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Li LN, Wu JM, Zheng ZJ, Li SX, Cai MY, Zou MC. N6-methyladenosine modification of THBS1 induced by affluent WTAP promotes Graves' ophthalmopathy progression through glycolysis to affect Th17/Treg balance. Autoimmunity 2025; 58:2433628. [PMID: 39689341 DOI: 10.1080/08916934.2024.2433628] [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: 07/26/2024] [Revised: 10/15/2024] [Accepted: 11/17/2024] [Indexed: 12/19/2024]
Abstract
Graves' ophthalmopathy (GO) obvious manifestation is the imbalance of Th17/Treg. N6-methyladenosine (m6A) methylation is an important regulator of Th17/Treg balance. However, few reports narrate how m6A regulators mediate the role of genes in GO progression. We explored the m6A modification of THBS1 mediated by WTAP, and the mechanism by which THBS1 regulated glycolysis and Th17/Treg balance. A total of 12 peripheral blood (4 GO samples, 4 GH samples, and 4 health samples) were collected to measure the percentage of Th17/Treg in monocytes by flow cytometry. RNA sequencing (RNA-seq) combined with MeRIP sequencing (MeRIP-seq) was used to screen differentially expressed and methylated genes. MeRIP-qPCR was performed to evaluate the m6A abundance of THBS1 after WTAP silencing. Glycolysis of CD4+ T cells was reflected by the lactate content and glucose uptake. The number of Th17 cells was increased in GO peripheral blood, whereas the Treg cells decreased. RNA-seq acquired 679 differentially expressed genes (308 up-regulated, and 371 down-regulated) in the CD4+ T cells of GO compared to healthy control. MeRIP-seq identified 3277 m6A peaks between the GO group and the healthy control group, corresponding with 2744 genes (1143 hypermethylated and 1601 hypomethylated). Combined analysis of RNA-seq and MeRIP-seq showed 81 hypermethylated and up-regulated genes. Among the six candidate genes in the PI3K-signaling pathway, THBS1 was the most significantly differentially expressed and hypermethylated. THBS1 silencing resulted in decreased lactate content and glucose uptake in CD4+ T cells. WTAP was significantly upregulated in CD4+ T cells of GO, and WTAP silencing significantly reduced m6A abundance and expression of THBS1. Upregulated and hypermethylated THBS1 mediated by WTAP promoted glycolysis of CD4+ T cells, affected Th17/Treg balance, and facilitated GO progression. We provided a novel potential target for GO treatment and revealed the molecular mechanism of WTAP and THBS1 in GO under the m6A perspective.
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Affiliation(s)
- Lin-Na Li
- Department of Endocrinology and Metabolism, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Jie-Man Wu
- Department of Health Management, Nanfang Hospital Zengcheng Campus, Guangzhou, China
| | - Zong-Ji Zheng
- Department of Endocrinology and Metabolism, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Shu-Xian Li
- Department of Endocrinology and Metabolism, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Meng-Yi Cai
- Department of Endocrinology and Metabolism, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Meng-Chen Zou
- Department of Endocrinology and Metabolism, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
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Zhao B, Zhang M, Liao S, Jiang T, Li J, Yang Z. Implication of serum soluble IL-2 receptor α in type 2 diabetes mellitus. J Diabetes Metab Disord 2025; 24:22. [PMID: 39712341 PMCID: PMC11659525 DOI: 10.1007/s40200-024-01536-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/16/2024] [Accepted: 10/01/2024] [Indexed: 12/24/2024]
Abstract
Objectives The aim of this study was to determine the association of serum soluble IL-2 receptor α (sIL-2RA) with T2DM-related characteristics and complications. Methods Serum sIL-2RA levels were determined in 156 T2DM patients, and the association with T2DM-related characteristics and complications was evaluated. Results Serum sIL-2RA levels were significantly increased in T2DM patients with diabetic kidney disease (DKD) (median, IQR, 1434.9, 958.1-1896.0, pg/ml), in comparison with those without DKD (median, IQR, 851.2, 660.2-1089.9, pg/ml)(P < 0.001). The ROC analysis revealed good performance of sIL-2RA for identifying DKD, with the areas under the curve of 0.789 (95%CI of 0.711-0.867, P < 0.001). The correlation analyses showed significantly positive correlations of serum sIL-2RA with urea (r = 0.458, P < 0.001), creatinine (r = 0.508, P < 0.001) and uACR (r = 0.469, P < 0.001), and negative correlation with eGFR (r=-0.561, P < 0.001). The multivariate analyses showed that serum sIL-2RA was independently associated with the increased risks of DKD (OR, 95%CI, 6.539, 1.401-30.529, P = 0.017) and DR (OR, 95%CI, 3.606, 1.073-12.114, P = 0.038). Additionally, serum sIL-2RA was significantly associated with inflammatory indicators in DKD patients, and with metablic indicators in non-DKD patients (all P < 0.05). Conclusion Serum sIL-2RA may be closely associated with inflammation, glucose and lipid metabolisms, DKD and DR risks in T2DM. Furthermore, it may be a potential biomarker for T2DM-related micro-vascular complications.
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Affiliation(s)
- Bing Zhao
- Department of Laboratory Medicine, Taizhou First People’s Hospital, Huangyan Hospital of Wenzhou Medical University, Taizhou, China
| | - Miaomiao Zhang
- Department of Laboratory Medicine, Taizhou First People’s Hospital, Huangyan Hospital of Wenzhou Medical University, Taizhou, China
| | - Shaoguang Liao
- Present Address: Department of Radiation Oncology, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, China
- Department of Oncology, Taizhou First People’s Hospital, Huangyan Hospital of Wenzhou Medical University, Taizhou, China
| | - Tingwang Jiang
- Key Laboratory, Department of Science and Technology, The Second People’s Hospital of Changshu, The Affiliated Changshu Hospital of Xuzhou Medical University, Changshu, Jiangshu China
| | - Jie Li
- Department of Laboratory Medicine, Taizhou First People’s Hospital, Huangyan Hospital of Wenzhou Medical University, Taizhou, China
| | - Zaixing Yang
- Department of Laboratory Medicine, Taizhou First People’s Hospital, Huangyan Hospital of Wenzhou Medical University, Taizhou, China
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Song M, Dai H, Zhou Q, Meng X. The immunology of diabetic cardiomyopathy. Front Endocrinol (Lausanne) 2025; 16:1542208. [PMID: 40260277 PMCID: PMC12009709 DOI: 10.3389/fendo.2025.1542208] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/09/2024] [Accepted: 03/18/2025] [Indexed: 04/23/2025] Open
Abstract
Diabetic cardiomyopathy is a notable microvascular complication of diabetes, characterized primarily by myocardial fibrosis and functional abnormalities. Long-term hyperglycemia induces excessive activation and recruitment of immune cells and triggers the cascade of inflammatory responses, resulting in systemic and local cardiac inflammation. Emerging evidence highlights the significant roles of immunology in modulating the pathology of diabetic cardiomyopathy. As the primary effectors of inflammatory reactions, immune cells are consistently present in cardiac tissue and can be recruited under pathological hyperglycemia circumstances. A disproportionate favor to proinflammatory types of immune cells and the increased proinflammatory cytokine levels mediate fibroblast proliferation, phenotypic transformation, and collagen synthesis and ultimately rise to cardiac fibrosis and hypertrophy. Meanwhile, the severity of cardiac fibrosis is also strongly associated with the diverse phenotypes and phenotypic alterations of the immune cells, including macrophages, dendritic cells, mast cells, neutrophils, and natural killer cells in innate immunity and CD4+ T lymphocytes, CD8+ T lymphocytes, and B lymphocytes in adaptive immunity. In this review, we synthesized the current analysis of the critical role played by the immune system and its components in the progression of diabetic cardiomyopathy. Finally, we highlight preclinical and clinical immune targeting strategies and translational implications.
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Affiliation(s)
| | | | | | - Xiao Meng
- State Key Laboratory for Innovation and Transformation of Luobing Theory, Key Laboratory of Cardiovascular Remodeling and Function Research of MOE, NHC, CAMS and Shandong Province, Department of Cardiology, Qilu Hospital of Shandong University, Jinan, China
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4
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Lei Y, Wang Y, Tang S, Yang J, Lai D, Qiu Q. The adaptive immune system in the retina of diabetics. Surv Ophthalmol 2025; 70:241-254. [PMID: 39566563 DOI: 10.1016/j.survophthal.2024.11.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2024] [Revised: 11/07/2024] [Accepted: 11/13/2024] [Indexed: 11/22/2024]
Abstract
As the prevalence of diabetes mellitus increases each year, its most common microvascular complication, diabetic retinopathy (DR), is also on the rise. DR is now regarded as an inflammatory disease in which innate immunity plays a crucial role, and a large number of innate immune cells with associated cytokines are involved in the pathologic process of DR. The role of adaptive immunity in DR is seldom mentioned, probably due to the general perception of the immune privileged environment of the retina; however, in recent years there has been a gradual increase in research on the role of adaptive immunity in DR, and with the discovery of the retinal lymphatic system, it seems that the role of adaptive immunity can no longer be ignored. Here, we discuss the immunosuppressive environment of the retina, the phenomenon and potential mechanisms of lymphocyte infiltration in DR, and the role of the adaptive immune system in the diabetic retina, which may point the way for future research.
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Affiliation(s)
- Yiou Lei
- Xiangya School of Medicine, Central South University, Changsha, Hunan, PR China; Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China; National Clinical Research Center for Eye Diseases, Shanghai Key Laboratory of Ocular Fundus Diseases, Shanghai Engineering Center for Visual Science and Photomedicine, Shanghai Engineering Center for Precise Diagnosis and Treatment of Eye Diseases, Shanghai, PR China
| | - Yani Wang
- Xiangya School of Medicine, Central South University, Changsha, Hunan, PR China; Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China; National Clinical Research Center for Eye Diseases, Shanghai Key Laboratory of Ocular Fundus Diseases, Shanghai Engineering Center for Visual Science and Photomedicine, Shanghai Engineering Center for Precise Diagnosis and Treatment of Eye Diseases, Shanghai, PR China
| | - Siao Tang
- Xiangya School of Medicine, Central South University, Changsha, Hunan, PR China; Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China; National Clinical Research Center for Eye Diseases, Shanghai Key Laboratory of Ocular Fundus Diseases, Shanghai Engineering Center for Visual Science and Photomedicine, Shanghai Engineering Center for Precise Diagnosis and Treatment of Eye Diseases, Shanghai, PR China
| | - Jiaqi Yang
- Xiangya School of Medicine, Central South University, Changsha, Hunan, PR China; Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China; National Clinical Research Center for Eye Diseases, Shanghai Key Laboratory of Ocular Fundus Diseases, Shanghai Engineering Center for Visual Science and Photomedicine, Shanghai Engineering Center for Precise Diagnosis and Treatment of Eye Diseases, Shanghai, PR China
| | - Dongwei Lai
- Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China; National Clinical Research Center for Eye Diseases, Shanghai Key Laboratory of Ocular Fundus Diseases, Shanghai Engineering Center for Visual Science and Photomedicine, Shanghai Engineering Center for Precise Diagnosis and Treatment of Eye Diseases, Shanghai, PR China.
| | - Qinghua Qiu
- Department of Ophthalmology, Tong Ren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China.
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Shi Z, Yun M, Liu H, Li S, Zhang X. Impact of geriatric nutritional risk index and diabetes mellitus on prognosis in ischaemic heart failure with reduced ejection fraction. Sci Rep 2025; 15:4226. [PMID: 39905242 PMCID: PMC11794575 DOI: 10.1038/s41598-025-88950-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2024] [Accepted: 02/01/2025] [Indexed: 02/06/2025] Open
Abstract
It is unclear whether diabetes mellitus (DM) affects the role of malnutrition in heart failure (HF). We evaluated the effect of the geriatric nutritional risk index (GNRI) on HF prognosis and DM's role in this relationship. This single-centre retrospective cohort study included 540 HF patients with nutritional data grouped by DM status and GNRI score. The primary endpoint was all-cause mortality. Eighty-four patients (15.6%) were classified as malnourished (GNRI ≤ 98). Over a median follow-up of 4.0 years, 102 patients died. The DM/low GNRI (L-GNRI) group had the highest risk of all-cause death (HRadj: 3.253, 95% CI 1.643-6.474, P < 0.001) and cardiac death (HRadj: 3.411, 95% CI 1.606-7.243, P < 0.001) compared to the non-DM/high GNRI group. The adverse impact of L-GNRI was more pronounced in DM than in non-DM patients (Pinteraction < 0.05). In the total population and DM subgroup, GNRI was independently associated with an increased risk of all-cause and cardiac death after adjustment (all P < 0.05). In patients with DM, the GNRI classification significantly enhanced the predictive value of the model (all P < 0.05). A negative correlation between GNRI and HbA1c was observed only in patients with DM. Patients with HF with DM and malnutrition had the poorest prognosis. Poor glycemic control is related to increased malnutrition risk.
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Affiliation(s)
- Zhiyong Shi
- Department of Nuclear Medicine, Molecular Imaging Lab, Beijing Anzhen Hospital, Capital Medical University, Beijing, China
| | - Mingkai Yun
- Department of Nuclear Medicine, Molecular Imaging Lab, Beijing Anzhen Hospital, Capital Medical University, Beijing, China
| | - Haiyan Liu
- Department of Nuclear Medicine, First Hospital of Shanxi Medical University, Taiyuan, Shanxi, China
| | - Sijin Li
- Department of Nuclear Medicine, First Hospital of Shanxi Medical University, Taiyuan, Shanxi, China
| | - Xiaoli Zhang
- Department of Nuclear Medicine, Molecular Imaging Lab, Beijing Anzhen Hospital, Capital Medical University, Beijing, China.
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Xu Y, Wang Z, Li S, Su J, Gao L, Ou J, Lin Z, Luo OJ, Xiao C, Chen G. An in-depth understanding of the role and mechanisms of T cells in immune organ aging and age-related diseases. SCIENCE CHINA. LIFE SCIENCES 2025; 68:328-353. [PMID: 39231902 DOI: 10.1007/s11427-024-2695-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/24/2024] [Accepted: 07/28/2024] [Indexed: 09/06/2024]
Abstract
T cells play a critical and irreplaceable role in maintaining overall health. However, their functions undergo alterations as individuals age. It is of utmost importance to comprehend the specific characteristics of T-cell aging, as this knowledge is crucial for gaining deeper insights into the pathogenesis of aging-related diseases and developing effective therapeutic strategies. In this review, we have thoroughly examined the existing studies on the characteristics of immune organ aging. Furthermore, we elucidated the changes and potential mechanisms that occur in T cells during the aging process. Additionally, we have discussed the latest research advancements pertaining to T-cell aging-related diseases. These findings provide a fresh perspective for the study of T cells in the context of aging.
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Affiliation(s)
- Yudai Xu
- Department of Microbiology and Immunology, School of Medicine; Institute of Geriatric Immunology, School of Medicine, Jinan University, Guangzhou, 510632, China
- Key Laboratory of Viral Pathogenesis & Infection Prevention and Control (Jinan University), Ministry of Education, Guangzhou, 510632, China
- Guangdong-Hong Kong-Macau Great Bay Area Geroscience Joint Laboratory, School of Medicine, Jinan University, Guangzhou, 510632, China
| | - Zijian Wang
- Department of Microbiology and Immunology, School of Medicine; Institute of Geriatric Immunology, School of Medicine, Jinan University, Guangzhou, 510632, China
- Key Laboratory of Viral Pathogenesis & Infection Prevention and Control (Jinan University), Ministry of Education, Guangzhou, 510632, China
- Guangdong-Hong Kong-Macau Great Bay Area Geroscience Joint Laboratory, School of Medicine, Jinan University, Guangzhou, 510632, China
| | - Shumin Li
- Department of Microbiology and Immunology, School of Medicine; Institute of Geriatric Immunology, School of Medicine, Jinan University, Guangzhou, 510632, China
- Key Laboratory of Viral Pathogenesis & Infection Prevention and Control (Jinan University), Ministry of Education, Guangzhou, 510632, China
- Guangdong-Hong Kong-Macau Great Bay Area Geroscience Joint Laboratory, School of Medicine, Jinan University, Guangzhou, 510632, China
| | - Jun Su
- First Affiliated Hospital, Jinan University, Guangzhou, 510630, China
| | - Lijuan Gao
- Department of Microbiology and Immunology, School of Medicine; Institute of Geriatric Immunology, School of Medicine, Jinan University, Guangzhou, 510632, China
- Key Laboratory of Viral Pathogenesis & Infection Prevention and Control (Jinan University), Ministry of Education, Guangzhou, 510632, China
- Guangdong-Hong Kong-Macau Great Bay Area Geroscience Joint Laboratory, School of Medicine, Jinan University, Guangzhou, 510632, China
| | - Junwen Ou
- Anti Aging Medical Center, Clifford Hospital, Guangzhou, 511495, China
| | - Zhanyi Lin
- Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, 510080, China
| | - Oscar Junhong Luo
- Department of Systems Biomedical Sciences, School of Medicine, Jinan University, Guangzhou, 510632, China
| | - Chanchan Xiao
- Department of Microbiology and Immunology, School of Medicine; Institute of Geriatric Immunology, School of Medicine, Jinan University, Guangzhou, 510632, China.
- Key Laboratory of Viral Pathogenesis & Infection Prevention and Control (Jinan University), Ministry of Education, Guangzhou, 510632, China.
- Guangdong-Hong Kong-Macau Great Bay Area Geroscience Joint Laboratory, School of Medicine, Jinan University, Guangzhou, 510632, China.
- The Sixth Affiliated Hospital of Jinan University (Dongguan Eastern Central Hospital), Jinan University, Dongguan, 523000, China.
- Zhuhai Institute of Jinan University, Jinan University, Zhuhai, 519070, China.
| | - Guobing Chen
- Department of Microbiology and Immunology, School of Medicine; Institute of Geriatric Immunology, School of Medicine, Jinan University, Guangzhou, 510632, China.
- Key Laboratory of Viral Pathogenesis & Infection Prevention and Control (Jinan University), Ministry of Education, Guangzhou, 510632, China.
