberg, Halle (Saale), Germany
| | - Dagmar Quandt
- Institute of Anatomy and Cell Biology, Medical Faculty of Martin Luther University Halle-Wittenberg, Halle (Saale), Germany.,Regenerative Medicine Institute (REMEDI) at CÚRAM Centre for Research in Medical Devices, School of Medicine, College of Medicine, Nursing and Health Sciences, National University of Ireland Galway, Galway, Ireland
| | - Anja Hauffe
- Institute of Anatomy and Cell Biology, Medical Faculty of Martin Luther University Halle-Wittenberg, Halle (Saale), Germany
| | - Heike Kielstein
- Institute of Anatomy and Cell Biology, Medical Faculty of Martin Luther University Halle-Wittenberg, Halle (Saale), Germany
| | - Ina Bähr
- Institute of Anatomy and Cell Biology, Medical Faculty of Martin Luther University Halle-Wittenberg, Halle (Saale), Germany
| | - Julia Spielmann
- Institute of Anatomy and Cell Biology, Medical Faculty of Martin Luther University Halle-Wittenberg, Halle (Saale), Germany
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29
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Weihe P, Spielmann J, Kielstein H, Henning-Klusmann J, Weihrauch-Blüher S. Childhood Obesity and Cancer Risk in Adulthood. Curr Obes Rep 2020; 9:204-212. [PMID: 32519271 DOI: 10.1007/s13679-020-00387-w] [Citation(s) in RCA: 62] [Impact Index Per Article: 12.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
PURPOSE OF REVIEW The purpose of this review is to summarize our current understanding of the association between childhood obesity and cancer risk later in life. RECENT FINDINGS Adipose tissue secrets a variety of adipocytokines, and expression and/or secretion rate of most of them seems to be increased or dysregulated in obesity. In addition, obesity leads to increased secretion of proinflammatory cytokines such as interferon-γ (IFN-γ), interleukin 6 (IL-6), and tumor necrosis factor-α (TNF-α), which promotes an infiltration of inflammatory immune cells into adipose tissue. This process may facilitate a state of "subclinical inflammation" (metaflammation) and may lead to the development of the metabolic syndrome (MetS), starting as early as during childhood. In addition, several oncogenes have been linked to inflammation and cancer development via different pathways, and several types of tumors need an inflammatory environment before a malignant change occurs. An inflammatory environment seems to promote the proliferation and survival of malignant cells as well as angiogenesis. Natural killer (NK) cells play an important role in this process, as they are able to kill transformed cells without prior sensitization and coordinate subsequent immune responses by producing distinct cytokines, thus providing antitumor immunity. First studies in children have suggested that NK cells from obese children are activated, metabolically stressed, and functionally deficient. This may lead to a suppression of antitumor immunity as early as during childhood, probably many years before the development of cancer. Epidemiological studies have shown a strong association between higher body mass index (BMI) during childhood and adolescence and increased risk for several malignancies in adulthood, including leukemia, Hodgkin's disease, colorectal cancer, and breast cancer. Underlying mechanisms are not completely understood, but several adipocytokines and inflammatory markers including NK cells seem to be "key players" in this process.
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Affiliation(s)
- Paul Weihe
- Clinic for Pediatrics I, University Hospital Halle (Saale), Ernst-Grube-Str. 40, 06120, Halle (Saale), Germany
| | - Julia Spielmann
- Institute of Anatomy and Cell Biology, Medical Faculty of Martin Luther University Halle-Wittenberg, Halle (Saale), Germany
| | - Heike Kielstein
- Institute of Anatomy and Cell Biology, Medical Faculty of Martin Luther University Halle-Wittenberg, Halle (Saale), Germany
| | - Jan Henning-Klusmann
- Clinic for Pediatrics I, University Hospital Halle (Saale), Ernst-Grube-Str. 40, 06120, Halle (Saale), Germany
| | - Susann Weihrauch-Blüher
- Clinic for Pediatrics I, University Hospital Halle (Saale), Ernst-Grube-Str. 40, 06120, Halle (Saale), Germany.
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30
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Arivazhagan L, Ruiz HH, Wilson R, Manigrasso M, Gugger PF, Fisher EA, Moore KJ, Ramasamy R, Schmidt AM. An Eclectic Cast of Cellular Actors Orchestrates Innate Immune Responses in the Mechanisms Driving Obesity and Metabolic Perturbation. Circ Res 2020; 126:1565-1589. [PMID: 32437306 PMCID: PMC7250004 DOI: 10.1161/circresaha.120.315900] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The escalating problem of obesity and its multiple metabolic and cardiovascular complications threatens the health and longevity of humans throughout the world. The cause of obesity and one of its chief complications, insulin resistance, involves the participation of multiple distinct organs and cell types. From the brain to the periphery, cell-intrinsic and intercellular networks converge to stimulate and propagate increases in body mass and adiposity, as well as disturbances of insulin sensitivity. This review focuses on the roles of the cadre of innate immune cells, both those that are resident in metabolic organs and those that are recruited into these organs in response to cues elicited by stressors such as overnutrition and reduced physical activity. Beyond the typical cast of innate immune characters invoked in the mechanisms of metabolic perturbation in these settings, such as neutrophils and monocytes/macrophages, these actors are joined by bone marrow-derived cells, such as eosinophils and mast cells and the intriguing innate lymphoid cells, which are present in the circulation and in metabolic organ depots. Upon high-fat feeding or reduced physical activity, phenotypic modulation of the cast of plastic innate immune cells ensues, leading to the production of mediators that affect inflammation, lipid handling, and metabolic signaling. Furthermore, their consequent interactions with adaptive immune cells, including myriad T-cell and B-cell subsets, compound these complexities. Notably, many of these innate immune cell-elicited signals in overnutrition may be modulated by weight loss, such as that induced by bariatric surgery. Recently, exciting insights into the biology and pathobiology of these cell type-specific niches are being uncovered by state-of-the-art techniques such as single-cell RNA-sequencing. This review considers the evolution of this field of research on innate immunity in obesity and metabolic perturbation, as well as future directions.
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Affiliation(s)
- Lakshmi Arivazhagan
- Diabetes Research Program, Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, NYU Grossman School of Medicine, New York, New York 10016
| | - Henry H. Ruiz
- Diabetes Research Program, Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, NYU Grossman School of Medicine, New York, New York 10016
| | - Robin Wilson
- Diabetes Research Program, Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, NYU Grossman School of Medicine, New York, New York 10016
| | - Michaele Manigrasso
- Diabetes Research Program, Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, NYU Grossman School of Medicine, New York, New York 10016
| | - Paul F. Gugger
- Diabetes Research Program, Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, NYU Grossman School of Medicine, New York, New York 10016
| | - Edward A. Fisher
- The Leon H. Charney Division of Cardiology, Department of Medicine, The Marc and Ruti Bell Program in Vascular Biology, NYU Langone Medical Center, New York 10016
- NYU Cardiovascular Research Center, NYU Grossman School of Medicine, New York, New York 10016
| | - Kathryn J. Moore
- The Leon H. Charney Division of Cardiology, Department of Medicine, The Marc and Ruti Bell Program in Vascular Biology, NYU Langone Medical Center, New York 10016
- NYU Cardiovascular Research Center, NYU Grossman School of Medicine, New York, New York 10016
| | - Ravichandran Ramasamy
- Diabetes Research Program, Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, NYU Grossman School of Medicine, New York, New York 10016
| | - Ann Marie Schmidt
- Diabetes Research Program, Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, NYU Grossman School of Medicine, New York, New York 10016
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31
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Bähr I, Spielmann J, Quandt D, Kielstein H. Obesity-Associated Alterations of Natural Killer Cells and Immunosurveillance of Cancer. Front Immunol 2020; 11:245. [PMID: 32231659 PMCID: PMC7082404 DOI: 10.3389/fimmu.2020.00245] [Citation(s) in RCA: 76] [Impact Index Per Article: 15.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2019] [Accepted: 01/30/2020] [Indexed: 12/13/2022] Open
Abstract
Obesity is accompanied by a systemic chronic low-grade inflammation as well as dysfunctions of several innate and adaptive immune cells. Recent findings emphasize an impaired functionality and phenotype of natural killer (NK) cells under obese conditions. This review provides a detailed overview on research related to overweight and obesity with a particular focus on NK cells. We discuss obesity-associated alterations in subsets, distribution, phenotype, cytotoxicity, cytokine secretion, and signaling cascades of NK cells investigated in vitro as well as in animal and human studies. In addition, we provide recent insights into the effects of physical activity and obesity-associated nutritional factors as well as the reduction of body weight and fat mass on NK cell functions of obese individuals. Finally, we highlight the impact of impaired NK cell physiology on obesity-associated diseases, focusing on the elevated susceptibility for viral infections and increased risk for cancer development and impaired treatment response.
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Affiliation(s)
- Ina Bähr
- Institute of Anatomy and Cell Biology, Medical Faculty of Martin Luther University Halle-Wittenberg, Halle (Saale), Germany
| | - Julia Spielmann
- Institute of Anatomy and Cell Biology, Medical Faculty of Martin Luther University Halle-Wittenberg, Halle (Saale), Germany
| | - Dagmar Quandt
- Institute of Anatomy and Cell Biology, Medical Faculty of Martin Luther University Halle-Wittenberg, Halle (Saale), Germany.,Regenerative Medicine Institute (REMEDI) at CÚRAM Centre for Research in Medical Devices, School of Medicine, College of Medicine, Nursing and Health Sciences, National University of Ireland Galway, Galway, Ireland
| | - Heike Kielstein
- Institute of Anatomy and Cell Biology, Medical Faculty of Martin Luther University Halle-Wittenberg, Halle (Saale), Germany
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32
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Cortese L, Terrazzano G, Pelagalli A. Leptin and Immunological Profile in Obesity and Its Associated Diseases in Dogs. Int J Mol Sci 2019; 20:2392. [PMID: 31091785 PMCID: PMC6566566 DOI: 10.3390/ijms20102392] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2019] [Revised: 05/06/2019] [Accepted: 05/08/2019] [Indexed: 12/29/2022] Open
Abstract
Growing scientific evidence has unveiled increased incidences of obesity in domestic animals and its influence on a plethora of associated disorders. Leptin, an adipokine regulating body fat mass, represents a key molecule in obesity, able to modulate immune responses and foster chronic inflammatory response in peripheral tissues. High levels of cytokines and inflammatory markers suggest an association between inflammatory state and obesity in dogs, highlighting the parallelism with humans. Canine obesity is a relevant disease always accompanied with several health conditions such as inflammation, immune-dysregulation, insulin resistance, pancreatitis, orthopaedic disorders, cardiovascular disease, and neoplasia. However, leptin involvement in many disease processes in veterinary medicine is poorly understood. Moreover, hyperleptinemia as well as leptin resistance occur with cardiac dysfunction as a consequence of altered cardiac mitochondrial metabolism in obese dogs. Similarly, leptin dysregulation seems to be involved in the pancreatitis pathophysiology. This review aims to examine literature concerning leptin and immunological status in obese dogs, in particular for the aspects related to obesity-associated diseases.
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Affiliation(s)
- Laura Cortese
- Department of Veterinary Medicine and Animal Productions, University of Naples Federico II, 80137 Naples, Italy.
| | - Giuseppe Terrazzano
- Department of Science, University of Basilicata, 85100 Potenza, Italy.
- Department of Translational Medical Sciences, University of Naples Federico II, 80131 Naples, Italy.
| | - Alessandra Pelagalli
- Department of Advanced Biomedical Sciences, University of Naples Federico II, 80131 Naples, Italy.
- Institute of Biostructures and Bioimages (IBB), National Research Council (CNR), 80131 Naples, Italy.
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Dysregulation of Natural Killer Cells in Obesity. Cancers (Basel) 2019; 11:cancers11040573. [PMID: 31018563 PMCID: PMC6521109 DOI: 10.3390/cancers11040573] [Citation(s) in RCA: 68] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2019] [Revised: 04/08/2019] [Accepted: 04/10/2019] [Indexed: 01/09/2023] Open
Abstract
Natural killer (NK) cells are a population of lymphocytes which classically form part of the innate immune system. They are defined as innate lymphocytes, due to their ability to kill infected or transformed cells without prior activation. In addition to their cytotoxic abilities, NK cells are also rapid producers of inflammatory cytokines such as interferon gamma (IFN-γ) and are therefore a critical component of early immune responses. Due to these unique abilities, NK cells are a very important component of host protection, especially anti-tumour and anti-viral immunity. Obesity is a worldwide epidemic, with over 600 million adults and 124 million children now classified as obese. It is well established that individuals who are obese are at a higher risk of many acute and chronic conditions, including cancer and viral infections. Over the past 10 years, many studies have investigated the impact of obesity on NK cell biology, detailing systemic dysregulation of NK cell functions. More recently, several studies have investigated the role of NK cells in the homeostasis of adipose tissue and the pathophysiology of obesity. In this review, we will discuss in detail these studies and focus on emerging data detailing the metabolic mechanisms altering NK cells in obesity.