- Guangdong-Hong Kong-Macau Great Bay Area Geroscience Joint Laboratory, School of Medicine, Jinan University, Guangzhou, 510632, China.
- The Sixth Affiliated Hospital of Jinan University (Dongguan Eastern Central Hospital), Jinan University, Dongguan, 523000, China.
- Zhuhai Institute of Jinan University, Jinan University, Zhuhai, 519070, China.
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Yang G, Su R, Bu J, Li Y, Lin X, Jin J, Zhang Y, Zhuang P, Guo H, Yin Q. Emerging role of adaptive immunity in diabetes-induced cognitive impairment: from the periphery to the brain. Metab Brain Dis 2025; 40:102. [PMID: 39821703 DOI: 10.1007/s11011-025-01532-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/10/2024] [Accepted: 01/09/2025] [Indexed: 01/19/2025]
Abstract
Diabetic cognitive impairment (DCI) is a central nervous system complication induced by peripheral metabolic dysfunction of diabetes mellitus. Cumulative studies have shown that neuro-immune crosstalk is involved in the pathological progression of DCI. However, current studies mostly focus on the interaction between innate immunity cells and neurons, while ignoring the role of adaptive immunity cells in DCI. Notably, recent studies have revealed adaptive immune cells are involved in cognitive development and the progression of neurodegenerative diseases. Equally important, accumulated past studies have also shown that diabetic patients experience imbalanced peripheral adaptive immune homeostasis and disrupted transmission of adaptive immune cells to the central system. Therefore, this review first updated the cognitive mechanism of adaptive immune regulation, and then summarized the contribution of adaptive immunity to DCI from the aspects of peripheral adaptive immune homeostasis, transmission pathways, and brain tissue infiltration. Furthermore, we also summarized the potential of anti-diabetic drugs to regulate adaptive immunity, and looked forward to the potential value of regulatory adaptive immunity in the prevention and treatment of DCI, to provide a new strategy for the prevention and treatment of DCI.
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Affiliation(s)
- Genhui Yang
- National Key Laboratory of Chinese Medicine Modernization, Tianjin University of Traditional Chinese Medicine, Jinghai District, Tianjin, 301617, China
- Haihe Laboratory of Modern Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China
| | - Runtao Su
- National Key Laboratory of Chinese Medicine Modernization, Tianjin University of Traditional Chinese Medicine, Jinghai District, Tianjin, 301617, China
- Haihe Laboratory of Modern Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China
| | - Jie Bu
- National Key Laboratory of Chinese Medicine Modernization, Tianjin University of Traditional Chinese Medicine, Jinghai District, Tianjin, 301617, China
- Haihe Laboratory of Modern Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China
| | - Ying Li
- National Key Laboratory of Chinese Medicine Modernization, Tianjin University of Traditional Chinese Medicine, Jinghai District, Tianjin, 301617, China
- Haihe Laboratory of Modern Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China
| | - Xueling Lin
- National Key Laboratory of Chinese Medicine Modernization, Tianjin University of Traditional Chinese Medicine, Jinghai District, Tianjin, 301617, China
- Haihe Laboratory of Modern Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China
| | - Jiahui Jin
- National Key Laboratory of Chinese Medicine Modernization, Tianjin University of Traditional Chinese Medicine, Jinghai District, Tianjin, 301617, China
- Haihe Laboratory of Modern Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China
| | - Yanjun Zhang
- National Key Laboratory of Chinese Medicine Modernization, Tianjin University of Traditional Chinese Medicine, Jinghai District, Tianjin, 301617, China
- Haihe Laboratory of Modern Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, 300193, China
- National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, 300193, China
| | - Pengwei Zhuang
- National Key Laboratory of Chinese Medicine Modernization, Tianjin University of Traditional Chinese Medicine, Jinghai District, Tianjin, 301617, China.
- Haihe Laboratory of Modern Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China.
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, 300193, China.
- National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, 300193, China.
| | - Hong Guo
- National Key Laboratory of Chinese Medicine Modernization, Tianjin University of Traditional Chinese Medicine, Jinghai District, Tianjin, 301617, China.
- Haihe Laboratory of Modern Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China.
| | - Qingsheng Yin
- National Key Laboratory of Chinese Medicine Modernization, Tianjin University of Traditional Chinese Medicine, Jinghai District, Tianjin, 301617, China.
- Haihe Laboratory of Modern Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China.
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Li H, Zou L, Long Z, Zhan J. Immunometabolic alterations in type 2 diabetes mellitus revealed by single-cell RNA sequencing: insights into subtypes and therapeutic targets. Front Immunol 2025; 15:1537909. [PMID: 39877357 PMCID: PMC11772204 DOI: 10.3389/fimmu.2024.1537909] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2024] [Accepted: 12/23/2024] [Indexed: 01/31/2025] Open
Abstract
Background Type 2 Diabetes Mellitus (T2DM) represents a major global health challenge, marked by chronic hyperglycemia, insulin resistance, and immune system dysfunction. Immune cells, including T cells and monocytes, play a pivotal role in driving systemic inflammation in T2DM; however, the underlying single-cell mechanisms remain inadequately defined. Methods Single-cell RNA sequencing of peripheral blood mononuclear cells (PBMCs) from 37 patients with T2DM and 11 healthy controls (HC) was conducted. Immune cell types were identified through clustering analysis, followed by differential expression and pathway analysis. Metabolic heterogeneity within T cell subpopulations was evaluated using Gene Set Variation Analysis (GSVA). Machine learning models were constructed to classify T2DM subtypes based on metabolic signatures, and T-cell-monocyte interactions were explored to assess immune crosstalk. Transcription factor (TF) activity was analyzed, and drug enrichment analysis was performed to identify potential therapeutic targets. Results In patients with T2DM, a marked increase in monocytes and a decrease in CD4+ T cells were observed, indicating immune dysregulation. Significant metabolic diversity within T cell subpopulations led to the classification of patients with T2DM into three distinct subtypes (A-C), with HC grouped as D. Enhanced intercellular communication, particularly through the MHC-I pathway, was evident in T2DM subtypes. Machine learning models effectively classified T2DM subtypes based on metabolic signatures, achieving an AUC > 0.84. Analysis of TF activity identified pivotal regulators, including NF-kB, STAT3, and FOXO1, associated with immune and metabolic disturbances in T2DM. Drug enrichment analysis highlighted potential therapeutic agents targeting these TFs and related pathways, including Suloctidil, Chlorpropamide, and other compounds modulating inflammatory and metabolic pathways. Conclusion This study underscores significant immunometabolic dysfunction in T2DM, characterized by alterations in immune cell composition, metabolic pathways, and intercellular communication. The identification of critical TFs and the development of drug enrichment profiles highlight the potential for personalized therapeutic strategies, emphasizing the need for integrated immunological and metabolic approaches in T2DM management.
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Affiliation(s)
- Huahua Li
- Department of Geriatric, Hunan Provincial People’s Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha, China
| | - Lingling Zou
- Department of Geriatric, Hunan Provincial People’s Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha, China
| | - Zhaowei Long
- Department of Geriatric, The Third Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Junkun Zhan
- Department of Geriatrics, The Second Xiangya Hospital, Central South University, Changsha, China
- Institute of Aging and Age-related Disease Research, Central South University, Changsha, China
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9
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Ruiz-Pozo VA, Guevara-Ramírez P, Paz-Cruz E, Tamayo-Trujillo R, Cadena-Ullauri S, Frias-Toral E, Simancas-Racines D, Altuna-Roshkova Y, Reytor-González C, Zambrano AK. The role of the Mediterranean diet in prediabetes management and prevention: a review of molecular mechanisms and clinical outcomes. FOOD AGR IMMUNOL 2024; 35. [DOI: 10.1080/09540105.2024.2398042] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2024] [Accepted: 08/23/2024] [Indexed: 01/04/2025] Open
Affiliation(s)
- Viviana A. Ruiz-Pozo
- Centro de Investigación Genética y Genómica, Facultad de Ciencias de la Salud Eugenio Espejo, Universidad UTE, Quito, Ecuador
| | - Patricia Guevara-Ramírez
- Centro de Investigación Genética y Genómica, Facultad de Ciencias de la Salud Eugenio Espejo, Universidad UTE, Quito, Ecuador
| | - Elius Paz-Cruz
- Centro de Investigación Genética y Genómica, Facultad de Ciencias de la Salud Eugenio Espejo, Universidad UTE, Quito, Ecuador
| | - Rafael Tamayo-Trujillo
- Centro de Investigación Genética y Genómica, Facultad de Ciencias de la Salud Eugenio Espejo, Universidad UTE, Quito, Ecuador
| | - Santiago Cadena-Ullauri
- Centro de Investigación Genética y Genómica, Facultad de Ciencias de la Salud Eugenio Espejo, Universidad UTE, Quito, Ecuador
| | | | - Daniel Simancas-Racines
- Centro de Investigación de Salud Pública y Epidemiología Clínica (CISPEC), Universidad UTE, Quito, Ecuador
| | - Yekaterina Altuna-Roshkova
- Centro de Investigación de Salud Pública y Epidemiología Clínica (CISPEC), Universidad UTE, Quito, Ecuador
| | - Claudia Reytor-González
- Centro de Investigación de Salud Pública y Epidemiología Clínica (CISPEC), Universidad UTE, Quito, Ecuador
| | - Ana Karina Zambrano
- Centro de Investigación Genética y Genómica, Facultad de Ciencias de la Salud Eugenio Espejo, Universidad UTE, Quito, Ecuador
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Vena W, Pigni S, Betella N, Navarra A, Mirani M, Mazziotti G, Lania AG, Bossi AC. COVID-19 vaccines and blood glucose control: Friend or foe? Hum Vaccin Immunother 2024; 20:2363068. [PMID: 38860457 PMCID: PMC11178329 DOI: 10.1080/21645515.2024.2363068] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2024] [Accepted: 05/30/2024] [Indexed: 06/12/2024] Open
Abstract
PURPOSE To overview the recent literature regarding the relationship between COVID-19 vaccines and glycemic control. METHODS Data were extracted from text and tables of all available articles published up to September 2023 in PubMed Database describing glucose homeostasis data in subjects exposed to COVID-19 vaccines, focusing on patients with diabetes mellitus (DM). RESULTS It is debated if the immune system impairment observed in diabetic patients makes them susceptible to lower efficacy of vaccines, but evidence suggests a possible improvement in immune response in those with good glycemic control. Despite their proven protective role lowering infection rates and disease severity, COVID-19 vaccines can result in diabetic ketoacidosis, new-onset diabetes, or episodes of hyper- or hypoglycemia. CONCLUSIONS Evidence with COVID-19 vaccines highlights the strong relationship existing between DM and immune system function. Clinicians should strive to achieve optimal glucose control before vaccination and promptly manage possible glucose homeostasis derangement following vaccine exposure.
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Affiliation(s)
- Walter Vena
- Department of Biomedical Sciences, Humanitas University, Milan, Pieve Emanuele, Italy
- Diabetes Center, Humanitas Gavazzeni Institute, Bergamo, Italy
| | - Stella Pigni
- Department of Biomedical Sciences, Humanitas University, Milan, Pieve Emanuele, Italy
- Endocrinology, Diabetology and Medical Andrology Unit, IRCCS Humanitas Research Hospital, Milan, Rozzano, Italy
| | | | | | - Marco Mirani
- Endocrinology, Diabetology and Medical Andrology Unit, IRCCS Humanitas Research Hospital, Milan, Rozzano, Italy
| | - Gherardo Mazziotti
- Department of Biomedical Sciences, Humanitas University, Milan, Pieve Emanuele, Italy
- Endocrinology, Diabetology and Medical Andrology Unit, IRCCS Humanitas Research Hospital, Milan, Rozzano, Italy
| | - Andrea G. Lania
- Department of Biomedical Sciences, Humanitas University, Milan, Pieve Emanuele, Italy
- Endocrinology, Diabetology and Medical Andrology Unit, IRCCS Humanitas Research Hospital, Milan, Rozzano, Italy
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11
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Gray V, Chen W, Tan RJY, Teo JMN, Huang Z, Fong CHY, Law TWH, Ye ZW, Yuan S, Bao X, Hung IFN, Tan KCB, Lee CH, Ling GS. Hyperglycemia-triggered lipid peroxidation destabilizes STAT4 and impairs anti-viral Th1 responses in type 2 diabetes. Cell Metab 2024; 36:2511-2527.e7. [PMID: 39488214 DOI: 10.1016/j.cmet.2024.10.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/15/2024] [Revised: 07/08/2024] [Accepted: 10/04/2024] [Indexed: 11/04/2024]
Abstract
Patients with type 2 diabetes (T2D) are more susceptible to severe respiratory viral infections, but the underlying mechanisms remain elusive. Here, we show that patients with T2D and coronavirus disease 2019 (COVID-19) infections, and influenza-infected T2D mice, exhibit defective T helper 1 (Th1) responses, which are an essential component of anti-viral immunity. This defect stems from intrinsic metabolic perturbations in CD4+ T cells driven by hyperglycemia. Mechanistically, hyperglycemia triggers mitochondrial dysfunction and excessive fatty acid synthesis, leading to elevated oxidative stress and aberrant lipid accumulation within CD4+ T cells. These abnormalities promote lipid peroxidation (LPO), which drives carbonylation of signal transducer and activator of transcription 4 (STAT4), a crucial Th1-lineage-determining factor. Carbonylated STAT4 undergoes rapid degradation, causing reduced T-bet induction and diminished Th1 differentiation. LPO scavenger ameliorates Th1 defects in patients with T2D who have poor glycemic control and restores viral control in T2D mice. Thus, this hyperglycemia-LPO-STAT4 axis underpins reduced Th1 activity in T2D hosts, with important implications for managing T2D-related viral complications.
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Affiliation(s)
- Victor Gray
- School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
| | - Weixin Chen
- School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
| | - Rachael Julia Yuenyinn Tan
- School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
| | - Jia Ming Nickolas Teo
- School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
| | - Zhihao Huang
- Department of Chemistry, Faculty of Science, The University of Hong Kong, Hong Kong SAR, China
| | - Carol Ho-Yi Fong
- Department of Medicine, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong SAR, China
| | - Tommy Wing Hang Law
- Department of Medicine, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong SAR, China
| | - Zi-Wei Ye
- School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
| | - Shuofeng Yuan
- Department of Microbiology, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong SAR, China; State Key Laboratory of Emerging Infectious Diseases, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong SAR, China
| | - Xiucong Bao
- School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
| | - Ivan Fan-Ngai Hung
- Department of Medicine, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong SAR, China
| | - Kathryn Choon-Beng Tan
- Department of Medicine, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong SAR, China.
| | - Chi-Ho Lee
- Department of Medicine, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong SAR, China.
| | - Guang Sheng Ling
- School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China; Department of Medicine, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong SAR, China; The University of Hong Kong-Shenzhen Hospital, Shenzhen, Guangdong, China.
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12
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Zhang J, Cai Y, Qin Y, Liu J, Ding J, Xu M, Yang L, Zheng Y, Zhang X. Heat shock protein 70 promotes the progression of type 2 diabetic nephropathy by inhibiting T-cell immunoglobulin and mucin domain-3 and thereby promoting Th17/Treg imbalance. Nephrology (Carlton) 2024; 29:806-814. [PMID: 39434257 DOI: 10.1111/nep.14396] [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: 07/12/2023] [Revised: 09/04/2024] [Accepted: 09/13/2024] [Indexed: 10/23/2024]
Abstract
AIM Diabetic nephropathy (DN) is the most common complication of diabetes mellitus. We aimed to investigate the role of regulatory T cells (Tregs) and helper T cells 17 (Th17) in the development and progression of DN. METHODS A mouse type 2 diabetic nephropathy (T2DN) model was established. Immunohistochemistry was used to detect the expression of HSP70 and Tim-3 in mouse kidney tissues, and western blotting was used to detect the expression levels of HSP70 and Tim-3. PAS staining and Masson's trichrome staining were used to detect the degree of kidney injury. Flow cytometry was used to detect the number of Th17 and Treg cells in blood and kidney tissues. The expression levels of interleukin 17 (IL-17) and interleukin 10 (IL-10) in the serum were measured via ELISA. RESULTS The expression of HSP70 was significantly increased while the expression of Tim-3 was significantly decreased in the kidneys of mice in the T2DN group compared with those in the control (NC) group. Additionally, the inhibition of HSP70 upregulated the expression of Tim-3 in T2DN mice. The Th17/Treg ratio was significantly greater in the blood and kidneys of the mice in the T2DN group than in those of the NC group, the expression of serum IL-17 was increased, and the expression of IL-10 was decreased. CONCLUSION Increased HSP70 inhibits Tim-3 expression in T2DN mouse kidney tissues, and subsequently causes a Th17/Treg imbalance and an inflammatory response, ultimately leading to kidney injury. The inhibition of HSP70 may alleviate the progression of T2DN.