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Metabolic reprogramming of natural killer cells in obesity limits antitumor responses. Nat Immunol 2018; 19:1330-1340. [PMID: 30420624 DOI: 10.1038/s41590-018-0251-7] [Citation(s) in RCA: 422] [Impact Index Per Article: 60.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2017] [Accepted: 10/02/2018] [Indexed: 02/06/2023]
Abstract
Up to 49% of certain types of cancer are attributed to obesity, and potential mechanisms include overproduction of hormones, adipokines, and insulin. Cytotoxic immune cells, including natural killer (NK) cells and CD8+ T cells, are important in tumor surveillance, but little is known about the impact of obesity on immunosurveillance. Here, we show that obesity induces robust peroxisome proliferator-activated receptor (PPAR)-driven lipid accumulation in NK cells, causing complete 'paralysis' of their cellular metabolism and trafficking. Fatty acid administration, and PPARα and PPARδ (PPARα/δ) agonists, mimicked obesity and inhibited mechanistic target of rapamycin (mTOR)-mediated glycolysis. This prevented trafficking of the cytotoxic machinery to the NK cell-tumor synapse. Inhibiting PPARα/δ or blocking the transport of lipids into mitochondria reversed NK cell metabolic paralysis and restored cytotoxicity. In vivo, NK cells had blunted antitumor responses and failed to reduce tumor growth in obesity. Our results demonstrate that the lipotoxic obese environment impairs immunosurveillance and suggest that metabolic reprogramming of NK cells may improve cancer outcomes in obesity.
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Frydrych LM, Bian G, O'Lone DE, Ward PA, Delano MJ. Obesity and type 2 diabetes mellitus drive immune dysfunction, infection development, and sepsis mortality. J Leukoc Biol 2018; 104:525-534. [PMID: 30066958 DOI: 10.1002/jlb.5vmr0118-021rr] [Citation(s) in RCA: 184] [Impact Index Per Article: 26.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2018] [Revised: 06/18/2018] [Accepted: 06/19/2018] [Indexed: 12/14/2022] Open
Abstract
Obesity and type 2 diabetes mellitus (T2D) are global pandemics. Worldwide, the prevalence of obesity has nearly tripled since 1975 and the prevalence of T2D has almost doubled since 1980. Both obesity and T2D are indolent and chronic diseases that develop gradually, with cellular physiologic changes occurring before the clinical signs and symptoms of the diseases become apparent. Individuals with obesity and T2D are physiologically frail and have an increased risk of infections and mortality from sepsis. Improvement in the morbidity and mortality of these at-risk populations would provide a great societal benefit. We believe that the worsened outcomes observed in these patient populations is due to immune system dysfunction that is triggered by the chronic low-grade inflammation present in both diseases. As immune modulatory therapies have been utilized in other chronic inflammatory diseases, there is an emerging role for immune modulatory therapies that target the chronically affected immune pathways in obese and T2D patients. Additionally, bariatric surgery is currently the most successful treatment for obesity and is the only weight loss method that also causes a sustained, substantial improvement of T2D. Consequently, bariatric surgery may also have a role in improving immunity in these patient populations.
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Affiliation(s)
- Lynn M Frydrych
- Department of Surgery, Division of Acute Care Surgery, University of Michigan, Ann Arbor, Michigan, USA
| | - Guowu Bian
- Department of Surgery, Division of Acute Care Surgery, University of Michigan, Ann Arbor, Michigan, USA
| | - David E O'Lone
- Department of Surgery, Division of Acute Care Surgery, University of Michigan, Ann Arbor, Michigan, USA
| | - Peter A Ward
- Department of Pathology, University of Michigan, Ann Arbor, Michigan, USA
| | - Matthew J Delano
- Department of Surgery, Division of Acute Care Surgery, University of Michigan, Ann Arbor, Michigan, USA
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Rosenstock P, Horstkorte R, Gnanapragassam VS, Harth J, Kielstein H. Siglec-7 expression is reduced on a natural killer (NK) cell subset of obese humans. Immunol Res 2018; 65:1017-1024. [PMID: 28786023 PMCID: PMC5613057 DOI: 10.1007/s12026-017-8942-y] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Obesity leads to an altered adipocytokine production negatively effecting the function of natural killer cells (NK cells), which are important effector cells of the innate immune system. NK cells provide a defence against tumour cells or virus infected cells and have different activating and inhibitory surface receptors to distinguish between normal and transformed cells. One group of the inhibitory receptors are the sialic acid-binding immunoglobulin-like lectins (Siglecs). The aim of this study was to compare the expression of Siglecs-7, -9 and -10 on NK cells from normal weight and obese subjects. Therefore peripheral blood mononuclear cells (PBMC) were isolated from 10 normal weight (BMI < 25 kg/m2) and 11 obese (BMI > 30 kg/m2) blood donors and analysed by flow cytometry. Moreover, the amount of sialic acid on NK cell was determined using a fluorescent labelled lectin that binds terminal sialic acids. Percentages of immune cells were not altered between normal weight and obese individuals. CD56bright NK cells from obese subjects had a reduced expression of Siglec-7 while the expression of Siglec-9 was not altered. The reduction of Siglec-7 expression on CD56bright NK cells might be a marker for their dysfunction. Moreover, Siglecs-7, -9 and -10 are not expressed on the NK cell lines NK-92 and NKL. When comparing the two NK cell subpopulations CD56bright and CD56dim, CD56bright NK cells had a higher amount of sialic acids on their surface compared to CD56dim NK cells regardless of body weight.