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Affiliation(s)
- Juntai Zhang
- Department of Nephrology & Immunology, Affiliated Calmette Hospital of Kunming Medical University, Kunming, Yunnan, China
| | - Yan Cai
- Department of Nephrology, The Fifth Affiliated Hospital of Kunming Medical University, Gejiu, Yunnan, China
| | - Yan Qin
- Department of Nephrology & Immunology, Affiliated Calmette Hospital of Kunming Medical University, Kunming, Yunnan, China
| | - Jie Liu
- Department of Pathology, Affiliated Calmette Hospital of Kunming Medical University, Kunming, Yunnan, China
| | - Jie Ding
- Department of Ultrasound, Affiliated Calmette Hospital of Kunming Medical University, Kunming, Yunnan, China
| | - Mengying Xu
- Department of Nephrology & Immunology, Affiliated Calmette Hospital of Kunming Medical University, Kunming, Yunnan, China
| | - Li Yang
- Department of Nephrology & Immunology, Affiliated Calmette Hospital of Kunming Medical University, Kunming, Yunnan, China
| | - Yuanxin Zheng
- Department of Nephrology & Immunology, Affiliated Calmette Hospital of Kunming Medical University, Kunming, Yunnan, China
| | - Xi Zhang
- Department of Nephrology & Immunology, Affiliated Calmette Hospital of Kunming Medical University, Kunming, Yunnan, China
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Lobato TB, Santos ESDS, Iser-Bem PN, Falcão HDS, Gimenes GM, Pauferro JRB, Rodrigues GT, Correa IS, Pereira ACG, Passos MEP, Borges JCDO, Alves ACDA, Santos CSD, Araújo MJLD, Diniz VLS, Levada-Pires AC, Pithon-Curi TC, Masi LN, Curi R, Hirabara SM, Gorjão R. Omega-3 Fatty Acids Weaken Lymphocyte Inflammatory Features and Improve Glycemic Control in Nonobese Diabetic Goto-Kakizaki Rats. Nutrients 2024; 16:4106. [PMID: 39683500 DOI: 10.3390/nu16234106] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2024] [Revised: 10/30/2024] [Accepted: 11/03/2024] [Indexed: 12/18/2024] Open
Abstract
BACKGROUND/OBJECTIVES Goto-Kakizaki (GK) rats exhibit insulin resistance and type 2 diabetes mellitus (T2DM) without obesity. This study explored the effects of ω-3 fatty acid supplementation on T lymphocyte polarization in Wistar (WT) and GK rats. METHODS They were administered ω-3 fatty acid-rich fish oil (FO) containing eicosapentaenoic (540 mg/g) and docosahexaenoic acids (100 mg/g) by oral gavage at 2 g/kg, thrice a week for 8 weeks. The control groups (WT CT and GK CT) received the same volume of water. The following groups were investigated: GK CT, n = 14; GK ω-3, n = 15; Wistar CT, n = 15; and Wistar ω-3, n = 11. Glucose and insulin tolerance tests (GTT and ITT) were performed. Fasting plasma insulinemia and glycemia were measured. After euthanasia, the lymphocytes were extracted from the mesenteric lymph nodes. RESULTS The results showed that GK rats supplemented with FO had significantly improved glucose tolerance and insulin sensitivity (kITT). It also promoted greater polarization of lymphocytes toward T regulatory (Treg) features and a reduction in Th1 and Th17 profiles. Additionally, the GK ω-3 group exhibited lower cell proliferation, decreased pro-inflammatory cytokines, and increased IL-10 levels compared to the GK control. CONCLUSIONS In conclusion, FO supplementation benefited GK rats by improving glucose intolerance, suppressing insulin resistance, and modulating lymphocytes toward Treg polarization.
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Affiliation(s)
- Tiago Bertola Lobato
- Interdisciplinary Post-Graduate Program in Health Sciences, Cruzeiro do Sul University, São Paulo 01506-000, Brazil
| | | | - Patrícia Nancy Iser-Bem
- Interdisciplinary Post-Graduate Program in Health Sciences, Cruzeiro do Sul University, São Paulo 01506-000, Brazil
- National Commercial Learning Service (SENAC), São Paulo 01102-000, Brazil
| | - Henrique de Souza Falcão
- Interdisciplinary Post-Graduate Program in Health Sciences, Cruzeiro do Sul University, São Paulo 01506-000, Brazil
| | - Gabriela Mandú Gimenes
- Interdisciplinary Post-Graduate Program in Health Sciences, Cruzeiro do Sul University, São Paulo 01506-000, Brazil
| | | | - Glayce Tavares Rodrigues
- Interdisciplinary Post-Graduate Program in Health Sciences, Cruzeiro do Sul University, São Paulo 01506-000, Brazil
| | - Ilana Souza Correa
- Interdisciplinary Post-Graduate Program in Health Sciences, Cruzeiro do Sul University, São Paulo 01506-000, Brazil
| | - Ana Carolina Gomes Pereira
- Interdisciplinary Post-Graduate Program in Health Sciences, Cruzeiro do Sul University, São Paulo 01506-000, Brazil
| | | | | | | | - Camila Soares Dos Santos
- Interdisciplinary Post-Graduate Program in Health Sciences, Cruzeiro do Sul University, São Paulo 01506-000, Brazil
| | | | | | | | - Tânia Cristina Pithon-Curi
- Interdisciplinary Post-Graduate Program in Health Sciences, Cruzeiro do Sul University, São Paulo 01506-000, Brazil
| | - Laureane Nunes Masi
- Interdisciplinary Post-Graduate Program in Health Sciences, Cruzeiro do Sul University, São Paulo 01506-000, Brazil
- Department of Physiological Sciences, Multicenter Graduate Program in Physiological Sciences, Federal University of Santa Catarina, Florianópolis 88040-900, Brazil
| | - Rui Curi
- Interdisciplinary Post-Graduate Program in Health Sciences, Cruzeiro do Sul University, São Paulo 01506-000, Brazil
- Educantion Center, Butantan Institute, São Paulo 05585-000, Brazil
| | - Sandro Massao Hirabara
- Interdisciplinary Post-Graduate Program in Health Sciences, Cruzeiro do Sul University, São Paulo 01506-000, Brazil
| | - Renata Gorjão
- Interdisciplinary Post-Graduate Program in Health Sciences, Cruzeiro do Sul University, São Paulo 01506-000, Brazil
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Alhamawi RM, Damfo S, Aloufi N, Almutawif YA, Suliman BA. Investigating the potential role of T helper 17 cells among women experiencing overweight and obesity and their possible therapeutic targeting of the RORγt molecule. Sci Rep 2024; 14:29279. [PMID: 39592819 PMCID: PMC11599566 DOI: 10.1038/s41598-024-81070-1] [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: 06/25/2024] [Accepted: 11/25/2024] [Indexed: 11/28/2024] Open
Abstract
Obesity is a growing healthcare problem globally. In Saudi Arabia, 24% of adults aged 15 years and above have been living with Obesity. It is considered a chronic inflammatory condition that is linked to a wide range of disorders including type 2 diabetes mellitus, insulin resistance and cardiovascular diseases. In this study, we aimed to assess the influence of obesity on the proportion of Th17 cells among healthy, overweight, and obese women in Saudi Arabia. Additionally, we aimed to explore potential ligands targeting the master transcription factor of Th17 cells: RORγt. A cross-sectional study was conducted, wherein their body mass index (BMI) and waist circumference (WC) were measured. The proportion of peripheral Th17 cells was determined using flow cytometry. We found a decrease in the proportion of peripheral Th17 among women with central obesity, though this was observed among overweight and obese participants. Interestingly, both BMI and WC were inversely correlated with the proportion of peripheral Th17 cells in women experiencing overweight or obesity, while no change was observed among healthy participants. Notably, the analysis revealed a significant moderate negative correlation between the proportion of Th17 cells and HbA1c levels, observed only among the overweight and obese participants. In this study, we identified three potential binding sites on RORγt molecules of Th17 cells, bound to 58 chemical ligands. The majority of the chemical structures (72.4%) were targeted binding pocket 1 of the RORγt molecule. These findings could provide a new insight to develop new pharmaceutical molecules targeting immune cells to combat obesity and related metabolic disorders.
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Affiliation(s)
- Renad M Alhamawi
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Taibah University, Madinah, Saudi Arabia.
| | - Shymaa Damfo
- Department of Pharmacognosy and Pharmaceutical Chemistry, College of Pharmacy, Taibah University, Madinah, Saudi Arabia
| | - Noof Aloufi
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Taibah University, Madinah, Saudi Arabia
| | - Yahya A Almutawif
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Taibah University, Madinah, Saudi Arabia
| | - Bandar A Suliman
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Taibah University, Madinah, Saudi Arabia
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15
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Saotome M, Kuraji R, Numabe Y. Hyperglycemia Exacerbates Periodontal Destruction via Systemic Suppression of Regulatory T Cell Number and Function. J Periodontal Res 2024. [PMID: 39578679 DOI: 10.1111/jre.13366] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2024] [Revised: 10/28/2024] [Accepted: 11/07/2024] [Indexed: 11/24/2024]
Abstract
AIM Diabetes is a significant risk factor that exacerbates the pathological progression of periodontal disease. In recent years, attention has focused on the effect of regulatory T cells (Tregs), which play a central role in immune tolerance, on inflammatory processes in periodontal tissue, suggesting a link with diabetes-associated periodontitis. In this study, we examined the dynamics of Tregs in periodontal tissue of mice with streptozotocin (STZ)-induced hyperglycemia. METHODS Eleven-week-old male C57BL/6J mice were divided into four treatment groups: Untreated (C group), ligature placed around the maxillary second molars with silk sutures (PD group), intraperitoneal administration of STZ (HG group), and ligature placed after STZ administration (PHG group). Establishment of hyperglycemia was assessed 14 days after STZ administration, and ligation was performed 7 days later. After another 7 days of ligation, the mice were euthanized. The right side of the maxilla was observed histopathologically, whereas the palatal gingiva on the left side of the maxilla was analyzed genetically, and the microstructure of the alveolar bone was also assessed. In addition, lymphocytes from peripheral blood, spleen, and periodontal tissue were analyzed using flow cytometry. RESULTS In bone structure analyses, alveolar bone height, bone volume/tissue volume (BV/TV), and bone mineral density (BMD) were lower in the PHG group than the PD group. In the gingival tissue, expression of the Foxp3 gene was up-regulated in the PHG group compared with the C group, and IL-17a was up-regulated in the PHG group compared with the PD group. Flow cytometry analyses showed that the number of Tregs (CD4+CD25+Foxp3+ cells) in the blood and gingival tissue was significantly higher in the PD and PHG groups than the C group. The number of CD4+CD25-Foxp3+ cells, which are reportedly functionally attenuated as Tregs, was increased in blood of the PHG group. Immunofluorescence staining of periodontal tissue showed that the number of CD25+Foxp3+ cells was significantly increased only in the PD group, whereas a trend toward an increased number of CD25-Foxp3+ cells was observed in the PHG group. CONCLUSION The present study showed that STZ-induced hyperglycemia numerically and functionally attenuates Tregs in a mouse model of experimental periodontitis. Furthermore, impaired immune tolerance capacity appears to be involved in exacerbating inflammation and bone destruction in periodontal tissue.
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Affiliation(s)
- Masami Saotome
- Department of Periodontology, The Nippon Dental University School of Life Dentistry at Tokyo, Tokyo, Japan
| | - Ryutaro Kuraji
- Department of Periodontology, The Nippon Dental University School of Life Dentistry at Tokyo, Tokyo, Japan
| | - Yukihiro Numabe
- Department of Periodontology, The Nippon Dental University School of Life Dentistry at Tokyo, Tokyo, Japan
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Lee H, Kim MJ, Lee IK, Hong CW, Jeon JH. Impact of hyperglycemia on immune cell function: a comprehensive review. Diabetol Int 2024; 15:745-760. [PMID: 39469566 PMCID: PMC11512986 DOI: 10.1007/s13340-024-00741-6] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/13/2024] [Accepted: 06/10/2024] [Indexed: 10/30/2024]
Abstract
Hyperglycemia, a hallmark of diabetes and various metabolic disorders, has profound implications for immune cell function. The relationship between elevated blood glucose levels and immune cell function is a topic of significant medical interest. In this review, we aim to comprehensively review effects of hyperglycemia on various immune cell types and its clinical implications, particularly T cells, macrophages, natural killer cells, and neutrophils. It aims to consolidate current knowledge on the subject, with a focus on both type 1 and type 2 diabetes, as well as other pathological states where hyperglycemia is a concern. A comprehensive examination of recent studies and clinical data was conducted to assess effects of hyperglycemia on immune cell function. Evidence indicates that hyperglycemia can significantly alter immune cell function, with different diabetic conditions showing varied responses. Roles of key metabolic hormones in regulating T cell function highlight potential therapeutic targets for restoring immune balance. In addition, reprogramming of innate immune cells such as macrophages and natural killer cells under hyperglycemic conditions suggests a complex metabolic-immunological interface. This review will contribute to a better understanding of the link between diabetes, other metabolic disorders, and immune function. By examining recent research and clinical findings, this review will enhance our comprehension of the mechanisms at play and guide future medical strategies for managing and treating conditions associated with hyperglycemia.
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Affiliation(s)
- Hoyul Lee
- Research Institute of Aging and Metabolism, Kyungpook National University, Daegu, Republic of Korea
| | - Min-Ji Kim
- Department of Internal Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Chilgok Hospital, 807 Hoguk-Ro, Buk-Gu, Daegu, 41404 Republic of Korea
| | - In-Kyu Lee
- Department of Internal Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu, Republic of Korea
| | - Chang-Won Hong
- Department of Physiology, School of Medicine, Kyungpook National University, Daegu, Republic of Korea
| | - Jae-Han Jeon
- Department of Internal Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Chilgok Hospital, 807 Hoguk-Ro, Buk-Gu, Daegu, 41404 Republic of Korea
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Lobato TB, Manoel R, Pereira ACG, Correa IS, Iser-Bem PN, Santos ESDS, Pereira JNB, de Araújo MJL, Borges JCDO, Pauferro JRB, Diniz VLS, Scervino MVM, Serdan TD, Pithon-Curi TC, Masi LN, Hirabara SM, Curi R, Gorjão R. Insulin resistance in nonobese type 2 diabetic Goto Kakizaki rats is associated with a proinflammatory T lymphocyte profile. FEBS Lett 2024; 598:2566-2580. [PMID: 39095330 DOI: 10.1002/1873-3468.14977] [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: 02/14/2024] [Revised: 05/27/2024] [Accepted: 06/01/2024] [Indexed: 08/04/2024]
Abstract
Goto-Kakizaki (GK) rats develop a well-defined insulin resistance (IR) and type 2 diabetes mellitus (T2DM) without presenting obesity. The lymphocyte profile in nonobese diabetic conditions is not yet characterized. Therefore, GK rats were chosen to explore T lymphocyte (TL) dynamics at various stages (21, 60, and 120 days) compared to Wistar rats. GK rats exhibit progressive disruption of glucose regulation, with early glucose intolerance at 21 days and reduced insulin sensitivity at 60 days, confirming IR. Glucose transporter 1 (GLUT1) expression was consistently elevated in GK rats, suggesting heightened TL activation. T-regulatory lymphocyte markers diminished at 21 days. However, GK rats showed increased Th1 markers and reduced Gata-3 expression (crucial for Th2 cell differentiation) at 120 days. These findings underscore an early breakdown of anti-inflammatory mechanisms in GK rats, indicating a proinflammatory TL profile that may worsen chronic inflammation in T2DM.
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Affiliation(s)
- Tiago Bertola Lobato
- Interdisciplinary Post-Graduate Program in Health Sciences, Cruzeiro do Sul University, São Paulo, Brazil
| | - Richelieau Manoel
- Interdisciplinary Post-Graduate Program in Health Sciences, Cruzeiro do Sul University, São Paulo, Brazil
| | - Ana Carolina Gomes Pereira
- Interdisciplinary Post-Graduate Program in Health Sciences, Cruzeiro do Sul University, São Paulo, Brazil
| | - Ilana Souza Correa
- Interdisciplinary Post-Graduate Program in Health Sciences, Cruzeiro do Sul University, São Paulo, Brazil
| | - Patrícia Nancy Iser-Bem
- Interdisciplinary Post-Graduate Program in Health Sciences, Cruzeiro do Sul University, São Paulo, Brazil
| | | | | | | | | | | | | | | | - Tamires Duarte Serdan
- Interdisciplinary Post-Graduate Program in Health Sciences, Cruzeiro do Sul University, São Paulo, Brazil
| | - Tania Cristina Pithon-Curi
- Interdisciplinary Post-Graduate Program in Health Sciences, Cruzeiro do Sul University, São Paulo, Brazil
| | - Laureane Nunes Masi
- Interdisciplinary Post-Graduate Program in Health Sciences, Cruzeiro do Sul University, São Paulo, Brazil
- Department of Physiological Sciences, Center of Biological Sciences, Federal University of Santa Catarina-UFSC, Brazil
| | - Sandro Massao Hirabara
- Interdisciplinary Post-Graduate Program in Health Sciences, Cruzeiro do Sul University, São Paulo, Brazil
| | - Rui Curi
- Interdisciplinary Post-Graduate Program in Health Sciences, Cruzeiro do Sul University, São Paulo, Brazil
- Immunobiological Production Section, Bioindustrial Center, Butantan Institute, São Paulo, Brazil
| | - Renata Gorjão
- Interdisciplinary Post-Graduate Program in Health Sciences, Cruzeiro do Sul University, São Paulo, Brazil
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18
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Yang F, Li J, Wei L, Qin S, Shi Q, Lu S, Chu S. The characteristics of intestinal microbiota in patients with type 2 diabetes and the correlation with the percentage of T-helper cells. Front Microbiol 2024; 15:1443743. [PMID: 39397795 PMCID: PMC11466775 DOI: 10.3389/fmicb.2024.1443743] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2024] [Accepted: 08/22/2024] [Indexed: 10/15/2024] Open
Abstract
Background Type 2 diabetes (T2D) is related to intestinal microflora changes and immune inflammation. We aimed to investigate the pattern of intestinal flora-systematic T helper (Th) cell linkage in T2D patients. Methods Participants with T2D diagnosed by physicians and healthy controls were enrolled in the study. The Th1, Th2, and Th17 cells from the peripheral blood were assessed by flow cytometry. The feces were collected. The V3-V4 variable region of 16S rRNA was sequenced and analyzed using bioinformatics. Principal coordinate analysis (PCoA) and non-metric multidimensional scaling (NMDS) analysis were performed to assess the beta diversity. The linear discriminant analysis (LDA) effect size (LEfSe) method was applied to identify amicrobial taxon specific to T2D. The Phylogenetic Investigation of Communities by Reconstruction of Unobserved States (PICRUSt) was conducted to identify the metabolic pathways. A network analysis was conducted by constructing a co-occurrence network. Results The percentages of the Th1 and Th17 cells in the peripheral blood were higher in patients with T2D than in controls. Among the top 30 genera of the intestinal microbiota, the levels of Lachnospiraceae_NK4A136_group, Ruminococcaceae_UCG002, and Eubacterium_hallii_group were lower in the patients with T2D than in controls. In the LEfSe analysis, it was observed that the Lachnospiraceae and Ruminococcaceae families were significantly different between patients with T2D and controls. Moreover, the Th1/Th2 ratio was positively correlated with the abundance of the Lachnoclostridium and Ruminococcus_torques_group genera. In the network analysis, the Th1/Th2 ratio, Ruminococcaceae_UCG-002, and Lachnospiraceae_NK4A136_group were the important nodes. Conclusion This study provided a preliminary picture of the crosstalk between the intestinal microbiome and systematic Th cells in patients with T2D. The findings of the study suggested that the network relationship among the intestinal microbiota, metabolites, and CD4+T lymphocyte immunity was unbalanced in the patients with T2D, which might have promoted the development of T2D. This presents a therapeutic opportunity to modulate gut immune reaction and then chronic inflammation by manipulating microbiome-specific Th-cell response.