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Affiliation(s)
- Philip Rosenstock
- Institute for Physiological Chemistry, Martin Luther University Halle-Wittenberg, Hollystraße 1, 06114, Halle (Saale), Germany. .,Department of Anatomy and Cell Biology, Martin Luther University Halle-Wittenberg, Grosse Steinstrasse 52 1, 06108, Halle (Saale), Germany.
| | - Rüdiger Horstkorte
- Institute for Physiological Chemistry, Martin Luther University Halle-Wittenberg, Hollystraße 1, 06114, Halle (Saale), Germany
| | | | - Jörg Harth
- Department of Transfusion Medicine, University Hospital Halle (Saale), Ernst-Grube-Straße 40, 06097, Halle (Saale), Germany
| | - Heike Kielstein
- Department of Anatomy and Cell Biology, Martin Luther University Halle-Wittenberg, Grosse Steinstrasse 52 1, 06108, Halle (Saale), Germany
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Francisco V, Pino J, Campos-Cabaleiro V, Ruiz-Fernández C, Mera A, Gonzalez-Gay MA, Gómez R, Gualillo O. Obesity, Fat Mass and Immune System: Role for Leptin. Front Physiol 2018; 9:640. [PMID: 29910742 PMCID: PMC5992476 DOI: 10.3389/fphys.2018.00640] [Citation(s) in RCA: 276] [Impact Index Per Article: 39.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2017] [Accepted: 05/11/2018] [Indexed: 12/13/2022] Open
Abstract
Obesity is an epidemic disease characterized by chronic low-grade inflammation associated with a dysfunctional fat mass. Adipose tissue is now considered an extremely active endocrine organ that secretes cytokine-like hormones, called adipokines, either pro- or anti-inflammatory factors bridging metabolism to the immune system. Leptin is historically one of most relevant adipokines, with important physiological roles in the central control of energy metabolism and in the regulation of metabolism-immune system interplay, being a cornerstone of the emerging field of immunometabolism. Indeed, leptin receptor is expressed throughout the immune system and leptin has been shown to regulate both innate and adaptive immune responses. This review discusses the latest data regarding the role of leptin as a mediator of immune system and metabolism, with particular emphasis on its effects on obesity-associated metabolic disorders and autoimmune and/or inflammatory rheumatic diseases.
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Affiliation(s)
- Vera Francisco
- The NEIRID Group (Neuroendocrine Interactions in Rheumatology and Inflammatory Diseases), Servizo Galego de Saude and Instituto de Investigación Sanitaria de Santiago, Santiago University Clinical Hospital, Santiago de Compostela, Spain
| | - Jesús Pino
- The NEIRID Group (Neuroendocrine Interactions in Rheumatology and Inflammatory Diseases), Servizo Galego de Saude and Instituto de Investigación Sanitaria de Santiago, Santiago University Clinical Hospital, Santiago de Compostela, Spain
| | - Victor Campos-Cabaleiro
- The NEIRID Group (Neuroendocrine Interactions in Rheumatology and Inflammatory Diseases), Servizo Galego de Saude and Instituto de Investigación Sanitaria de Santiago, Santiago University Clinical Hospital, Santiago de Compostela, Spain
| | - Clara Ruiz-Fernández
- The NEIRID Group (Neuroendocrine Interactions in Rheumatology and Inflammatory Diseases), Servizo Galego de Saude and Instituto de Investigación Sanitaria de Santiago, Santiago University Clinical Hospital, Santiago de Compostela, Spain
| | - Antonio Mera
- Servizo Galego de Saude, Division of Rheumatology, Santiago University Clinical Hospital, Santiago de Compostela, Spain
| | - Miguel A Gonzalez-Gay
- Epidemiology, Genetics and Atherosclerosis Research Group on Systemic Inflammatory Diseases, Hospital Universitario Marqués de Valdecilla, Universidad de Cantabria and IDIVAL, Santander, Spain
| | - Rodolfo Gómez
- Musculoskeletal Pathology Group, Servizo Galego de Saude and Instituto de Investigación Sanitaria de Santiago, Santiago University Clinical Hospital, Santiago de Compostela, Spain
| | - Oreste Gualillo
- The NEIRID Group (Neuroendocrine Interactions in Rheumatology and Inflammatory Diseases), Servizo Galego de Saude and Instituto de Investigación Sanitaria de Santiago, Santiago University Clinical Hospital, Santiago de Compostela, Spain
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38
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Lee GY, Park CY, Cha KS, Lee SE, Pae M, Han SN. Differential effect of dietary vitamin D supplementation on natural killer cell activity in lean and obese mice. J Nutr Biochem 2018; 55:178-184. [PMID: 29525609 DOI: 10.1016/j.jnutbio.2018.01.004] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2017] [Revised: 11/12/2017] [Accepted: 01/10/2018] [Indexed: 12/21/2022]
Abstract
Vitamin D has an immunoregulatory effect on both innate and adaptive immunity. Contradictory results regarding vitamin D and natural killer (NK) cell functions have been reported with in vitro studies, but little is known about this in vivo. We investigated whether vitamin D levels (50, 1000 or 10,000 IU/kg of diet: DD, DC or DS) affect NK cell functions in mice fed a control or high-fat diet (10% or 45% kcal fat: CD or HFD) for 12 weeks. The splenic NK cell activity was significantly higher in the CD-DS group than the HFD-DS group, and the CD-DS group showed significantly higher NK cell activity compared with the CD-DD and CD-DC groups. However, no difference in NK cell activity was observed among the HFD groups fed different levels of vitamin D. The splenic population of NK cells was significantly higher in the CD-DS group than the HFD-DS group. There was no difference in the intracellular expression of IFN-γ and the surface expression of NKG2D and CD107a in NK cells by both dietary fat and vitamin D content. The splenic mRNA expression of Ifng and Ccl5 was significantly lower in the HFD groups compared with the CD groups, but there was no difference in the mRNA levels of Vdup1 and Vdr among the groups. Taken together, these results suggest that dietary vitamin D supplementation can modulate innate immunity by increasing NK activity in control mice but not in obese mice. This effect might be mediated through alternation of the splenic NK cell population.
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Affiliation(s)
- Ga Young Lee
- Department of Food and Nutrition, College of Human Ecology, Seoul National University, Seoul, Korea.
| | - Chan Yoon Park
- Department of Food and Nutrition, College of Human Ecology, Seoul National University, Seoul, Korea.
| | - Kyeong Sun Cha
- Department of Food and Nutrition, College of Human Ecology, Seoul National University, Seoul, Korea.
| | - Seung Eun Lee
- Department of Food and Nutrition, College of Human Ecology, Seoul National University, Seoul, Korea.
| | - Munkyong Pae
- Department of Food and Nutrition, College of Human Ecology, Chungbuk National University, Cheongju, Korea.
| | - Sung Nim Han
- Department of Food and Nutrition, College of Human Ecology, Seoul National University, Seoul, Korea; Research Institute of Human Ecology, Seoul National University, Seoul, Korea.
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Ruffner MA, Sullivan KE. Complications Associated with Underweight Primary Immunodeficiency Patients: Prevalence and Associations Within the USIDNET Registry. J Clin Immunol 2018; 38:283-293. [PMID: 29619656 DOI: 10.1007/s10875-018-0492-0] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2017] [Accepted: 03/19/2018] [Indexed: 02/06/2023]
Abstract
PURPOSE The point prevalence of underweight status and obesity in primary immunodeficiency disease (PID) is unknown, despite the described associations between PID and weight loss and failure to thrive. The goal of this study is to estimate the prevalence of underweight status and obesity in PID patients and to investigate the associations between abnormal body weight and complications of PID. METHODS Using the US Immunodeficiency Network (USIDNET), we performed a retrospective analysis of 653 pediatric (age 2 to 20 years) and 514 adult (age > 20) patient records with information on patient body mass index (BMI). Prevalence of underweight and obese status in PID patients was compared to data from the National Health and Nutrition Examination Survey (NHANES). RESULTS After separating BMI data by year of entry to the database, we demonstrated that both adult and pediatric patients with PID had significantly higher prevalence of underweight patients in multiple years of analysis. Further examination of underweight patients by PID diagnosis revealed that underweight status in adults with CVID was associated with granulomatous disease as well as earlier age of CVID diagnosis. In the pediatric CVID cohort, underweight status was significantly associated with lymphopenia. Examination of obesity in pediatric and adult PID patients compared to NHANES database revealed only a single year when obesity in PID patients was significantly less prevalent. In other 2-year time intervals from 2005 to 2014, the prevalence of obesity was unchanged in children and adults. CONCLUSIONS These results quantify the prevalence of underweight status in PID in a North American population and demonstrate that whether as a result of weight loss or poor weight gain, underweight status is more prevalent in the PID population than in the general US population. The prevalence of obesity in PID patients was similar to that seen in the general population. This highlights the need for continued education on the association of low weight and PID. CLINICAL TRIAL REGISTRATION NCT01953016.
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Affiliation(s)
- Melanie A Ruffner
- Division of Allergy and Immunology, Children's Hospital of Philadelphia, Philadelphia, PA, USA
- Department of Pediatrics, Perelman School of Medicine at University of Pennsylvania, Philadelphia, PA, USA
| | - Kathleen E Sullivan
- Division of Allergy and Immunology, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
- Department of Pediatrics, Perelman School of Medicine at University of Pennsylvania, Philadelphia, PA, USA.
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40
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Bähr I, Jahn J, Zipprich A, Pahlow I, Spielmann J, Kielstein H. Impaired natural killer cell subset phenotypes in human obesity. Immunol Res 2018; 66:234-244. [PMID: 29560551 PMCID: PMC5899081 DOI: 10.1007/s12026-018-8989-4] [Citation(s) in RCA: 56] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Obesity is associated with alterations in functionality of immune cells, like macrophages and natural killer (NK) cells, leading to an increased risk for severe infections and several cancer types. This study aimed to examine immune cell populations and functional NK cell parameters focusing on NK cell subset phenotypes in normal-weight and obese humans. Therefore, peripheral blood mononuclear cells (PBMCs) were isolated from normal-weight and obese individuals and analyzed by flow cytometry. Results show no significant changes in the frequency of monocytes, B lymphocytes, or NKT cells but a significantly increased frequency of T lymphocytes in obesity. The frequency of total NK cells was unaltered, whereas the number of low cytotoxic CD56bright NK cell subset was increased, and the number of high cytotoxic CD56dim NK cell subset was decreased in obese subjects. In addition, the frequency of CD56bright NK cells expressing the activating NK cell receptor NKG2D as well as intracellular interferon (IFN)-γ was elevated in the obese study group. In contrast, the frequency of NKG2D- and IFN-γ-positive CD56dim NK cells was lower in obesity compared to normal-weight individuals. Moreover, the expression of the activation marker CD69 was decreased in NK cells, which can be attributed to a reduction of CD69-positive CD56dim NK cells in obese subjects. In conclusion, data reveal an impaired NK cell phenotype and NK cell subset alterations in obese individuals. This NK cell dysfunction might be one link to the higher cancer risk and the elevated susceptibility for viral infections in obesity.
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Affiliation(s)
- Ina Bähr
- Department of Anatomy and Cell Biology, Faculty of Medicine, Martin Luther University Halle-Wittenberg, Grosse Steinstrasse 52, 06108, Halle/Saale, Germany.
| | - Janine Jahn
- Department of Anatomy and Cell Biology, Faculty of Medicine, Martin Luther University Halle-Wittenberg, Grosse Steinstrasse 52, 06108, Halle/Saale, Germany
| | - Alexander Zipprich
- Clinic of Internal Medicine I, University Hospital of Martin Luther University Halle-Wittenberg, Ernst-Grube-Strasse 40, 06120, Halle/Saale, Germany
| | - Inge Pahlow
- Department of Anatomy and Cell Biology, Faculty of Medicine, Martin Luther University Halle-Wittenberg, Grosse Steinstrasse 52, 06108, Halle/Saale, Germany
| | - Julia Spielmann
- Department of Anatomy and Cell Biology, Faculty of Medicine, Martin Luther University Halle-Wittenberg, Grosse Steinstrasse 52, 06108, Halle/Saale, Germany
| | - Heike Kielstein
- Department of Anatomy and Cell Biology, Faculty of Medicine, Martin Luther University Halle-Wittenberg, Grosse Steinstrasse 52, 06108, Halle/Saale, Germany
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41
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Kim M, Kim M, Yoo HJ, Lee JH. Natural Killer Cell Activity and Interleukin-12 in Metabolically Healthy versus Metabolically Unhealthy Overweight Individuals. Front Immunol 2017; 8:1700. [PMID: 29238351 PMCID: PMC5712537 DOI: 10.3389/fimmu.2017.01700] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2017] [Accepted: 11/17/2017] [Indexed: 12/17/2022] Open
Abstract
The purpose of this study was to determine whether the immune system is involved in the different metabolic circumstances in healthy and unhealthy overweight individuals. We examined the metabolic and immune characteristics of 117 overweight individuals. Subjects were classified as metabolically healthy overweight (MHO, n = 72) or metabolically unhealthy overweight (MUO, n = 45). The immune response was measured by circulating levels of natural killer (NK) cell activity and cytokines. Both groups were comparable with regards to age, sex distribution, smoking and drinking status, and body mass index. When compared to the MHO group, the MUO group showed higher systolic and diastolic blood pressure, serum levels of triglyceride, glucose, glucose-related markers, and lower levels of HDL cholesterol. Compared to the MHO group, the MUO group showed 39% lower interferon-γ levels (not significant) and 41% lower interleukin (IL)-12 levels (significant). The MUO group also showed lower NK cell activity at E:T ratios of 10:1, 5:1, 2.5:1, and 1.25:1 (all Ps < 0.05) than the MHO group. This study indicates that individuals displaying the MUO phenotype present an unfavorable immune system with lower NK cell activities under all assay conditions and lower serum levels of IL-12 than the activities and levels in similarly overweight MHO individuals. This result suggests that the immune system may be altered in overweight individuals who are at risk for overweight/obesity-related comorbidities.