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Affiliation(s)
- Fan Yang
- Department of Endocrinology, Guilin People's Hospital, Guilin, China
- Research Service Department, Guilin People's Hospital, Guilin, China
| | - Jinyan Li
- Department of Endocrinology, Guilin People's Hospital, Guilin, China
- Department of Endocrinology, Affiliated Hospital of Guilin Medical University, Guilin, China
- Medical Department, The Reproductive Hospital of Guangxi Zhuang Autonomous Region, Nanning, China
| | - Longqin Wei
- Research Service Department, Guilin People's Hospital, Guilin, China
| | - Shenghua Qin
- Health Management Center, Guilin People's Hospital, Guilin, China
| | - Qingfeng Shi
- Laboratory Department, Guilin People's Hospital, Guilin, China
| | - Siyan Lu
- Rheumatology and Immunology Department, The Second Affiliated Hospital of Guilin Medical University, Guilin, China
| | - Shuyuan Chu
- Laboratory of Respiratory Disease, Affiliated Hospital of Guilin Medical University, Guilin, China
- Guangxi Clinical Research Center for Diabetes and Metabolic Diseases, The Second Affiliated Hospital of Guilin Medical University, Guilin, China
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19
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Giardinelli S, Meliota G, Mentino D, D’Amato G, Faienza MF. Molecular Basis of Cardiomyopathies in Type 2 Diabetes. Int J Mol Sci 2024; 25:8280. [PMID: 39125850 PMCID: PMC11313011 DOI: 10.3390/ijms25158280] [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: 06/22/2024] [Revised: 07/23/2024] [Accepted: 07/26/2024] [Indexed: 08/12/2024] Open
Abstract
Diabetic cardiomyopathy (DbCM) is a common complication in individuals with type 2 diabetes mellitus (T2DM), and its exact pathogenesis is still debated. It was hypothesized that chronic hyperglycemia and insulin resistance activate critical cellular pathways that are responsible for numerous functional and anatomical perturbations in the heart. Interstitial inflammation, oxidative stress, myocardial apoptosis, mitochondria dysfunction, defective cardiac metabolism, cardiac remodeling, hypertrophy and fibrosis with consequent impaired contractility are the most common mechanisms implicated. Epigenetic changes also have an emerging role in the regulation of these crucial pathways. The aim of this review was to highlight the increasing knowledge on the molecular mechanisms of DbCM and the new therapies targeting specific pathways.
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Affiliation(s)
- Silvia Giardinelli
- Department of Medical Sciences, Pediatrics, University of Ferrara, 44121 Ferrara, Italy;
| | - Giovanni Meliota
- Department of Pediatric Cardiology, Giovanni XXIII Pediatric Hospital, 70126 Bari, Italy;
| | - Donatella Mentino
- Pediatric Unit, Department of Precision and Regenerative Medicine and Ionian Area, University of Bari “Aldo Moro”, 70124 Bari, Italy;
| | - Gabriele D’Amato
- Neonatal Intensive Care Unit, Di Venere Hospital, 70012 Bari, Italy;
| | - Maria Felicia Faienza
- Pediatric Unit, Department of Precision and Regenerative Medicine and Ionian Area, University of Bari “Aldo Moro”, 70124 Bari, Italy;
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20
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Park DY, Kim CH, Park DY, Kim HJ, Cho HJ. Intermittent hypoxia induces Th17/Treg imbalance in a murine model of obstructive sleep apnea. PLoS One 2024; 19:e0305230. [PMID: 38913648 PMCID: PMC11195984 DOI: 10.1371/journal.pone.0305230] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2024] [Accepted: 05/28/2024] [Indexed: 06/26/2024] Open
Abstract
Obstructive sleep apnea (OSA) is characterized by cyclic normoxic and hypoxic conditions (intermittent hypoxia, IH) induced by the repeated closure of the upper-airway respiratory tract. As a pathomechanism of OSA, IH results in various comorbidities via chronic inflammation and related pathways. However, the role of other inflammatory cells, such as lymphocytes, has not been well-explored. This study aimed to examine the effects of IH on the distribution and balance of T cell subsets and other related cytokines, and mechanisms in the immune system. We modified OSA mouse model (male C57BL/6N male) using our customized chamber that controls specific sleep and oxygenic cycles. To induce hypoxia, the IH group was repeatedly exposed to 5% O2 and 21% O2 lasting for 120 s each for 7 h daily for 4 weeks. Mice were then subjected to a recovery period of 4 weeks, in which IH stimulation was ceased. T cells and related cytokines were analyzed using flow cytometry and immunohistochemistry. Compared with the control group, the IH group had significantly lower levels of CD4+CD25+Foxp3+ regulatory T cells but higher levels of Th 17, IL-4, HIF-1, and inflammatory cytokines. After the recovery period, these altered changes in the immune cells were recovered, and we found no significant difference in their levels between the control and recovery groups. This study revealed that the Th17/Treg ratio is increased by intermittent hypoxia, and this imbalance can explain immune-related diseases, including recently reported allergies, autoimmune, and even cancer diseases, arising from OSA.
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Affiliation(s)
- Do-Yang Park
- Department of Otolaryngology, Ajou University School of Medicine, Suwon, Republic of Korea
- Department of Medicine, Graduate School, Yonsei University, Seoul, Republic of Korea
| | - Chang-Hoon Kim
- Department of Otorhinolaryngology, Yonsei University College of Medicine, Seoul, Republic of Korea
- The Airway Mucus Institute, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Da-Young Park
- Department of Otolaryngology, Ajou University School of Medicine, Suwon, Republic of Korea
| | - Hyun Jun Kim
- Department of Otolaryngology, Ajou University School of Medicine, Suwon, Republic of Korea
| | - Hyung-Ju Cho
- Department of Otorhinolaryngology, Yonsei University College of Medicine, Seoul, Republic of Korea
- The Airway Mucus Institute, Yonsei University College of Medicine, Seoul, Republic of Korea
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21
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Joshi G, Das A, Verma G, Guchhait P. Viral infection and host immune response in diabetes. IUBMB Life 2024; 76:242-266. [PMID: 38063433 DOI: 10.1002/iub.2794] [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: 03/17/2023] [Accepted: 11/05/2023] [Indexed: 04/24/2024]
Abstract
Diabetes, a chronic metabolic disorder disrupting blood sugar regulation, has emerged as a prominent silent pandemic. Uncontrolled diabetes predisposes an individual to develop fatal complications like cardiovascular disorders, kidney damage, and neuropathies and aggravates the severity of treatable infections. Escalating cases of Type 1 and Type 2 diabetes correlate with a global upswing in diabetes-linked mortality. As a growing global concern with limited preventive interventions, diabetes necessitates extensive research to mitigate its healthcare burden and assist ailing patients. An altered immune system exacerbated by chronic hyperinflammation heightens the susceptibility of diabetic individuals to microbial infections, including notable viruses like SARS-CoV-2, dengue, and influenza. Given such a scenario, we scrutinized the literature and compiled molecular pathways and signaling cascades related to immune compartments in diabetics that escalate the severity associated with the above-mentioned viral infections in them as compared to healthy individuals. The pathogenesis of these viral infections that trigger diabetes compromises both innate and adaptive immune functions and pre-existing diabetes also leads to heightened disease severity. Lastly, this review succinctly outlines available treatments for diabetics, which may hold promise as preventive or supportive measures to effectively combat these viral infections in the former.
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Affiliation(s)
- Garima Joshi
- Regional Centre for Biotechnology, National Capital Region Biotech Science Cluster, Faridabad, India
| | - Anushka Das
- Regional Centre for Biotechnology, National Capital Region Biotech Science Cluster, Faridabad, India
| | - Garima Verma
- Regional Centre for Biotechnology, National Capital Region Biotech Science Cluster, Faridabad, India
| | - Prasenjit Guchhait
- Regional Centre for Biotechnology, National Capital Region Biotech Science Cluster, Faridabad, India
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22
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Lin DW, Yang TM, Ho C, Shih YH, Lin CL, Hsu YC. Targeting Macrophages: Therapeutic Approaches in Diabetic Kidney Disease. Int J Mol Sci 2024; 25:4350. [PMID: 38673935 PMCID: PMC11050450 DOI: 10.3390/ijms25084350] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2024] [Revised: 04/10/2024] [Accepted: 04/11/2024] [Indexed: 04/28/2024] Open
Abstract
Diabetes is not solely a metabolic disorder but also involves inflammatory processes. The immune response it incites is a primary contributor to damage in target organs. Research indicates that during the initial phases of diabetic nephropathy, macrophages infiltrate the kidneys alongside lymphocytes, initiating a cascade of inflammatory reactions. The interplay between macrophages and other renal cells is pivotal in the advancement of kidney disease within a hyperglycemic milieu. While M1 macrophages react to the inflammatory stimuli induced by elevated glucose levels early in the disease progression, their subsequent transition to M2 macrophages, which possess anti-inflammatory and tissue repair properties, also contributes to fibrosis in the later stages of nephropathy by transforming into myofibroblasts. Comprehending the diverse functions of macrophages in diabetic kidney disease and regulating their activity could offer therapeutic benefits for managing this condition.
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Affiliation(s)
- Da-Wei Lin
- Department of Internal Medicine, St. Martin De Porres Hospital, Chiayi City 60069, Taiwan;
| | - Tsung-Ming Yang
- Division of Pulmonary and Critical Care Medicine, Chang Gung Memorial Hospital, Chiayi County 61363, Taiwan;
- School of Traditional Chinese Medicine, College of Medicine, Chang Gung University, Taoyuan 33303, Taiwan;
| | - Cheng Ho
- Division of Endocrinology and Metabolism, Chang Gung Memorial Hospital, Chiayi County 61363, Taiwan;
| | - Ya-Hsueh Shih
- Departments of Nephrology, Chang Gung Memorial Hospital, Chiayi County 61363, Taiwan;
- Kidney and Diabetic Complications Research Team (KDCRT), Chang Gung Memorial Hospital, Chiayi County 61363, Taiwan
| | - Chun-Liang Lin
- School of Traditional Chinese Medicine, College of Medicine, Chang Gung University, Taoyuan 33303, Taiwan;
- Departments of Nephrology, Chang Gung Memorial Hospital, Chiayi County 61363, Taiwan;
- Kidney and Diabetic Complications Research Team (KDCRT), Chang Gung Memorial Hospital, Chiayi County 61363, Taiwan
- Kidney Research Center, Chang Gung Memorial Hospital, Taipei 10507, Taiwan
- Center for Shockwave Medicine and Tissue Engineering, Chang Gung Memorial Hospital, Kaohsiung 83301, Taiwan
| | - Yung-Chien Hsu
- Departments of Nephrology, Chang Gung Memorial Hospital, Chiayi County 61363, Taiwan;
- Kidney and Diabetic Complications Research Team (KDCRT), Chang Gung Memorial Hospital, Chiayi County 61363, Taiwan
- School of Medicine, College of Medicine, Chang Gung University, Taoyuan 33303, Taiwan
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23
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Rose S, Landes RD, Vyas KK, Delhey L, Blossom S. Regulatory T cells and bioenergetics of peripheral blood mononuclear cells linked to pediatric obesity. IMMUNOMETABOLISM (COBHAM, SURREY) 2024; 6:e00040. [PMID: 38680993 PMCID: PMC11045398 DOI: 10.1097/in9.0000000000000040] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 12/04/2023] [Accepted: 03/14/2024] [Indexed: 05/01/2024]
Abstract
Background Obesity-associated inflammation drives the development of insulin resistance and type 2 diabetes. We sought to identify associations of circulating regulatory T cells (Treg) with the degree of obesity (eg, body mass index Z-score [BMIz]), insulin resistance (homeostatic model of insulin resistance [HOMA-IR]), and glycemic control (HbA1c) in children and adolescents. We further sought to examine associations among bioenergetics of peripheral blood mononuclear cells (PBMCs) and CD4 T cells and BMIz, HOMA-IR, and HbA1c. Methods A total of 65 children and adolescents between the ages 5 and 17 years were studied. HbA1c and fasting levels of plasma glucose and insulin were measured. We quantified circulating Tregs (CD3+CD4+CD25+CD127-FoxP3+) by flow cytometry, and measured mitochondrial respiration (oxygen consumption rate [OCR]) and glycolysis (extracellular acidification rate [ECAR]) in PBMCs and isolated CD4 T cells by Seahorse extracellular flux analysis. Results Tregs (% CD4) are negatively associated with BMIz but positively associated with HOMA-IR. In PBMCs, OCR/ECAR (a ratio of mitochondrial respiration to glycolysis) is positively associated with BMIz but negatively associated with HbA1c. Conclusions In children, Tregs decrease as body mass index increases; however, the metabolic stress and inflammation associated with insulin resistance may induce a compensatory increase in Tregs. The degree of obesity is also associated with a shift away from glycolysis in PBMCs but as HbA1c declines, metabolism shifts back toward glycolysis. Comprehensive metabolic assessment of the immune system is needed to better understand the implications immune cell metabolic alterations in the progression from a healthy insulin-sensitive state toward glucose intolerance in children. Trial registration This observational study was registered at the ClinicalTrials.gov (NCT03960333, https://clinicaltrials.gov/study/NCT03960333?term=NCT03960333&rank=1).
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Affiliation(s)
- Shannon Rose
- Department of Pediatrics, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR, USA
- Arkansas Children’s Research Institute, Little Rock, AR, USA
| | - Reid D. Landes
- Department of Biostatistics, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR, USA
| | - Kanan K. Vyas
- Department of Pediatrics, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR, USA
- Arkansas Children’s Research Institute, Little Rock, AR, USA
| | - Leanna Delhey
- Department of Epidemiology, University of Michigan School of Public Health, Ann Arbor, MI, USA
| | - Sarah Blossom
- Department of Pharmaceutical Sciences, College of Pharmacy, University of New Mexico, Albuquerque, NM, USA
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Ahmadzadeh F, Esmaili M, Ehsan Enderami S, Ghasemi M, Azadeh H, Abediankenari S. Epigallocatechin-3-gallate maintains Th1/Th2 response balance and mitigates type-1 autoimmune diabetes induced by streptozotocin through promoting the effect of bone-marrow-derived mesenchymal stem cells. Gene 2024; 894:148003. [PMID: 37977318 DOI: 10.1016/j.gene.2023.148003] [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: 07/30/2023] [Revised: 11/01/2023] [Accepted: 11/14/2023] [Indexed: 11/19/2023]
Abstract
Stem-cell-based therapy is one of the most promising therapeutic strategies owing to its regenerative and immunomodulatory properties. Epigallocatechin-3-gallate (EGCG), a known antioxidant and anti-inflammatory agent, has beneficial effects on cellular protection. We aimed to elucidate the feasibility of using EGCG, along with bone marrow-derived mesenchymal stem cells (BM-MSCs), to improve pancreatic damage through their immune regulatory functions in an experimental model of type 1 diabetes mellitus (T1DM) induced by multiple injections of streptozotocin (STZ). BM-MSCs were isolated from C57BL/6 mice and characterized. The diabetic groups were treated intraperitoneally with PBS, MSCs, EGCG, and a combination of MSCs and EGCG. Real-time PCR assays showed that MSCs with EGCG modulated T-bet and GATA-3 expression and upregulated the mRNA levels of Foxp-3 more efficiently. Analyses of spleen-isolated lymphocytes revealed that combinational treatment pronouncedly increased regulatory cytokines and decreased pro-inflammatory cytokines and splenocyte proliferation. The histopathological assessment demonstrated that co-treatment significantly reduced insulitis and recovered pancreatic islet morphology. Furthermore, the combination of MSCs and EGCG is associated with downregulated blood glucose and enhanced insulin levels. Therefore, combined therapy with EGCG and MSCs holds clinical potential for treating T1DM through synergetic effects in maintaining the Th1/Th2 response balance and promoting the regeneration of damaged pancreatic tissues.
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Affiliation(s)
- Fatemeh Ahmadzadeh
- Department of Immunology, School of Medicine, Mazandaran University of Medical Sciences, Sari, Iran; Immunogenetics Research Center, School of Medicine, Mazandaran University of Medical Sciences, Sari, Iran
| | - Mozhgan Esmaili
- Department of Immunology, School of Medicine, Mazandaran University of Medical Sciences, Sari, Iran
| | - Seyed Ehsan Enderami
- Immunogenetics Research Center, Department of Medical Biotechnology, School of Advanced Technologies in Medicine, Mazandaran University of Medical Sciences, Sari, Iran
| | - Maryam Ghasemi
- Department of Pathology, School of Medicine, Mazandaran University of Medical Sciences, Sari, Iran
| | - Hossein Azadeh
- Department of Internal Medicine, School of Medicine, Mazandaran University of Medical Sciences, Sari, Iran
| | - Saeid Abediankenari
- Department of Immunology, School of Medicine, Mazandaran University of Medical Sciences, Sari, Iran; Immunogenetics Research Center, School of Medicine, Mazandaran University of Medical Sciences, Sari, Iran.
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25
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Vivek S, Crimmins EM, Prizment AE, Meier HCS, Ramasubramanian R, Barcelo H, Faul J, Thyagarajan B. Age-related Differences in T-cell Subsets and Markers of Subclinical Inflammation in Aging Are Independently Associated With Type 2 Diabetes in the Health and Retirement Study. Can J Diabetes 2023; 47:594-602.e6. [PMID: 37269981 PMCID: PMC10592537 DOI: 10.1016/j.jcjd.2023.05.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2022] [Revised: 05/02/2023] [Accepted: 05/26/2023] [Indexed: 06/05/2023]
Abstract
OBJECTIVES Age-related changes in adaptive immunity and subclinical inflammation are both important risk factors for diabetes in older adults. We evaluated the independent association between T-cell subsets, subclinical inflammation, and diabetes risk in the Health and Retirement Study (HRS). METHODS We measured 11 T-cell subsets, 5 pro-inflammatory markers, and 2 anti-inflammatory markers from the 2016 wave of the HRS (baseline). Diabetes/prediabetes status was estimated at the 2016, 2018, and 2020 waves of HRS, based on levels of blood glucose/glycated hemoglobin in plasma or self-reported status. We used survey generalized logit models to evaluate the cross-sectional associations and Cox proportional hazard models to evaluate longitudinal associations. RESULTS Among 8,540 participants (56 to 107 years of age), 27.6% had prevalent type 2 diabetes and 31.1% had prediabetes in the 2016 survey. After adjusting for age, sex, race/ethnicity, education, obesity, smoking, comorbidity index, and cytomegalovirus seropositivity, individuals with type 2 diabetes had lower naive T cells and higher memory and terminal effector T cells as compared with normoglycemic individuals. Among 3,230 normoglycemic participants in the 2016 survey, the incidence of diabetes was 1.8% over 4 years of follow-up. The baseline percentage of CD4+ effector memory T cells was associated with a lower risk of incident diabetes (hazard ratio [HR]=0.63, 95% confidence interval [CI] 0.49 to 0.80, p=0.0003) after adjustment for covariates. Baseline level of interleukin-6 (IL-6) was associated with risk of incident diabetes (HR=1.52, 95% CI 1.18 to 1.97, p=0.002). The associations between age-related changes in CD4+ effector memory T cells and risk of incident diabetes remained unchanged after adjustment for subclinical inflammation, although adjusting for CD4+ effector memory T cells nullified the association between IL-6 and incident diabetes. CONCLUSIONS This study showed that the baseline percentage of CD4+ effector memory T cells was inversely associated with incident diabetes independent of subclinical inflammation, but CD4+ effector memory T-cell subsets affected the relationship between IL-6 and incident diabetes. Further studies are needed to confirm and investigate mechanisms by which T-cell immunity affects diabetes risk.
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Affiliation(s)
- Sithara Vivek
- Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, Minnesota, United States
| | - Eileen M Crimmins
- Davis School of Gerontology, University of Southern California, Los Angeles, California, United States
| | - Anna E Prizment
- Division of Hematology, Oncology and Transplantation, Medical School, University of Minnesota, Minneapolis, Minnesota, United States
| | - Helen C S Meier
- Institute for Social Research, Survey Research Center, University of Michigan, Ann Arbor, Michigan, United States
| | - Ramya Ramasubramanian
- Division of Epidemiology and Community Health, University of Minnesota School of Public Health, Minneapolis, Minnesota, United States
| | - Helene Barcelo
- Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, Minnesota, United States
| | - Jessica Faul
- Institute for Social Research, Survey Research Center, University of Michigan, Ann Arbor, Michigan, United States
| | - Bharat Thyagarajan
- Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, Minnesota, United States.
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Tan G, Zheng G, Li J, Zhu Y, Liang Z, Li H, Yu H, Wang X. Association of genetic variations in FoxP3 gene with Graves' disease in a Southwest Chinese Han population. Immun Inflamm Dis 2023; 11:e1046. [PMID: 37904681 PMCID: PMC10571500 DOI: 10.1002/iid3.1046] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2023] [Revised: 09/16/2023] [Accepted: 09/25/2023] [Indexed: 11/01/2023] Open
Abstract
BACKGROUND Graves' disease (GD) is a T cell-mediated organ-specific autoimmune disease. Forkhead box P3 (FoxP3) is an excellent marker for the induction and development of regulatory T cells (Tregs). Recent studies showed that single-nucleotide polymorphisms (SNPs) in the FoxP3 gene were associated with the increased susceptibility to several autoimmune diseases. In the present study, we investigated the association of FoxP3 gene polymorphisms with GD in a Southwest Chinese Han population. METHODS A two-stage case-control study was performed in 890 healthy controls (male, 282; female, 608) and 503 patients with GD (male, 138; female, 365). Four SNPs (rs3761548, rs3761549, rs3761547, and rs2280883) were genotyped by the polymerase chain reaction-restriction fragment length polymorphism assay. The χ2 test was used to compare the genotype distributions and allele frequencies between GD patients and healthy controls. RESULTS In the first stage, the significantly increased frequencies of the A allele (p = .031, odds ratio [OR] = 1.635) and AA genotype (p = .023, OR = 3.257), together with a significantly decreased frequency of the C allele (p = .031, OR = 0.611) of FoxP3/rs3761548 were found in female patients with GD. None of the other FoxP3 SNPs was associated with GD susceptibility. Subsequent validation and combination of data confirmed the association between FoxP3/rs3761548 and the female patients with GD (A allele: p < .001, OR = 1.672; AA genotype: p = .005, OR = 2.488; CC genotype: p = .001, OR = 0.622; C allele: p < .001, OR = 0.615, respectively). CONCLUSION Our findings suggest that FoxP3/rs3761548 is significantly associated with female GD patients in a Southwest Chinese Han population.
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Affiliation(s)
- Guiqin Tan
- School of Basic Medical Sciences, Special Key Laboratory of Ocular Diseases of Guizhou ProvinceZunyi Medical UniversityZunyiChina
- The Second Affiliated Hospital of Zunyi Medical UniversityZunyiChina
| | - Guangbing Zheng
- School of Basic Medical Sciences, Special Key Laboratory of Ocular Diseases of Guizhou ProvinceZunyi Medical UniversityZunyiChina
| | - Jiang Li
- School of Basic Medical Sciences, Special Key Laboratory of Ocular Diseases of Guizhou ProvinceZunyi Medical UniversityZunyiChina
| | - Yingping Zhu
- School of Basic Medical Sciences, Special Key Laboratory of Ocular Diseases of Guizhou ProvinceZunyi Medical UniversityZunyiChina
| | - Zhongzhi Liang
- School of Basic Medical Sciences, Special Key Laboratory of Ocular Diseases of Guizhou ProvinceZunyi Medical UniversityZunyiChina
| | - Hua Li
- Yongchuan HospitalChongqing Medical UniversityChongqingChina
| | - Hongsong Yu
- School of Basic Medical Sciences, Special Key Laboratory of Ocular Diseases of Guizhou ProvinceZunyi Medical UniversityZunyiChina
| | - Xin Wang
- School of Basic Medical Sciences, Special Key Laboratory of Ocular Diseases of Guizhou ProvinceZunyi Medical UniversityZunyiChina
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27
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Bae HR, Shin SK, Yoo JH, Kim S, Young HA, Kwon EY. Chronic inflammation in high-fat diet-fed mice: Unveiling the early pathogenic connection between liver and adipose tissue. J Autoimmun 2023; 139:103091. [PMID: 37595410 DOI: 10.1016/j.jaut.2023.103091] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2023] [Revised: 06/22/2023] [Accepted: 07/11/2023] [Indexed: 08/20/2023]
Abstract
Obesity-induced chronic inflammation has been linked to several autoimmune diseases, including rheumatoid arthritis, type 1 diabetes, and multiple sclerosis. The underlying mechanisms are not yet fully understood, but it is believed that chronic inflammation in adipose tissue can lead to the production of pro-inflammatory cytokines and chemokines, which can trigger immune responses and contribute to the development of autoimmune diseases. However, the underlying mechanisms that lead to the infiltration of immune cells into adipose tissue are not fully understood. In this study, we observed a time-dependent response to a high-fat diet in the liver and epididymal white adipose tissue using gene set enrichment analysis. Our findings revealed a correlation between early abnormal innate immune responses in the liver and late inflammatory response in the adipose tissue, that eventually leads to systemic inflammation. Specifically, our data suggest that the dysregulated NADH homeostasis in the mitochondrial matrix, interacting with the mitochondrial translation process, could serve as a sign marking the transition from liver inflammation to adipose tissue inflammation. Taken together, our study provides valuable insights into the molecular mechanisms underlying the development of chronic inflammation and associated autoimmune diseases in obesity.
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Affiliation(s)
- Heekyong R Bae
- Department of Food Science and Nutrition, Kyungpook National University, Daegu, 41566, Republic of Korea; Center for Food and Nutritional Genomics, Kyungpook National University, Daegu, 41566, Republic of Korea
| | - Su-Kyung Shin
- Department of Food Science and Nutrition, Kyungpook National University, Daegu, 41566, Republic of Korea; Center for Food and Nutritional Genomics, Kyungpook National University, Daegu, 41566, Republic of Korea
| | - Ji-Hyeon Yoo
- Department of Food Science and Nutrition, Kyungpook National University, Daegu, 41566, Republic of Korea; Center for Food and Nutritional Genomics, Kyungpook National University, Daegu, 41566, Republic of Korea
| | - Suntae Kim
- Omixplus, LLC., Gaithersburg, MD, 20850, USA
| | - Howard A Young
- Cancer Innovation Laboratory, Center for Cancer Research, National Cancer Institute, Frederick, MD, 21702, USA
| | - Eun-Young Kwon
- Department of Food Science and Nutrition, Kyungpook National University, Daegu, 41566, Republic of Korea; Center for Food and Nutritional Genomics, Kyungpook National University, Daegu, 41566, Republic of Korea.
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28
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Krause R, Warren CM, Simmons JD, Rebeiro PF, Maruri F, Karim F, Sterling TR, Koethe JR, Leslie A, van der Heijden YF. Failure to decrease HbA1c levels following TB treatment is associated with elevated Th1/Th17 CD4+ responses. Front Immunol 2023; 14:1151528. [PMID: 37313404 PMCID: PMC10258338 DOI: 10.3389/fimmu.2023.1151528] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2023] [Accepted: 05/17/2023] [Indexed: 06/15/2023] Open
Abstract
Introduction The rising global burden of metabolic disease impacts the control of endemic tuberculosis (TB) in many regions, as persons with diabetes mellitus (DM) are up to three times more likely to develop active TB than those without DM. Active TB can also promote glucose intolerance during both acute infection and over a longer term, potentially driven by aspects of the immune response. Identifying patients likely to have persistent hyperglycemia following TB treatment would enable closer monitoring and care, and an improved understanding of underlying immunometabolic dysregulation. Methods We measured the relationship of plasma cytokine levels, T cell phenotypes and functional responses with the change in hemoglobin A1c (HbA1c) before and after treatment of pulmonary TB in a prospective observational cohort in Durban, South Africa. Participants were stratified based on stable/increased HbA1c (n = 16) versus decreased HbA1c (n = 46) levels from treatment initiation to 12 month follow-up. Results CD62 P-selectin was up- (1.5-fold) and IL-10 downregulated (0.85-fold) in plasma among individuals whose HbA1c remained stable/increased during TB treatment. This was accompanied by increased pro-inflammatory TB-specific IL-17 production (Th17). In addition, Th1 responses were upregulated in this group, including TNF-α production and CX3CR1 expression, with decreased IL-4 and IL-13 production. Finally, the TNF-α+ IFNγ+ CD8+ T cells were associated with stable/increased HbA1c. These changes were all significantly different in the stable/increased HbA1c relative to the decreased HbA1c group. Discussion Overall, these data suggest that patients with stable/increased HbA1c had an increased pro-inflammatory state. Persistent inflammation and elevated T cell activity in individuals with unresolved dysglycemia following TB treatment may indicate failure to fully resolve infection or may promote persistent dysglycemia in these individuals, and further studies are needed to explore potential mechanisms.
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Affiliation(s)
- Robert Krause
- Africa Health Research Institute (AHRI), Durban, South Africa
- College of Health Sciences, School of Laboratory Medicine & Medical Sciences, University of KwaZulu Natal, Durban, South Africa
| | - Christian M. Warren
- Division of Infectious Diseases, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, United States
| | - Joshua D. Simmons
- Division of Infectious Diseases, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, United States
| | - Peter F. Rebeiro
- Division of Infectious Diseases, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, United States
- Department of Biostatistics, Vanderbilt University School of Medicine, Nashville, TN, United States
- Vanderbilt Tuberculosis Center, Vanderbilt University School of Medicine, Nashville, TN, United States
| | - Fernanda Maruri
- Division of Infectious Diseases, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, United States
- Vanderbilt Tuberculosis Center, Vanderbilt University School of Medicine, Nashville, TN, United States
| | - Farina Karim
- Africa Health Research Institute (AHRI), Durban, South Africa
- College of Health Sciences, School of Laboratory Medicine & Medical Sciences, University of KwaZulu Natal, Durban, South Africa
- Vanderbilt Tuberculosis Center, Vanderbilt University School of Medicine, Nashville, TN, United States
| | - Timothy R. Sterling
- Division of Infectious Diseases, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, United States
- Vanderbilt Tuberculosis Center, Vanderbilt University School of Medicine, Nashville, TN, United States
| | - John R. Koethe
- Division of Infectious Diseases, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, United States
| | - Al Leslie
- Africa Health Research Institute (AHRI), Durban, South Africa
- College of Health Sciences, School of Laboratory Medicine & Medical Sciences, University of KwaZulu Natal, Durban, South Africa
- Division of Infection and Immunity, University College London, London, United Kingdom
| | - Yuri F. van der Heijden
- Division of Infectious Diseases, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, United States
- Vanderbilt Tuberculosis Center, Vanderbilt University School of Medicine, Nashville, TN, United States
- The Aurum Institute, Johannesburg, South Africa
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Wang HW, Tang J, Sun L, Li Z, Deng M, Dai Z. Mechanism of immune attack in the progression of obesity-related type 2 diabetes. World J Diabetes 2023; 14:494-511. [PMID: 37273249 PMCID: PMC10236992 DOI: 10.4239/wjd.v14.i5.494] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/28/2022] [Revised: 03/06/2023] [Accepted: 03/30/2023] [Indexed: 05/15/2023] Open
Abstract
Obesity and overweight are widespread issues in adults, children, and adolescents globally, and have caused a noticeable rise in obesity-related complications such as type 2 diabetes mellitus (T2DM). Chronic low-grade inflammation is an important promotor of the pathogenesis of obesity-related T2DM. This proinflammatory activation occurs in multiple organs and tissues. Immune cell-mediated systemic attack is considered to contribute strongly to impaired insulin secretion, insulin resistance, and other metabolic disorders. This review focused on highlighting recent advances and underlying mechanisms of immune cell infiltration and inflammatory responses in the gut, islet, and insulin-targeting organs (adipose tissue, liver, skeletal muscle) in obesity-related T2DM. There is current evidence that both the innate and adaptive immune systems contribute to the development of obesity and T2DM.
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Affiliation(s)
- Hua-Wei Wang
- Department of Endocrinology, Zhongnan Hospital of Wuhan University, Wuhan 430071, Hubei Province, China
| | - Jun Tang
- Department of Endocrinology, Zhongnan Hospital of Wuhan University, Wuhan 430071, Hubei Province, China
| | - Li Sun
- Department of Endocrinology, Zhongnan Hospital of Wuhan University, Wuhan 430071, Hubei Province, China
| | - Zhen Li
- Department of Hepatobiliary and Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Wuhan 430071, Hubei Province, China
| | - Ming Deng
- Department of Radiology, Zhongnan Hospital of Wuhan University, Wuhan 430071, Hubei Province, China
| | - Zhe Dai
- Department of Endocrinology, Zhongnan Hospital of Wuhan University, Wuhan 430071, Hubei Province, China
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Li T, Yuan D, Wang P, Zeng G, Jia S, Zhang C, Zhu P, Song Y, Tang X, Gao R, Xu B, Yuan J. Association of prognostic nutritional index level and diabetes status with the prognosis of coronary artery disease: a cohort study. Diabetol Metab Syndr 2023; 15:58. [PMID: 36966329 PMCID: PMC10039549 DOI: 10.1186/s13098-023-01019-8] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/22/2022] [Accepted: 03/05/2023] [Indexed: 03/27/2023] Open
Abstract
BACKGROUND Malnutrition and inflammation are associated with adverse clinical outcomes in patients with diabetes or coronary artery disease (CAD). Prognostic nutritional index (PNI) is a comprehensive and simple indicator reflecting nutritional condition and immunological status. Whether there is a crosstalk between nutritional-immunological status and diabetes status for the impact on the prognosis of coronary artery disease (CAD) is unclear. METHODS A total of 9429 consecutive CAD patients undergoing percutaneous coronary intervention were grouped by diabetes status [diabetes (DM) and non-diabetes (non-DM)] and preprocedural PNI level [high PNI (H-PNI) and low PNI (L-PNI)] categorized by the statistically optimal cut-off value of 48.49. The primary endpoint was all-cause death. RESULTS During a median follow-up of 5.1 years (interquartile range: 5.0-5.1 years), 366 patients died. Compared with the non-DM/H-PNI group, the DM/L-PNI group yielded the highest risk of all-cause death (adjusted hazard ratio: 2.65, 95% confidence interval: 1.97-3.56, p < 0.001), followed by the non-DM/L-PNI group (adjusted hazard ratio: 1.44, 95% confidence interval: 1.05-1.98, p = 0.026), while DM/H-PNI was not associated with the risk of all-cause death. The negative effect of L-PNI on all-cause death was significantly stronger in diabetic patients than in nondiabetic patients (p for interaction = 0.037). Preprocedural PNI category significantly improved the Global Registry of Acute Coronary Events (GRACE) risk score for predicting all-cause death in patients with acute coronary syndrome, especially in those with diabetes. CONCLUSIONS CAD patients with diabetes and L-PNI experienced the worst prognosis. The presence of diabetes amplifies the negative effect of L-PNI on all-cause death. Poor nutritional-immunological status outweighs diabetes in increasing the risk of all-cause death in CAD patients. Preprocedural PNI can serve as an assessment tool for nutritional and inflammatory risk and an independent prognostic factor in CAD patients, especially in those with diabetes.