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Affiliation(s)
- Minjoo Kim
- Research Center for Silver Science, Institute of Symbiotic Life-TECH, Yonsei University, Seoul, South Korea
| | - Minkyung Kim
- Research Center for Silver Science, Institute of Symbiotic Life-TECH, Yonsei University, Seoul, South Korea
| | - Hye Jin Yoo
- Department of Food and Nutrition, Brain Korea 21 PLUS Project, College of Human Ecology, Yonsei University, Seoul, South Korea
| | - Jong Ho Lee
- Research Center for Silver Science, Institute of Symbiotic Life-TECH, Yonsei University, Seoul, South Korea.,Department of Food and Nutrition, Brain Korea 21 PLUS Project, College of Human Ecology, Yonsei University, Seoul, South Korea.,National Leading Research Laboratory of Clinical Nutrigenetics/Nutrigenomics, Department of Food and Nutrition, College of Human Ecology, Yonsei University, Seoul, South Korea
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42
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Kobayashi T, Mattarollo SR. Natural killer cell metabolism. Mol Immunol 2017; 115:3-11. [PMID: 29179986 DOI: 10.1016/j.molimm.2017.11.021] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2017] [Revised: 11/16/2017] [Accepted: 11/20/2017] [Indexed: 12/24/2022]
Abstract
Natural killer (NK) cells are a critical component in the innate immune response against disease. NK cell function is tightly regulated by specific cytokine and activation/inhibitory receptor signalling, leading to diverse effector responses. Like all living cells, energy metabolism is a fundamental requirement for NK cell activation and survival. There is growing evidence that distinct functional profiles of NK cells are determined by alterations to cellular metabolic pathways. In this review, we summarise current literature that has explored NK cell metabolism to provide insight into how metabolic regulation controls NK cell function. We focus on metabolism pathways induced by different NK cell stimuli, metabolic regulatory proteins, and nutrient and hormonal levels in health and disease which impact on NK cell metabolic and functional activity.
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Affiliation(s)
- Takumi Kobayashi
- The University of Queensland Diamantina Institute, The University of Queensland, Translational Research Institute, Brisbane 4102, Queensland, Australia
| | - Stephen R Mattarollo
- The University of Queensland Diamantina Institute, The University of Queensland, Translational Research Institute, Brisbane 4102, Queensland, Australia.
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Spielmann J, Hanke J, Knauf D, Ben-Eliyahu S, Jacobs R, Stangl GI, Bähr I, Kielstein H. Significantly enhanced lung metastasis and reduced organ NK cell functions in diet-induced obese rats. BMC OBESITY 2017; 4:24. [PMID: 28690853 PMCID: PMC5496225 DOI: 10.1186/s40608-017-0161-5] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/19/2016] [Accepted: 06/22/2017] [Indexed: 12/21/2022]
Abstract
BACKGROUND Obesity was identified as a major risk factor for malignant diseases, but underlying mechanisms remain unclear. Natural killer (NK) cells, a pivotal aspect of innate immunity, are capable of identifying and killing virally infected and tumor cells. Previous studies have shown altered NK cell functions in obesity, and the current study aimed to investigate the relationship between altered NK cell functions and increased cancer risk in obesity. METHODS To induce obesity male F344-rats received a high-fat diet (34% fat) or a control diet (4% fat). Thereafter, syngeneic mammary adenocarcinoma cells (MADB106) or a vehicle were intravenously (i.v.) injected. 15 min after injection, half of each group of rats were killed, lungs removed and immunohistochemically stained. Numbers of NK cells, MADB106 cells and NK cell-tumor cell interactions were quantified. Twenty-one days after tumor-cell injection the other half group of rats was killed and lung metastases were counted and relative mRNA concentrations of different NK cell receptors were determined. RESULTS After short-term MADB106-challenge, DIO fed animals showed significantly decreased NK cell numbers in the blood and NK cell-tumor cell interactions in the lung as compared to their control littermates. Twenty-one days after MADB106 injection, the lungs of the DIO fed rats showed significantly more lung metastases compared to control animals, accompanied by reduced relative mRNA concentrations of the activating NK cell receptor NKG2D. CONCLUSIONS We conclude that induction of obesity in F344-rats leads to reduced lung NK cell function against tumor cells and results in significantly enhanced lung metastasis as compared to lean animals. It can be hypothesized that obesity-induced altered NK cell functions play an important role in cancer growth and metastasis.
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Affiliation(s)
- J Spielmann
- Department of Anatomy and Cell Biology, Martin Luther University Halle-Wittenberg, Faculty of Medicine, Grosse Steinstrasse 52, 06108 Halle (Saale), Germany
| | - J Hanke
- Department of Orthopaedics, Trauma and Reconstructive Surgery, Martin Luther University Halle-Wittenberg, Faculty of Medicine, Ernst-Grube Str. 40, 06097 Halle (Saale), Germany
| | - D Knauf
- Department of Anatomy and Cell Biology, Martin Luther University Halle-Wittenberg, Faculty of Medicine, Grosse Steinstrasse 52, 06108 Halle (Saale), Germany
| | - S Ben-Eliyahu
- Neuroimmunology Research Unit, The Sagol School of Neuroscience, The School of Psychological Sciences, Tel Aviv University, 69978 Tel Aviv, Israel
| | - R Jacobs
- Department of Clinical Immunology and Rheumatology, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany
| | - G I Stangl
- Department of Human Nutrition, Martin Luther University Halle-Wittenberg, Von-Danckelmann-Platz 2, 06120 Halle (Saale), Germany
| | - I Bähr
- Department of Anatomy and Cell Biology, Martin Luther University Halle-Wittenberg, Faculty of Medicine, Grosse Steinstrasse 52, 06108 Halle (Saale), Germany
| | - H Kielstein
- Department of Anatomy and Cell Biology, Martin Luther University Halle-Wittenberg, Faculty of Medicine, Grosse Steinstrasse 52, 06108 Halle (Saale), Germany
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Adipokine Contribution to the Pathogenesis of Osteoarthritis. Mediators Inflamm 2017; 2017:5468023. [PMID: 28490838 PMCID: PMC5401756 DOI: 10.1155/2017/5468023] [Citation(s) in RCA: 106] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2016] [Revised: 02/25/2017] [Accepted: 03/07/2017] [Indexed: 12/13/2022] Open
Abstract
Recent studies have shown that overweight and obesity play an important role in the development of osteoarthritis (OA). However, joint overload is not the only risk factor in this disease. For instance, the presence of OA in non-weight-bearing joints such as the hand suggests that metabolic factors may also contribute to its pathogenesis. Recently, white adipose tissue (WAT) has been recognized not only as an energy reservoir but also as an important secretory organ of adipokines. In this regard, adipokines have been closely associated with obesity and also play an important role in bone and cartilage homeostasis. Furthermore, drugs such as rosuvastatin or rosiglitazone have demonstrated chondroprotective and anti-inflammatory effects in cartilage explants from patients with OA. Thus, it seems that adipokines are important factors linking obesity, adiposity, and inflammation in OA. In this review, we are focused on establishing the physiological mechanisms of adipokines on cartilage homeostasis and evaluating their role in the pathophysiology of OA based on evidence derived from experimental research as well as from clinical-epidemiological studies.
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Diet-Induced Obesity Is Associated with an Impaired NK Cell Function and an Increased Colon Cancer Incidence. J Nutr Metab 2017; 2017:4297025. [PMID: 28357137 PMCID: PMC5357539 DOI: 10.1155/2017/4297025] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2016] [Revised: 02/06/2017] [Accepted: 02/15/2017] [Indexed: 12/29/2022] Open
Abstract
Obesity is associated with an increased colon cancer incidence, but underlying mechanisms remained unclear. Previous studies showed altered Natural killer (NK) cell functions in obese individuals. Therefore, we studied the impact of an impaired NK cell functionality on the increased colon cancer risk in obesity. In vitro investigations demonstrated a decreased IFN-γ secretion and cytotoxicity of human NK cells against colon tumor cells after NK cell preincubation with the adipokine leptin. In addition, leptin incubation decreased the expression of activating NK cell receptors. In animal studies, colon cancer growth was induced by injection of azoxymethane (AOM) in normal weight and diet-induced obese rats. Body weight and visceral fat mass were increased in obese animals compared to normal weight rats. AOM-treated obese rats showed an increased quantity, size, and weight of colon tumors compared to the normal weight tumor group. Immunohistochemical analyses demonstrated a decreased number of NK cells in spleen and liver in obesity. Additionally, the expression levels of activating NK cell receptors were lower in spleen and liver of obese rats. The results show for the first time that the decreased number and impaired NK cell function may be one cause for the higher colon cancer risk in obesity.
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Abella V, Scotece M, Conde J, Pino J, Gonzalez-Gay MA, Gómez-Reino JJ, Mera A, Lago F, Gómez R, Gualillo O. Leptin in the interplay of inflammation, metabolism and immune system disorders. Nat Rev Rheumatol 2017; 13:100-109. [PMID: 28053336 DOI: 10.1038/nrrheum.2016.209] [Citation(s) in RCA: 359] [Impact Index Per Article: 44.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Leptin is one of the most relevant factors secreted by adipose tissue and the forerunner of a class of molecules collectively called adipokines. Initially discovered in 1994, its crucial role as a central regulator in energy homeostasis has been largely described during the past 20 years. Once secreted into the circulation, leptin reaches the central and peripheral nervous systems and acts by binding and activating the long form of leptin receptor (LEPR), regulating appetite and food intake, bone mass, basal metabolism, reproductive function and insulin secretion, among other processes. Research on the regulation of different adipose tissues has provided important insights into the intricate network that links nutrition, metabolism and immune homeostasis. The neuroendocrine and immune systems communicate bi-directionally through common ligands and receptors during stress responses and inflammation, and control cellular immune responses in several pathological situations including immune-inflammatory rheumatic diseases. This Review discusses the latest findings regarding the role of leptin in the immune system and metabolism, with particular emphasis on its effect on autoimmune and/or inflammatory rheumatic diseases, such as rheumatoid arthritis and osteoarthritis.