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Affiliation(s)
- Tianyu Li
- National Clinical Research Center for Cardiovascular Diseases, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, 167, North Lishi Road, Xicheng District, Beijing, 100037, China
| | - Deshan Yuan
- National Clinical Research Center for Cardiovascular Diseases, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, 167, North Lishi Road, Xicheng District, Beijing, 100037, China
| | - Peizhi Wang
- National Clinical Research Center for Cardiovascular Diseases, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, 167, North Lishi Road, Xicheng District, Beijing, 100037, China
| | - Guyu Zeng
- National Clinical Research Center for Cardiovascular Diseases, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, 167, North Lishi Road, Xicheng District, Beijing, 100037, China
| | - Sida Jia
- Department of Cardiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, 167, North Lishi Road, Xicheng District, Beijing, 100037, China
| | - Ce Zhang
- Department of Cardiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, 167, North Lishi Road, Xicheng District, Beijing, 100037, China
| | - Pei Zhu
- Department of Cardiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, 167, North Lishi Road, Xicheng District, Beijing, 100037, China
| | - Ying Song
- Department of Cardiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, 167, North Lishi Road, Xicheng District, Beijing, 100037, China
| | - Xiaofang Tang
- Department of Cardiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, 167, North Lishi Road, Xicheng District, Beijing, 100037, China
| | - Runlin Gao
- Department of Cardiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, 167, North Lishi Road, Xicheng District, Beijing, 100037, China
| | - Bo Xu
- Catheterization Laboratories, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, 167, North Lishi Road, Xicheng District, Beijing, 100037, China
| | - Jinqing Yuan
- National Clinical Research Center for Cardiovascular Diseases, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, 167, North Lishi Road, Xicheng District, Beijing, 100037, China.
- Department of Cardiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, 167, North Lishi Road, Xicheng District, Beijing, 100037, China.
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Wang Y, Fang S, Zhou H. Pathogenic role of Th17 cells in autoimmune thyroid disease and their underlying mechanisms. Best Pract Res Clin Endocrinol Metab 2023; 37:101743. [PMID: 36841747 DOI: 10.1016/j.beem.2023.101743] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/11/2023]
Abstract
Autoimmune thyroid disease, encompassing Graves' disease and Hashimoto's thyroiditis, has a very complex etiology. Pathogenesis of the disease involves both genetic susceptibility and environmental triggers. Traditionally, imbalance of T helper cell 1 and 2 was thought to result in the immune disorders in Graves' disease and Hashimoto's thyroiditis. However, increasing evidence recently revealed the important role of T helper 17 cell and its relative cellular and secretory components in the pathogenesis and progression of autoimmune thyroid disease. This review is aimed to summarize the published studies on the involvement of T helper 17 cell in autoimmune thyroid disease and discuss the underlying regulatory mechanisms, which could possibly serve as the foundation of discovering new therapeutic targets.
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Affiliation(s)
- Yi Wang
- Department of Ophthalmology, Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai 200011, China; Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai 200011, China; Chinese Consortium for Thyroid Eye Disease (CCTED), China; Department of Immunology and Microbiology, Shanghai Institute of Immunology, Shanghai JiaoTong University School of Medicine, Shanghai 200025, China.
| | - Sijie Fang
- Department of Ophthalmology, Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai 200011, China; Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai 200011, China; Chinese Consortium for Thyroid Eye Disease (CCTED), China; Department of Immunology and Microbiology, Shanghai Institute of Immunology, Shanghai JiaoTong University School of Medicine, Shanghai 200025, China.
| | - Huifang Zhou
- Department of Ophthalmology, Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai 200011, China; Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai 200011, China; Chinese Consortium for Thyroid Eye Disease (CCTED), China.
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Sardarmelli Z, Sheikh V, Solgi G, Behzad M. Enhanced production of interleukin-29 and related genes are associated with T helper 1 cell parameters in patients with type 2 diabetes mellitus. Hum Immunol 2023; 84:235-240. [PMID: 36635158 DOI: 10.1016/j.humimm.2023.01.002] [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: 11/02/2022] [Revised: 12/27/2022] [Accepted: 01/05/2023] [Indexed: 01/12/2023]
Abstract
OBJECTIVE The production of interleukin (IL)-29 andthe genes related to IL-29 signaling pathway (STAT1, NF-κB, and NFATc1), and T helper (Th) 1 cells (T-bet, IFN-γ, TNF-α, and IL-2) were evaluated in type 2 diabetes mellitus (T2DM). Correlations between IL-29 and diabetes parameters, and between gene expression in IL-29 pathway and Th1 cells were also examined. MATERIALS AND METHODS 41 newly diagnosed patients with T2DM and 41 healthy controls were recruited. CD4+ T cells were purifed and the production of IL-29 in the supernatant of anti- CD3 and anti- CD28 activated Th cells was detected using ELISA. The expression of IL-29- and Th1- related genes was determined with real-time PCR. RESULTS The secretion of IL-29 and the expression levels of NF-κB, NFATc1, IFN-γ, and TNF-α in Th cells were seen to be increased in diabetes persons compared to controls. Positive connections between IL-29 with hemoglobin A1c (HbA1c) and fasting plasma glucose (FPG) were found in diabetes persons. IL-29 was positively correlated with NFATc1 and TNF-α. NFATc1 was positively related to TNF-α. CONCLUSION Abnormal expression levels of IL-29- and Th1- related genes are linked with T2DM pathogenesis. IL-29 may amplify the expression of Th1-specific genes especially TNF-α by upregulating NFATc1 expression.
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Affiliation(s)
- Zahra Sardarmelli
- Department of Immunology, School of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Vida Sheikh
- Department of Internal Medicine, School of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Ghasem Solgi
- Department of Immunology, School of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Mahdi Behzad
- Department of Immunology, School of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran.
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Peng C, Zhang Y, Lang X, Zhang Y. Role of mitochondrial metabolic disorder and immune infiltration in diabetic cardiomyopathy: new insights from bioinformatics analysis. J Transl Med 2023; 21:66. [PMID: 36726122 PMCID: PMC9893675 DOI: 10.1186/s12967-023-03928-8] [Citation(s) in RCA: 47] [Impact Index Per Article: 23.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2022] [Accepted: 01/25/2023] [Indexed: 02/03/2023] Open
Abstract
BACKGROUND Diabetic cardiomyopathy (DCM) is one of the common cardiovascular complications of diabetes and a leading cause of death in diabetic patients. Mitochondrial metabolism and immune-inflammation are key for DCM pathogenesis, but their crosstalk in DCM remains an open issue. This study explored the separate roles of mitochondrial metabolism and immune microenvironment and their crosstalk in DCM with bioinformatics. METHODS DCM chip data (GSE4745, GSE5606, and GSE6880) were obtained from NCBI GEO, while mitochondrial gene data were downloaded from MitoCarta3.0 database. Differentially expressed genes (DEGs) were screened by GEO2R and processed for GSEA, GO and KEGG pathway analyses. Mitochondria-related DEGs (MitoDEGs) were obtained. A PPI network was constructed, and the hub MitoDEGs closely linked to DCM or heart failure were identified with CytoHubba, MCODE and CTD scores. Transcription factors and target miRNAs of the hub MitoDEGs were predicted with Cytoscape and miRWalk database, respectively, and a regulatory network was established. The immune infiltration pattern in DCM was analyzed with ImmuCellAI, while the relationship between MitoDEGs and immune infiltration abundance was investigated using Spearman method. A rat model of DCM was established to validate the expression of hub MitoDEGs and their relationship with cardiac function. RESULTS MitoDEGs in DCM were significantly enriched in pathways involved in mitochondrial metabolism, immunoregulation, and collagen synthesis. Nine hub MitoDEGs closely linked to DCM or heart failure were obtained. Immune analysis revealed significantly increased infiltration of B cells while decreased infiltration of DCs in immune microenvironment of DCM. Spearman analysis demonstrated that the hub MitoDEGs were positively associated with the infiltration of pro-inflammatory immune cells, but negatively associated with the infiltration of anti-inflammatory or regulatory immune cells. In the animal experiment, 4 hub MitoDEGs (Pdk4, Hmgcs2, Decr1, and Ivd) showed an expression trend consistent with bioinformatics analysis result. Additionally, the up-regulation of Pdk4, Hmgcs2, Decr1 and the down-regulation of Ivd were distinctly linked to reduced cardiac function. CONCLUSIONS This study unraveled the interaction between mitochondrial metabolism and immune microenvironment in DCM, providing new insights into the research on potential pathogenesis of DCM and the exploration of novel targets for medical interventions.
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Affiliation(s)
- Cheng Peng
- grid.412463.60000 0004 1762 6325Department of Cardiology, the Second Affiliated Hospital of Harbin Medical University, Harbin, 150001 China ,grid.410736.70000 0001 2204 9268Key Laboratory of Myocardial Ischemia, Ministry of Education, Harbin Medical University, Harbin, 150001 China
| | - Yanxiu Zhang
- grid.412463.60000 0004 1762 6325Department of Cardiology, the Second Affiliated Hospital of Harbin Medical University, Harbin, 150001 China ,grid.410736.70000 0001 2204 9268Key Laboratory of Myocardial Ischemia, Ministry of Education, Harbin Medical University, Harbin, 150001 China
| | - Xueyan Lang
- grid.412463.60000 0004 1762 6325Department of Cardiology, the Second Affiliated Hospital of Harbin Medical University, Harbin, 150001 China ,grid.410736.70000 0001 2204 9268Key Laboratory of Myocardial Ischemia, Ministry of Education, Harbin Medical University, Harbin, 150001 China
| | - Yao Zhang
- Department of Cardiology, the Second Affiliated Hospital of Harbin Medical University, Harbin, 150001, China. .,Key Laboratory of Myocardial Ischemia, Ministry of Education, Harbin Medical University, Harbin, 150001, China.
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The role of cytokines and T-bet, GATA3, ROR-γt, and FOXP3 transcription factors of T cell subsets in the natural clinical progression of Type 1 Diabetes. Immunol Res 2023; 71:451-462. [PMID: 36595206 DOI: 10.1007/s12026-022-09355-z] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2022] [Accepted: 12/26/2022] [Indexed: 01/04/2023]
Abstract
Th cells play an important role in pathogenesis of type 1 diabetes (T1D). Peripheral blood mononuclear cells were isolated from peripheral blood samples from newly diagnosed (ND), 1-year (1YD), and 5-year T1D (5YD) patients (n:8 of each group), 8 healthy controls (HC), and cultured for 24 h under unstimulated (US) and stimulated conditions. Cell ratios of Th1, Th2, Th17, Treg, and intracellular levels of IFN-γ, TNF-α, IL-10, TGF-β, IL-5, IL-13, IL-17, and IL-21 cytokines were evaluated using the flow cytometry. mRNA expressions of transcription factors T-bet, GATA3, ROR-γt, and FOXP3 of these cells were determined by real-time PCR. Reduced CD4+CD25high cell ratios were detected in ND. CD4+CD25high cells were found to be reduced in ND and 1YD compared to HC under IL-2-stimulated conditions. Intracellular IFN-γ and TNF-α levels were low in all patients under US and IL-12-stimulated conditions. IL-17A and IL-21 were found to be high in patients with IL-6-stimulated conditions. Expressions of IL-10 and TGF-β have been observed to be reduced in patients. Th1/Th2, Th17/Treg, and Th1/Treg ratios were higher in patient groups. FOXP3 and GATA3 mRNA expressions were found to be low in patients, while RORγt and T-bet mRNA levels were higher than HC. Th1, Th17, and Treg cells and their cytokines have been shown to be associated with type 1 diabetes.
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Lobato TB, Gennari-Felipe M, Pauferro JRB, Correa IS, Santos BF, Dias BB, de Oliveira Borges JC, dos Santos CS, de Sousa Santos ES, de Araújo MJL, Ferreira LA, Pereira SA, Serdan TDA, Levada-Pires AC, Hatanaka E, Borges L, Cury-Boaventura MF, Vinolo MAR, Pithon-Curi TC, Masi LN, Curi R, Hirabara SM, Gorjão R. Leukocyte metabolism in obese type 2 diabetic individuals associated with COVID-19 severity. Front Microbiol 2022; 13:1037469. [PMID: 36406408 PMCID: PMC9670542 DOI: 10.3389/fmicb.2022.1037469] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2022] [Accepted: 10/12/2022] [Indexed: 03/27/2024] Open
Abstract
Recent studies show that the metabolic characteristics of different leukocytes, such as, lymphocytes, neutrophils, and macrophages, undergo changes both in the face of infection with SARS-CoV-2 and in obesity and type 2 diabetes mellitus (DM2) condition. Thus, the objective of this review is to establish a correlation between the metabolic changes caused in leukocytes in DM2 and obesity that may favor a worse prognosis during SARS-Cov-2 infection. Chronic inflammation and hyperglycemia, specific and usual characteristics of obesity and DM2, contributes for the SARS-CoV-2 replication and metabolic disturbances in different leukocytes, favoring the proinflammatory response of these cells. Thus, obesity and DM2 are important risk factors for pro-inflammatory response and metabolic dysregulation that can favor the occurrence of the cytokine storm, implicated in the severity and high mortality risk of the COVID-19 in these patients.
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Affiliation(s)
- Tiago Bertola Lobato
- Programa de Pós-graduação Interdisciplinar em Ciências da Saúde, Universidade Cruzeiro do Sul, São Paulo, São Paulo, Brasil
| | - Matheus Gennari-Felipe
- Programa de Pós-graduação Interdisciplinar em Ciências da Saúde, Universidade Cruzeiro do Sul, São Paulo, São Paulo, Brasil
| | | | - Ilana Souza Correa
- Programa de Pós-graduação Interdisciplinar em Ciências da Saúde, Universidade Cruzeiro do Sul, São Paulo, São Paulo, Brasil
| | - Beatriz Ferreira Santos
- Programa de Pós-graduação Interdisciplinar em Ciências da Saúde, Universidade Cruzeiro do Sul, São Paulo, São Paulo, Brasil
| | - Beatriz Belmiro Dias
- Programa de Pós-graduação Interdisciplinar em Ciências da Saúde, Universidade Cruzeiro do Sul, São Paulo, São Paulo, Brasil
| | - João Carlos de Oliveira Borges
- Programa de Pós-graduação Interdisciplinar em Ciências da Saúde, Universidade Cruzeiro do Sul, São Paulo, São Paulo, Brasil
| | - Camila Soares dos Santos
- Programa de Pós-graduação Interdisciplinar em Ciências da Saúde, Universidade Cruzeiro do Sul, São Paulo, São Paulo, Brasil
| | | | - Maria Janaína Leite de Araújo
- Programa de Pós-graduação Interdisciplinar em Ciências da Saúde, Universidade Cruzeiro do Sul, São Paulo, São Paulo, Brasil
| | - Liliane Araújo Ferreira
- Programa de Pós-graduação Interdisciplinar em Ciências da Saúde, Universidade Cruzeiro do Sul, São Paulo, São Paulo, Brasil
| | - Sara Araujo Pereira
- Programa de Pós-graduação Interdisciplinar em Ciências da Saúde, Universidade Cruzeiro do Sul, São Paulo, São Paulo, Brasil
| | | | - Adriana Cristina Levada-Pires
- Programa de Pós-graduação Interdisciplinar em Ciências da Saúde, Universidade Cruzeiro do Sul, São Paulo, São Paulo, Brasil
| | - Elaine Hatanaka
- Programa de Pós-graduação Interdisciplinar em Ciências da Saúde, Universidade Cruzeiro do Sul, São Paulo, São Paulo, Brasil
| | - Leandro Borges
- Programa de Pós-graduação Interdisciplinar em Ciências da Saúde, Universidade Cruzeiro do Sul, São Paulo, São Paulo, Brasil
| | - Maria Fernanda Cury-Boaventura
- Programa de Pós-graduação Interdisciplinar em Ciências da Saúde, Universidade Cruzeiro do Sul, São Paulo, São Paulo, Brasil
| | - Marco Aurélio Ramirez Vinolo
- Laboratory of Immunoinflammation, Department of Genetics, Evolution, Microbiology, and Immunology, Institute of Biology, University of Campinas, Campinas, Brazil
| | - Tania Cristina Pithon-Curi
- Programa de Pós-graduação Interdisciplinar em Ciências da Saúde, Universidade Cruzeiro do Sul, São Paulo, São Paulo, Brasil
| | - Laureane Nunes Masi
- Programa de Pós-graduação Interdisciplinar em Ciências da Saúde, Universidade Cruzeiro do Sul, São Paulo, São Paulo, Brasil
| | - Rui Curi
- Programa de Pós-graduação Interdisciplinar em Ciências da Saúde, Universidade Cruzeiro do Sul, São Paulo, São Paulo, Brasil
- Immunobiological Production Section, Bioindustrial Center, Butantan Institute, São Paulo, Brazil
| | - Sandro Massao Hirabara
- Programa de Pós-graduação Interdisciplinar em Ciências da Saúde, Universidade Cruzeiro do Sul, São Paulo, São Paulo, Brasil
| | - Renata Gorjão
- Programa de Pós-graduação Interdisciplinar em Ciências da Saúde, Universidade Cruzeiro do Sul, São Paulo, São Paulo, Brasil
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Borzouei S, Gholamian-Hamadan M, Behzad M. Impact of interleukin-32α on T helper cell-related cytokines, transcription factors, and proliferation in patients with type 2 diabetes mellitus. Immunopharmacol Immunotoxicol 2022; 45:268-276. [PMID: 36263937 DOI: 10.1080/08923973.2022.2138430] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
OBJECTIVE The ability of interleukin (IL)-32α to induce T helper (Th) 1, Th17, and Treg cytokines (IFN-γ, IL-17, and IL-10, respectively), and transcription factors [(signal transducer and activator of transcription (STAT) 1 and T-box (T-bet) for Th1, STAT3 and retinoid-related orphan receptor (ROR)-γt for Th17, and STAT5 and forkhead box P3 (Foxp3) for Treg)] were investigated in type 2 diabetes mellitus (T2DM). IL-32α effects on Th cell proliferation and related factors including IL-2 and NF-κB were also explored. METHODS Serum levels of IL-32α in 31 patients and 31 healthy controls (HCs) were determined by ELISA assay. CD4+ T cells cultured with polyclonal activators in the presence and absence of recombinant IL-32α (rIL-32α). Gene expressions in cultured Th cells were assessed with real-time PCR. Cytokines in supernatants were measured with ELISA. Proliferation experiments were assessed by flow cytometry. RESULTS The patients showed significant increase in IL-32α levels compared with HCs and its levels were positively correlated with fasting plasma glucose and hemoglobin A1c. rIL-32α enhanced IL-17 and IL-2 production, increased ROR-γt and NF-κB expression, and enhanced Th proliferation in both patients and HCs. In patients, IL-17, ROR-γt, NF-κB, and proliferation levels were higher than those in HCs, in cultures with and without rIL-32α (rIL-32α+ and rIL-32α-). IL-2 levels in rIL-32α+cultures of patients were significantly higher than the HCs, and it was positively correlated with proliferation rate and NF-κB expression. CONCLUSIONS Aberrant IL-32α levels are participated in T2DM pathogenesis. IL-32α potently induces Th17-related factors and amplifies the proliferative function of T cells.
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Affiliation(s)
- Shiva Borzouei
- Department of Internal Medicine, School of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
| | | | - Mahdi Behzad
- Department of Immunology, School of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
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Lee CH, Gray V, Teo JMN, Tam AR, Fong CHY, Lui DTW, Pang P, Chan KH, Hung IFN, Tan KCB, Ling GS. Comparing the B and T cell-mediated immune responses in patients with type 2 diabetes receiving mRNA or inactivated COVID-19 vaccines. Front Immunol 2022; 13:1018393. [PMID: 36304475 PMCID: PMC9592994 DOI: 10.3389/fimmu.2022.1018393] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2022] [Accepted: 09/26/2022] [Indexed: 12/05/2022] Open
Abstract
Acquiring protective immunity through vaccination is essential, especially for patients with type 2 diabetes who are vulnerable for adverse clinical outcomes during coronavirus disease 2019 (COVID-19) infection. Type 2 diabetes (T2D) is associated with immune dysfunction. Here, we evaluated the impact of T2D on the immunological responses induced by mRNA (BNT162b2) and inactivated (CoronaVac) vaccines, the two most commonly used COVID-19 vaccines. The study consisted of two parts. In Part 1, the sera titres of IgG antibodies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) alpha receptor binding domain (RBD), their neutralizing capacity, and antigen-specific CD4+T and CD8+T cell responses at 3-6 months after vaccination were compared between BNT162b2 (n=60) and CoronaVac (n=50) vaccinees with or without T2D. Part 2 was a time-course study investigating the initial B and T cell responses induced by BNT162b2 among vaccinees (n=16) with or without T2D. Our data showed that T2D impaired both cellular and humoral immune responses induced by CoronaVac. For BNT162b2, T2D patients displayed a reduction in CD4+T-helper 1 (Th1) differentiation following their first dose. However, this initial defect was rectified by the second dose of BNT162b2, resulting in comparable levels of memory CD4+ and CD8+T cells, anti-RBD IgG, and neutralizing antibodies with healthy individuals at 3-6 months after vaccination. Hence, T2D influences the effectiveness of COVID-19 vaccines depending on their platform. Our findings provide a potential mechanism for the susceptibility of developing adverse outcomes observed in COVID-19 patients with T2D and received either CoronaVac or just one dose of BNT162b2.
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Affiliation(s)
- Chi-Ho Lee
- Department of Medicine, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong, Hong Kong SAR, China
| | - Victor Gray
- School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, Hong Kong SAR, China
| | - Jia Ming Nickolas Teo
- School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, Hong Kong SAR, China
| | - Anthony Raymond Tam
- Department of Medicine, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong, Hong Kong SAR, China
| | - Carol Ho-Yi Fong
- Department of Medicine, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong, Hong Kong SAR, China
| | - David Tak-Wai Lui
- Department of Medicine, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong, Hong Kong SAR, China
| | - Polly Pang
- Department of Medicine, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong, Hong Kong SAR, China
| | - Kwok Hung Chan
- Department of Microbiology, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong, Hong Kong SAR, China
| | - Ivan Fan-Ngai Hung
- Department of Medicine, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong, Hong Kong SAR, China
- *Correspondence: Guang Sheng Ling, ; Ivan Fan-Ngai Hung, ; Kathryn Choon-Beng Tan,
| | - Kathryn Choon-Beng Tan
- Department of Medicine, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong, Hong Kong SAR, China
- *Correspondence: Guang Sheng Ling, ; Ivan Fan-Ngai Hung, ; Kathryn Choon-Beng Tan,
| | - Guang Sheng Ling
- School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, Hong Kong SAR, China
- *Correspondence: Guang Sheng Ling, ; Ivan Fan-Ngai Hung, ; Kathryn Choon-Beng Tan,
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Tan T, Xiang Y, Deng C, Cao C, Ren Z, Huang G, Zhou Z. Variable frequencies of peripheral T-lymphocyte subsets in the diabetes spectrum from type 1 diabetes through latent autoimmune diabetes in adults (LADA) to type 2 diabetes. Front Immunol 2022; 13:974864. [PMID: 36091068 PMCID: PMC9449581 DOI: 10.3389/fimmu.2022.974864] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2022] [Accepted: 08/08/2022] [Indexed: 11/13/2022] Open
Abstract
T lymphocytes are key players in the pathogenesis of autoimmune diabetes. We recruited subjects with T1D (n=81), LADA (n=82), T2D (n=95) and NGT (n=218) and analyzed the percentages of T-lymphocyte subsets, including T helper 1 (Th1), T helper 2 (Th2), T helper 17 (Th17), T cytotoxic 1 (Tc1), regulatory T cells (Tregs), effector T (Teff), naïve T, central memory T (Tcm), and effector memory T (Tem) cells by flow cytometry. LADA patients possessed similar frequencies of IFN-γ+CD4+ T (Th1), IFN-γ+CD8+ T and CD4+ Teff cells compared with T1D patients, but much lower than those of NGT subjects. Like T2D patients, LADA patients had increased frequencies of CD4+ Tem and CD8+ Tem cells with respect to T1D and NGT subjects. In LADA patients, Th2 cells were decreased while CD4+ Tcm cells were increased compared with NGT subjects. Notably, we observed significant negative correlations between the CD4+ Tcm cell frequency and C-peptide in LADA subjects. These data demonstrates that LADA patients possess T-cell subset changes resembling both T1D and T2D and represent the middle of the diabetes spectrum between T1D and T2D. Based on these T-cell subset alterations, we speculate that autoimmunity-induced β-cell destruction and inflammation-induced insulin resistance might both be involved in the pathogenesis of LADA.
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Rico-Fontalvo J, Aroca G, Cabrales J, Daza-Arnedo R, Yánez-Rodríguez T, Martínez-Ávila MC, Uparella-Gulfo I, Raad-Sarabia M. Molecular Mechanisms of Diabetic Kidney Disease. Int J Mol Sci 2022; 23:ijms23158668. [PMID: 35955802 PMCID: PMC9369345 DOI: 10.3390/ijms23158668] [Citation(s) in RCA: 33] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2022] [Revised: 08/01/2022] [Accepted: 08/02/2022] [Indexed: 12/18/2022] Open
Abstract
The inflammatory component of diabetic kidney disease has become of great interest in recent years, with genetic and epigenetic variants playing a fundamental role in the initiation and progression of the disease. Cells of the innate immune system play a major role in the pathogenesis of diabetic kidney disease, with a lesser contribution from the adaptive immune cells. Other components such as the complement system also play a role, as well as specific cytokines and chemokines. The inflammatory component of diabetic kidney disease is of great interest and is an active research field, with the hope to find potential innovative therapeutic targets.
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Affiliation(s)
- Jorge Rico-Fontalvo
- Colombian Nephrology Association, Bogotá 110221, Colombia
- Management of Technologies and Innovation, Department of Engineering, Universidad Simón Bolivar, Cl. 58 #55-132, Barranquilla 080002, Colombia
| | - Gustavo Aroca
- Colombian Nephrology Association, Bogotá 110221, Colombia
- Faculty of Medicine, Universidad Simón Bolívar, Barranquilla 080002, Colombia
| | - Jose Cabrales
- Nephrology Fellow, Stanford University School of Medicine, Palo Alto, CA 94305, USA
- Correspondence:
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Cross-Talk between the Cytokine IL-37 and Thyroid Hormones in Modulating Chronic Inflammation Associated with Target Organ Damage in Age-Related Metabolic and Vascular Conditions. Int J Mol Sci 2022; 23:ijms23126456. [PMID: 35742902 PMCID: PMC9224418 DOI: 10.3390/ijms23126456] [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: 05/05/2022] [Revised: 06/07/2022] [Accepted: 06/08/2022] [Indexed: 02/04/2023] Open
Abstract
Chronic inflammation is considered to be the main mechanism contributing to the development of age-related metabolic and vascular conditions. The phases of chronic inflammation that mediate the progression of target organ damage in these conditions are poorly known, however. In particular, there is a paucity of data on the link between chronic inflammation and metabolic disorders. Based on some of our own results and recent developments in our understanding of age-related inflammation as a whole-body response, we discuss the hypothesis that cross-talk between the cytokine IL-37 and thyroid hormones could be the key regulatory mechanism that justifies the metabolic effects of chronic tissue-related inflammation. The cytokine IL-37 is emerging as a strong natural suppressor of the chronic innate immune response. The effect of this cytokine has been identified in reversing metabolic costs of chronic inflammation. Thyroid hormones are known to regulate energy metabolism. There is a close link between thyroid function and inflammation in elderly individuals. Nonlinear associations between IL-37 and thyroid hormones, considered within the wider clinical context, can improve our understanding of the phases of chronic inflammation that are associated with target organ damage in age-related metabolic and vascular conditions.
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Use of Physical Activity and Exercise to Reduce Inflammation in Children and Adolescents with Obesity. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2022; 19:ijerph19116908. [PMID: 35682490 PMCID: PMC9180584 DOI: 10.3390/ijerph19116908] [Citation(s) in RCA: 36] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/06/2022] [Revised: 06/01/2022] [Accepted: 06/03/2022] [Indexed: 12/13/2022]
Abstract
Childhood obesity is a leading public health problem worldwide, as it is increasingly prevalent and therefore responsible for serious obesity-related comorbidities, not only in childhood but also in adulthood. In addition to cardio-metabolic obesity-related disorders, recent evidence suggests that excess adipose tissue in turn is associated with immune cell infiltration, increased adipokine release, and the development of low-grade systemic inflammation obesity. Exercise is considered a non-pharmacological intervention that can delay obesity-related comorbidities, improving cardiovascular fitness and modulating the inflammatory processes. It has been reported that the anti-inflammatory effect of regular exercise may be mediated by a reduction in visceral fat mass, with a subsequent decrease in the release of adipokines from adipose tissue (AT) and/or by the induction of an anti-inflammatory environment. In this narrative review, we discuss the role of AT as an endocrine organ associated with chronic inflammation and its role in obesity-related complications, focusing on the effect of exercise in reducing inflammation in children and adolescents with obesity. Regular physical exercise must be considered as a natural part of a healthy lifestyle, and promoting physical activity starting from childhood is useful to limit the negative effects of obesity on health. The crucial role of the immune system in the development of obesity-induced inflammatory processes and the efficacy of exercise as an anti-inflammatory, non-pharmacological intervention may provide possible targets for the development of new treatments and early preventive strategies.
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Elia E, Ministrini S, Carbone F, Montecucco F. Diabetic cardiomyopathy and inflammation: development of hostile microenvironment resulting in cardiac damage. Minerva Cardiol Angiol 2022; 70:357-369. [PMID: 33427423 DOI: 10.23736/s2724-5683.20.05454-7] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Diabetes mellitus is emerging as a major risk factor for heart failure. Diabetic cardiomyopathy is defined as a myocardial dysfunction that is not caused by underlying hypertension or coronary artery disease. Studies about clinical features, natural history and outcomes of the disease are few and often conflicting, because a universally accepted operative definition of diabetic cardiomyopathy is still lacking. Hyperglycemia and related metabolic and endocrine disorders are the triggering factors of myocardial damage in diabetic cardiomyopathy through multiple mechanisms. Among these mechanisms, inflammation has a relevant role, similar to other chronic myocardial disease, such as hypertensive or ischemic heart disease. A balance between inflammatory damage and healing processes is fundamental for homeostasis of myocardial tissue, whereas diabetes mellitus produces an imbalance, promoting inflammation and delaying healing. Therefore, diabetes-related chronic inflammatory state can produce a progressive qualitative deterioration of myocardial tissue, which reflects on progressive left ventricular functional impairment, which can be either diastolic, with prevalent myocardial hypertrophy, or systolic, with prevalent myocardial fibrosis. The aim of this narrative review is to summarize the existing evidence about the role of inflammation in diabetic cardiomyopathy onset and development. Ultimately, potential pharmacological strategies targeting inflammatory response will be reviewed and discussed.
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Affiliation(s)
- Edoardo Elia
- Division of Cardiology, Department of Internal Medicine, Città della Salute e della Scienza, Turin, Italy
| | - Stefano Ministrini
- First Clinic of Internal Medicine, Department of Internal Medicine, University of Genoa, Genoa, Italy
| | - Federico Carbone
- First Clinic of Internal Medicine, Department of Internal Medicine, University of Genoa, Genoa, Italy
- IRCCS Ospedale Policlinico San Martino, Genoa - Italian Cardiovascular Network, Genoa, Italy
| | - Fabrizio Montecucco
- First Clinic of Internal Medicine, Department of Internal Medicine, University of Genoa, Genoa, Italy -
- IRCCS Ospedale Policlinico San Martino, Genoa - Italian Cardiovascular Network, Genoa, Italy
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Ding Q, Gao Z, Chen K, Zhang Q, Hu S, Zhao L. Inflammation-Related Epigenetic Modification: The Bridge Between Immune and Metabolism in Type 2 Diabetes. Front Immunol 2022; 13:883410. [PMID: 35603204 PMCID: PMC9120428 DOI: 10.3389/fimmu.2022.883410] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2022] [Accepted: 04/11/2022] [Indexed: 12/11/2022] Open
Abstract
T2DM, as a typical metabolic inflammatory disease, is under the joint regulation of environmental factors and genetics, combining with a variety of epigenetic changes. Apart from epigenetic changes of islet β cells and glycometabolic tissues or organs, the inflammation-related epigenetics is also the core pathomechanism leading to β-cell dysfunction and insulin resistance. In this review, we focus on the epigenetic modification of immune cells’ proliferation, recruitment, differentiation and function, providing an overview of the key genes which regulated by DNA methylation, histone modifications, and non-coding RNA in the respect of T2DM. Meanwhile, we further summarize the present situation of T2DM epigenetic research and elucidate its prospect in T2DM clinical diagnosis and treatment.
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Affiliation(s)
- Qiyou Ding
- Department of Endocrinology, Guang’ anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
- Institute of Metabolic Diseases, Guang’ anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
- Graduate School, Beijing University of Chinese Medicine, Beijing, China
| | - Zezheng Gao
- Department of Endocrinology, Guang’ anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
- Institute of Metabolic Diseases, Guang’ anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Keyu Chen
- Department of Endocrinology, Guang’ anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
- Institute of Metabolic Diseases, Guang’ anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
- Graduate School, Beijing University of Chinese Medicine, Beijing, China
| | - Qiqi Zhang
- Department of Endocrinology, Guang’ anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
- Institute of Metabolic Diseases, Guang’ anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Shiwan Hu
- Department of Endocrinology, Guang’ anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
- Institute of Metabolic Diseases, Guang’ anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
- Graduate School, Beijing University of Chinese Medicine, Beijing, China
| | - Linhua Zhao
- Institute of Metabolic Diseases, Guang’ anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
- *Correspondence: Linhua Zhao,
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Wang R, Zhang J, Li D, Liu G, Fu Y, Li Q, Zhang L, Qian L, Hao L, Wang Y, Harris DCH, Wang D, Cao Q. Imbalance of circulating innate lymphoid cell subpopulations in patients with chronic kidney disease. Clin Immunol 2022; 239:109029. [PMID: 35525476 DOI: 10.1016/j.clim.2022.109029] [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: 07/22/2021] [Revised: 04/27/2022] [Accepted: 04/29/2022] [Indexed: 11/19/2022]
Abstract
Innate lymphoid cells (ILCs) are a newly identified heterogeneous family of innate immune cells. We conducted this study to investigate the frequency of circulating ILC subsets in various chronic kidney diseases (CKD). In DN, the proportion of total ILCs and certain ILC subgroups increased significantly. Positive correlations between proportion of total ILCs, ILC1s and body mass index, glycated hemoglobin were observed in DN. In LN, a significantly increased proportion of ILC1s was found in parallel with a reduced proportion of ILC2s. The proportions of total ILCs and ILC1s were correlated with WBC count and the level of C3. In all enrolled patients, the proportion of total ILCs and ILC1s was significantly correlated with the levels of ACR and GFR. In the present study, the proportion of circulating ILC subsets increased significantly in various types of CKD and correlated with clinico-pathological features, which suggests a possible role for ILCs in CKD.
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Affiliation(s)
- Ruifeng Wang
- Department of Nephrology, The Second Affiliated Hospital of Anhui Medical University, Hefei, China; Centre for Transplant and Renal Research, Westmead Institute for Medical Research, The University of Sydney, Sydney, NSW, Australia; Department of Nephrology, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Jingjing Zhang
- Department of Nephrology, The Second Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Dandan Li
- Department of Nephrology, The Second Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Guiling Liu
- Department of Nephrology, The Second Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Yuqin Fu
- Department of Nephrology, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Qing Li
- The Central Laboratory of Medical Research Center, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Lei Zhang
- Department of Rheumatology, The Second Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Long Qian
- Department of Rheumatology, The Second Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Li Hao
- Department of Nephrology, The Second Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Yiping Wang
- Centre for Transplant and Renal Research, Westmead Institute for Medical Research, The University of Sydney, Sydney, NSW, Australia
| | - David C H Harris
- Centre for Transplant and Renal Research, Westmead Institute for Medical Research, The University of Sydney, Sydney, NSW, Australia
| | - Deguang Wang
- Department of Nephrology, The Second Affiliated Hospital of Anhui Medical University, Hefei, China.
| | - Qi Cao
- Centre for Transplant and Renal Research, Westmead Institute for Medical Research, The University of Sydney, Sydney, NSW, Australia.