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Affiliation(s)
- Vanessa Abella
- SERGAS (Servizo Galego de Saude) and IDIS (Instituto de Investigación Sanitaria de Santiago), The NEIRID Group (Neuroendocrine Interactions in Rheumatology and Inflammatory Diseases), Santiago University Clinical Hospital, Building C, Travesía da Choupana S/N, Santiago de Compostela 15706, Spain
| | - Morena Scotece
- SERGAS (Servizo Galego de Saude) and IDIS (Instituto de Investigación Sanitaria de Santiago), The NEIRID Group (Neuroendocrine Interactions in Rheumatology and Inflammatory Diseases), Santiago University Clinical Hospital, Building C, Travesía da Choupana S/N, Santiago de Compostela 15706, Spain
| | - Javier Conde
- SERGAS (Servizo Galego de Saude) and IDIS (Instituto de Investigación Sanitaria de Santiago), The NEIRID Group (Neuroendocrine Interactions in Rheumatology and Inflammatory Diseases), Santiago University Clinical Hospital, Building C, Travesía da Choupana S/N, Santiago de Compostela 15706, Spain
| | - Jesús Pino
- SERGAS (Servizo Galego de Saude), Santiago University Clinical Hospital, Division of Orthopaedic Surgery and Traumatology, Travesía da Choupana S/N, Santiago de Compostela 15706, Spain
| | - Miguel Angel Gonzalez-Gay
- Epidemiology, Genetics and Atherosclerosis Research Group on Systemic Inflammatory Diseases, Universidad de Cantabria and IDIVAL, Hospital Universitario Marqués de Valdecilla, Av. Valdecilla, Santander 39008, Spain
| | - Juan J Gómez-Reino
- SERGAS (Servizo Galego de Saude), Santiago University Clinical Hospital, Division of Rheumatology, Travesía da Choupana S/N, Santiago de Compostela 15706, Spain
| | - Antonio Mera
- SERGAS (Servizo Galego de Saude), Santiago University Clinical Hospital, Division of Rheumatology, Travesía da Choupana S/N, Santiago de Compostela 15706, Spain
| | - Francisca Lago
- SERGAS (Servizo Galego de Saude) and IDIS (Instituto de Investigación Sanitaria de Santiago), Department of Cellular and Molecular Cardiology, CIBERCV (Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares), Building C, Travesía da Choupana S/N, Santiago de Compostela 15706, Spain
| | - Rodolfo Gómez
- SERGAS (Servizo Galego de Saude) and IDIS (Instituto de Investigación Sanitaria de Santiago), The NEIRID Group (Neuroendocrine Interactions in Rheumatology and Inflammatory Diseases), Santiago University Clinical Hospital, Building C, Travesía da Choupana S/N, Santiago de Compostela 15706, Spain
| | - Oreste Gualillo
- SERGAS (Servizo Galego de Saude) and IDIS (Instituto de Investigación Sanitaria de Santiago), The NEIRID Group (Neuroendocrine Interactions in Rheumatology and Inflammatory Diseases), Santiago University Clinical Hospital, Building C, Travesía da Choupana S/N, Santiago de Compostela 15706, Spain
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Wright C, Simone NL. Obesity and tumor growth: inflammation, immunity, and the role of a ketogenic diet. Curr Opin Clin Nutr Metab Care 2016; 19:294-9. [PMID: 27168354 DOI: 10.1097/mco.0000000000000286] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
PURPOSE OF REVIEW This article reviews the impact the obese state has on malignancy through inflammation and immune dysregulation using recent excerpts from the medical literature. RECENT FINDINGS The obese state creates a proinflammatory endocrinologic milieu altering cellular signaling between adipocytes, immunologic cells, and epithelial cells, leading to the over-activation of adipose tissue macrophages and the upregulation of compounds associated with carcinogenesis. Obesity correlates with a deficiency in numerous immunologic cells, including dendritic cells, natural killer cells, and T cells. In part, this can be attributed to a recent finding of leptin receptor expression on these immune cells and the upregulation of leptin signaling in the obese state. A number of clinical trials have demonstrated the feasibility of a high-fat, low-carbohydrate diet as an adjuvant treatment for cancer, and current trials are investigating the impact of this intervention on disease outcomes. In preclinical trials, a ketogenic diet has been shown to impede tumor growth in a variety of cancers through anti-angiogenic, anti-inflammatory, and proapoptotic mechanisms. SUMMARY Obesity is becoming more prevalent and its link to cancer is clearly established providing a rationale for the implementation of dietary interventions as an adjuvant therapeutic strategy for malignancy.
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Affiliation(s)
- Christopher Wright
- aSidney Kimmel Medical College at Thomas Jefferson University bDepartment of Radiation Oncology, Sidney Kimmel Cancer Center at Thomas Jefferson University, Philadelphia, Pennsylvania, USA
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Schenk A, Bloch W, Zimmer P. Natural Killer Cells--An Epigenetic Perspective of Development and Regulation. Int J Mol Sci 2016; 17:326. [PMID: 26938533 PMCID: PMC4813188 DOI: 10.3390/ijms17030326] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2016] [Revised: 02/18/2016] [Accepted: 02/22/2016] [Indexed: 12/25/2022] Open
Abstract
Based on their ability to recognize and eliminate various endo- and exogenous pathogens as well as pathological alterations, Natural Killer (NK) cells represent an important part of the cellular innate immune system. Although the knowledge about their function is growing, little is known about their development and regulation on the molecular level. Research of the past decade suggests that modifications of the chromatin, which do not affect the base sequence of the DNA, also known as epigenetic alterations, are strongly involved in these processes. Here, the impact of epigenetic modifications on the development as well as the expression of important activating and inhibiting NK-cell receptors and their effector function is reviewed. Furthermore, external stimuli such as physical activity and their influence on the epigenetic level are discussed.
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Affiliation(s)
- Alexander Schenk
- Department of Molecular and Cellular Sports Medicine, Institute for Cardiovascular Research and Sports Medicine, German Sport University Cologne, Am Sportpark Muengersdorf 6, 50933 Cologne, Germany.
| | - Wilhelm Bloch
- Department of Molecular and Cellular Sports Medicine, Institute for Cardiovascular Research and Sports Medicine, German Sport University Cologne, Am Sportpark Muengersdorf 6, 50933 Cologne, Germany.
| | - Philipp Zimmer
- Department of Molecular and Cellular Sports Medicine, Institute for Cardiovascular Research and Sports Medicine, German Sport University Cologne, Am Sportpark Muengersdorf 6, 50933 Cologne, Germany.
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Naylor C, Petri WA. Leptin Regulation of Immune Responses. Trends Mol Med 2016; 22:88-98. [PMID: 26776093 DOI: 10.1016/j.molmed.2015.12.001] [Citation(s) in RCA: 178] [Impact Index Per Article: 19.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2015] [Revised: 12/06/2015] [Accepted: 12/10/2015] [Indexed: 12/19/2022]
Abstract
Leptin is a regulatory hormone with multiple roles in the immune system. We favor the concept that leptin signaling 'licenses' various immune cells to engage in immune responses and/or to differentiate. Leptin is an inflammatory molecule that is capable of activating both adaptive and innate immunity. It can also 'enhance' immune functions, including inflammatory cytokine production in macrophages, granulocyte chemotaxis, and increased Th17 proliferation. Leptin can also 'inhibit' cells; CD4(+) T cells are inhibited from differentiating into regulatory T cells in the presence of elevated leptin, while NK cells can exhibit impaired cytotoxicity under the same circumstances. Consequently, understanding the effect of leptin signaling is important to appreciate various aspects of immune dysregulation observed in malnutrition, obesity, and autoimmunity.
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Affiliation(s)
- Caitlin Naylor
- Medical Research Council Unit, Atlantic Blvd, Serrekunda, Gambia.
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