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Kiran S, Rakib A, Kodidela S, Kumar S, Singh UP. High-Fat Diet-Induced Dysregulation of Immune Cells Correlates with Macrophage Phenotypes and Chronic Inflammation in Adipose Tissue. Cells 2022; 11:cells11081327. [PMID: 35456006 PMCID: PMC9031506 DOI: 10.3390/cells11081327] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2022] [Revised: 04/07/2022] [Accepted: 04/11/2022] [Indexed: 01/27/2023] Open
Abstract
Obesity is a complex disease associated with various metabolic abnormalities, cardiovascular diseases, and low-grade chronic inflammation. Inflammation associated with T helper 1 (Th1) immune cells is dominant in adipose tissue (AT) and exerts metabolically deleterious impacts. The precise mechanism of alteration in AT immune system and its effect on metabolic homeostasis remains unclear. In this study, we investigated how a high-fat diet (HFD) alters the AT immune response and influences inflammation during obesity. HFD consumption amends the metabolic parameters, including body weight, glucose, and insulin levels. We observed increased infiltration of Th17 cells, a subset of dendritic cells (CD103+), and M1 macrophages in AT of mice fed HFD compared to those fed a normal diet (ND). In mice that were fed HFD, we also observed a reduction in regulatory T cells (Tregs) relative to the numbers of these cells in mice fed ND. Corresponding with this, mice in the HFD group exhibited higher levels of proinflammatory cytokines and chemokines than those in the ND group. We also observed alterations in signaling pathways, including increased protein expression of IRF3, TGFβ1, and mRNA expression of IL-6, KLF4, and STAT3 in the AT of the mice fed HFD as compared to those fed ND. Further, HFD-fed mice exhibited decreased protein expression of peroxisome proliferator-activated receptor-gamma (PPAR-γ) compared to mice fed ND, suggesting that PPAR-γ functions as a negative regulator of Th17 cell differentiation. These results suggest that HFD induces increased levels of inflammatory cytokines and key immune cells, including Th17, M1 macrophages, and CD103+ dendritic cells, and reduces levels of PPAR-γ and Tregs to sustain AT inflammation. This study supports the notion that dysregulation of Th17/Tregs, which polarizes macrophages towards M1 phenotypes in part through TGFβ1-IRF3-STAT3 and negatively regulates PPAR-γ mediated pathways, results in AT inflammation during obesity.
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Phang RJ, Ritchie RH, Hausenloy DJ, Lees JG, Lim SY. Cellular interplay between cardiomyocytes and non-myocytes in diabetic cardiomyopathy. Cardiovasc Res 2022; 119:668-690. [PMID: 35388880 PMCID: PMC10153440 DOI: 10.1093/cvr/cvac049] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/01/2021] [Revised: 02/16/2022] [Accepted: 03/05/2022] [Indexed: 11/13/2022] Open
Abstract
Patients with Type 2 diabetes mellitus (T2DM) frequently exhibit a distinctive cardiac phenotype known as diabetic cardiomyopathy. Cardiac complications associated with T2DM include cardiac inflammation, hypertrophy, fibrosis and diastolic dysfunction in the early stages of the disease, which can progress to systolic dysfunction and heart failure. Effective therapeutic options for diabetic cardiomyopathy are limited and often have conflicting results. The lack of effective treatments for diabetic cardiomyopathy is due in part, to our poor understanding of the disease development and progression, as well as a lack of robust and valid preclinical human models that can accurately recapitulate the pathophysiology of the human heart. In addition to cardiomyocytes, the heart contains a heterogeneous population of non-myocytes including fibroblasts, vascular cells, autonomic neurons and immune cells. These cardiac non-myocytes play important roles in cardiac homeostasis and disease, yet the effect of hyperglycaemia and hyperlipidaemia on these cell types are often overlooked in preclinical models of diabetic cardiomyopathy. The advent of human induced pluripotent stem cells provides a new paradigm in which to model diabetic cardiomyopathy as they can be differentiated into all cell types in the human heart. This review will discuss the roles of cardiac non-myocytes and their dynamic intercellular interactions in the pathogenesis of diabetic cardiomyopathy. We will also discuss the use of sodium-glucose cotransporter 2 inhibitors as a therapy for diabetic cardiomyopathy and their known impacts on non-myocytes. These developments will no doubt facilitate the discovery of novel treatment targets for preventing the onset and progression of diabetic cardiomyopathy.
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Affiliation(s)
- Ren Jie Phang
- O'Brien Institute Department, St Vincent's Institute of Medical Research, Fitzroy, Victoria 3065, Australia.,Departments of Surgery and Medicine, University of Melbourne, Parkville, Victoria 3010, Australia
| | - Rebecca H Ritchie
- School of Biosciences, Parkville, Victoria 3010, Australia.,Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Parkville, Victoria 3052, Australia.,Department of Pharmacology, Monash University, Clayton, Victoria 3800, Australia
| | - Derek J Hausenloy
- National Heart Research Institute Singapore, National Heart Centre Singapore, Singapore, Singapore.,Cardiovascular and Metabolic Disorders Programme, Duke-NUS Medical School, Singapore, Singapore.,Yong Loo Lin School of Medicine, National University Singapore, Singapore, Singapore.,The Hatter Cardiovascular Institute, University College London, London, UK.,Cardiovascular Research Center, College of Medical and Health Sciences, Asia University, Taichung City, Taiwan
| | - Jarmon G Lees
- O'Brien Institute Department, St Vincent's Institute of Medical Research, Fitzroy, Victoria 3065, Australia.,Departments of Surgery and Medicine, University of Melbourne, Parkville, Victoria 3010, Australia
| | - Shiang Y Lim
- O'Brien Institute Department, St Vincent's Institute of Medical Research, Fitzroy, Victoria 3065, Australia.,Departments of Surgery and Medicine, University of Melbourne, Parkville, Victoria 3010, Australia.,National Heart Research Institute Singapore, National Heart Centre Singapore, Singapore, Singapore
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Xie L, Xiao Y, Tai S, Yang H, Zhou S, Zhou Z. Emerging Roles of Sodium Glucose Cotransporter 2 (SGLT-2) Inhibitors in Diabetic Cardiovascular Diseases: Focusing on Immunity, Inflammation and Metabolism. Front Pharmacol 2022; 13:836849. [PMID: 35295328 PMCID: PMC8920092 DOI: 10.3389/fphar.2022.836849] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2021] [Accepted: 02/07/2022] [Indexed: 11/29/2022] Open
Abstract
Diabetes mellitus (DM) is one of the most fast evolving global issues characterized by hyperglycemia. Patients with diabetes are considered to face with higher risks of adverse cardiovascular events. Those are the main cause of mortality and disability in diabetes patients. There are novel antidiabetic agents that selectively suppress sodium-glucose cotransporter-2 (SGLT-2). They work by reducing proximal tubule glucose reabsorption. Although increasing evidence has shown that SGLT-2 inhibitors can contribute to a series of cardiovascular benefits in diabetic patients, including a reduced incidence of major adverse cardiovascular events and protection of extracardiac organs, the potential mechanisms of SGLT2 inhibitors’ cardiovascular protective effects are still not fully elucidated. Given the important role of inflammation and metabolism in diabetic cardiovascular diseases, this review is intended to rationally compile the multifactorial mechanisms of SGLT-2 inhibitors from the point of immunity, inflammation and metabolism, depicting the fundamental cellular and molecular processing of SGLT-2 inhibitors exerting regulating immunity, inflammation and metabolism. Finally, future directions and perspectives to prevent or delay cardiovascular complications in DM by SGLT-2 inhibitors are presented.
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Affiliation(s)
- Lingxiang Xie
- Key Laboratory of Diabetes Immunology, Department of Metabolism and Endocrinology, National Clinical Research Center for Metabolic Diseases, Ministry of Education, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Yang Xiao
- Key Laboratory of Diabetes Immunology, Department of Metabolism and Endocrinology, National Clinical Research Center for Metabolic Diseases, Ministry of Education, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Shi Tai
- Department of Cardiovascular Medicine, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Huijie Yang
- Key Laboratory of Diabetes Immunology, Department of Metabolism and Endocrinology, National Clinical Research Center for Metabolic Diseases, Ministry of Education, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Shenghua Zhou
- Department of Cardiovascular Medicine, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Zhiguang Zhou
- Key Laboratory of Diabetes Immunology, Department of Metabolism and Endocrinology, National Clinical Research Center for Metabolic Diseases, Ministry of Education, The Second Xiangya Hospital of Central South University, Changsha, China
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BAILIN SS, KUNDU S, WELLONS M, FREIBERG MS, DOYLE MF, TRACY RP, JUSTICE AC, WANJALLA CN, LANDAY AL, SO-ARMAH K, MALLAL S, KROPSKI JA, KOETHE JR. Circulating CD4+ TEMRA and CD4+ CD28- T cells and incident diabetes among persons with and without HIV. AIDS 2022; 36:501-511. [PMID: 34860194 PMCID: PMC8881388 DOI: 10.1097/qad.0000000000003137] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
OBJECTIVE A higher proportion of circulating memory CD4+ T cells is associated with prevalent diabetes mellitus in persons with HIV (PWH) and HIV-negative persons. We assessed whether circulating T-cell subsets could also identify individuals who will subsequently develop diabetes. DESIGN This is a longitudinal follow-up study of PWH and similar HIV-negative individuals from the Veterans Aging Cohort Study who provided peripheral mononuclear blood cells between 2005 and 2007. METHODS We quantified T-cell subsets using flow cytometry and functional assays to identify CD4+ and CD8+ naive, activated, senescent, memory (central, effector, and effector RA+), and TH1, TH2, and TH17-phenotype cells. The occurrence of an incident diabetes diagnosis (i.e. after baseline blood draw) was adjudicated by a two-physician chart review. Cox proportional hazards models adjusted for traditional risk factors, cytomegalovirus serostatus, and plasma inflammatory biomarkers assessed the relationship between T-cell subsets and incident diabetes. RESULTS One thousand, eight hundred and thirty-seven participants (1259 PWH) without diabetes at baseline were included; 69% were black, 95% were men, and median follow-up was 8.6 years. Higher baseline frequencies of CD4+ T effector memory RA+ (TEMRA) cells defined as CD45RA+ CD27- (P = 0.04) and senescent T cells defined as CD4+ CD28- (P = 0.04) were associated with incident diabetes in PWH only. CONCLUSIONS Higher frequencies of CD4+ TEMRA and CD4+ CD28- T cells were associated with incident diabetes in PWH only after adjustment for other factors. Additional studies are necessary to assess whether these cells act in blood via inflammatory mediators or reflect T-cell populations in metabolically active tissues.
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Affiliation(s)
- Samuel S. BAILIN
- Division of Infectious Diseases, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Suman KUNDU
- Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Melissa WELLONS
- Divison of Diabetes, Endocrinology, and Metabolism, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Matthew S. FREIBERG
- Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
- Veterans Affairs Tennessee Valley Healthcare System, Nashville, Tennessee, USA
| | - Margaret F. DOYLE
- Department of Pathology and Laboratory Medicine, University of Vermont, Burlington, Vermont, USA
| | - Russell P. TRACY
- Department of Pathology and Laboratory Medicine, University of Vermont, Burlington, Vermont, USA
| | - Amy C. JUSTICE
- Veterans Affairs Connecticut Healthcare System, West Haven, Connecticut, USA
- Department of Internal Medicine, Yale School of Medicine, West Haven, Connecticut, USA
| | - Celestine N. WANJALLA
- Division of Infectious Diseases, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Alan L. LANDAY
- Department of Internal Medicine, Rush University Medical Center, Chicago, Illinois, USA
| | - Kaku SO-ARMAH
- Boston University School of Medicine, Boston, Massachusetts, USA
| | - Simon MALLAL
- Division of Infectious Diseases, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
- Center for Translational Immunology and Infectious Diseases, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Jonathan A. KROPSKI
- Veterans Affairs Tennessee Valley Healthcare System, Nashville, Tennessee, USA
- Division of Allergy, Pulmonary and Critical Care Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - John R. KOETHE
- Division of Infectious Diseases, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
- Veterans Affairs Tennessee Valley Healthcare System, Nashville, Tennessee, USA
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Irwandi RA, Kuswandani SO, Harden S, Marletta D, D'Aiuto F. Circulating inflammatory cell profiling and periodontitis: A systematic review and meta-analysis. J Leukoc Biol 2022; 111:1069-1096. [PMID: 35199874 DOI: 10.1002/jlb.5ru1021-524r] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2021] [Revised: 01/14/2022] [Accepted: 01/31/2022] [Indexed: 12/13/2022] Open
Abstract
Inflammation is a key driver of common noncommunicable diseases. Among common triggers of inflammation, chronic gingival inflammation (periodontitis) triggers a consistent humoral host inflammatory response, but little is known on its impact on circulating inflammatory cell profiles. We aimed to systematically appraise all the evidence linking periodontitis and its treatment to circulating inflammatory cell profiles. From 6 databases, 157 studies were eligible for qualitative synthesis and 29 studies for meta-analysis. Our meta-analysis showed that participants with periodontitis exhibited a significant mean increase in circulating CD4+ , CD4+ CD45RO+ , IFNγ-expressing CD4+ and CD8+ T cells, CD19+ CD27+ and CD5+ B cells, CD14+ CD16+ monocytes, and CD16+ neutrophils but decrease in CD8+ T and CD14++ CD16- monocytes. Our qualitative synthesis revealed that peripheral blood neutrophils of patients with periodontitis consistently showed elevated production of reactive oxygen species (ROS) when compared with those of healthy controls. Some evidence suggested that the treatment of periodontitis reversed the exaggerated ROS production, but limited and inconclusive data were found on several circulating inflammatory cell profiling. We conclude that periodontitis and its treatment are associated with minor but consistent alterations in circulating inflammatory cell profiles. These changes could represent key mechanisms explaining the association of periodontitis with other comorbidities such as cardiovascular disease, diabetes, and rheumatoid arthritis.
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Affiliation(s)
- Rizky A Irwandi
- Periodontology Unit, Eastman Dental Institute, University College London, London, United Kingdom
| | - Sandra O Kuswandani
- Periodontology Unit, Eastman Dental Institute, University College London, London, United Kingdom.,Department of Periodontology, Faculty of Dentistry, Universitas Indonesia, Jakarta, Indonesia
| | - Simon Harden
- Department of Statistical Science, University College London, London, United Kingdom
| | - Debora Marletta
- Cruciform Hub, University College London, London, United Kingdom
| | - Francesco D'Aiuto
- Periodontology Unit, Eastman Dental Institute, University College London, London, United Kingdom
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50
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Cifuentes-Mendiola SE, Solis-Suarez DL, Martínez-Dávalos A, Godínez-Victoria M, García-Hernández AL. CD4 + T-cell activation of bone marrow causes bone fragility and insulin resistance in type 2 diabetes. Bone 2022; 155:116292. [PMID: 34896656 DOI: 10.1016/j.bone.2021.116292] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/21/2021] [Revised: 12/02/2021] [Accepted: 12/03/2021] [Indexed: 12/14/2022]
Abstract
Type 2 diabetes mellitus (T2DM) causes an increased risk of bone fractures. However, the pathophysiology of diabetic bone fragility is not completely understood. It has been proposed that an inflammatory microenvironment in bone could be a major mechanism by inducing uncontrolled bone resorption, inadequate bone formation and consequently more porous bones. We propose that activated T-cells in the bone marrow cause a pro-inflammatory microenvironment in bone, and cause bone fragility in T2DM. We induced T2DM in C57BL/6 male mice through a hypercaloric diet rich in carbohydrates and low doses of streptozocin. In T2DM mice we inhibited systemic activation of T-cells with a fusion protein between the extracellular domain of Cytotoxic T-Lymphocyte Antigen 4 and the Fc domain of human immunoglobulin G (CTLA4-Ig). We analysed the effects of T2DM or CTLA4-Ig in lymphocyte cell subsets and antigen-presenting cells in peripheral blood and femoral bone marrow; and their effect on the metabolic phenotype, blood and bone cytokine concentration, femoral bone microarchitecture and biomechanical properties, and the number of osteoblast-like cells in the femoral endosteum. We performed a Pearson multiple correlation analysis between all variables in order to understand the global mechanism. Results demonstrated that CTLA4-Ig decreased the number of activated CD4+ T-cells in the femoral bone marrow and consequently decreased TNF-α and RANK-L concentration in bone, notably improved femoral bone microarchitecture and biomechanical properties, increased the number of osteoblast-like cells, and reduces osteoclastic activity compared to T2DM mice that did not receive the inhibitor. Interestingly, we observed that blood glucose levels and insulin resistance may be related to the increase in activated CD4+ T-cells in the bone marrow. We conclude that bone marrow activated CD4+ T-cells cause poor bone quality and insulin resistance in T2DM.
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Affiliation(s)
- S E Cifuentes-Mendiola
- Laboratory of Dental Research, Section of Osteoimmunology and Oral Immunology, FES Iztacala, National Autonomous University of Mexico, A. Jiménez Gallardo SN, San Sebastián Xhala, Cuautitlán Izcalli, Estado de México, CP 54714, Mexico; Postgraduate in Biological Sciences, National Autonomous University of Mexico, Mexico, Mexico
| | - D L Solis-Suarez
- Laboratory of Dental Research, Section of Osteoimmunology and Oral Immunology, FES Iztacala, National Autonomous University of Mexico, A. Jiménez Gallardo SN, San Sebastián Xhala, Cuautitlán Izcalli, Estado de México, CP 54714, Mexico
| | - A Martínez-Dávalos
- Physics Institute, National Autonomous University of Mexico, Circuito de la Investigación Científica, Ciudad Universitaria, 04510 México City, Mexico
| | - M Godínez-Victoria
- Sección de Estudios de Posgrado e Investigación, Escuela Superior de Medicina, Instituto Politécnico Nacional, Mexico, Mexico
| | - A L García-Hernández
- Laboratory of Dental Research, Section of Osteoimmunology and Oral Immunology, FES Iztacala, National Autonomous University of Mexico, A. Jiménez Gallardo SN, San Sebastián Xhala, Cuautitlán Izcalli, Estado de México, CP 54714, Mexico.
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