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Kim S, Choi C, Son Y, Lee J, Joo S, Lee YH. BNIP3-mediated mitophagy in macrophages regulates obesity-induced adipose tissue metaflammation. Autophagy 2025:1-19. [PMID: 40195021 DOI: 10.1080/15548627.2025.2487035] [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: 11/18/2024] [Revised: 03/20/2025] [Accepted: 03/27/2025] [Indexed: 04/09/2025] Open
Abstract
Adipose tissue macrophages (ATMs) are key cellular components that respond to nutritional excess, contributing to obesity-induced inflammation and insulin resistance. However, the mechanisms underlying macrophage polarization and recruitment in adipose tissue during obesity remain unclear. In this study, we investigated mitophagy-dependent metabolic reprogramming in ATMs and identified a crucial role of the mitophagy receptor BNIP3 in regulating macrophage polarization in response to obesity. Mitophagic flux in ATMs increased following 12 weeks of high-fat diet (HFD) feeding, with Bnip3 levels upregulated in a HIF1A dependent manner, without affecting other mitophagy receptors. Macrophage-specific bnip3 knockout reduced HFD-induced adipose tissue inflammation and improved glucose tolerance and insulin sensitivity. Mechanistically, hypoxic conditions in vitro induced HIF1A-BNIP3-mediated mitophagy and glycolytic shift in macrophages. Furthermore, HIF1A-BNIP3 signaling-enhanced lipopolysaccharide-induced pro-inflammatory activation in macrophages. These findings demonstrate that BNIP3-mediated mitophagy regulates the glycolytic shift and pro-inflammatory polarization in macrophages and suggest that BNIP3 could be a therapeutical target for obesity-related metabolic diseases.Abbreviation: 2-DG: 2-deoxyglucose; ACADM/MCAD: acyl-CoA dehydrogenase medium chain; ADGRE1/F4/80: adhesion G protein-coupled receptor E1; ATMs: adipose tissue macrophages; BNIP3: BCL2 interacting protein 3; BNIP3L/NIX: BCL2 interacting protein 3 like; CLS: crown-like structure; CoCl2: cobalt(II) chloride; COX4/COXIV: cytochrome c oxidase subunit 4; ECAR: extracellular acidification rate; ECM: extraceullular matrix; gWAT: gonadal white adipose tissue; HFD: high-fat diet; HIF1A/HIF-1 α: hypoxia inducible factor 1 subunit alpha; IL1B/IL-1β: interleukin 1 beta; ITGAM/CD11B: integrin subunit alpha M; KO: knockout; LAMs: lipid-associated macrophages; LPS: lipopolysaccharide; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MRC1/CD206: mannose receptor C-type 1; mtDNA: mitochondrial DNA; NCD: normal chow diet; OCR: oxygen consumption rate; OXPHOS: oxidative phosphorylation; PINK1: PTEN induced kinase 1; PRKN/Parkin: parkin RBR E3 ubiquitin protein ligase; PTPRC/CD45: protein tyrosine phosphatase receptor type C; SVFs: stromal vascular fractions; TEM: transmission electron microscopy; TMRM: tetramethylrhodamine methyl ester; TOMM20: Translocase of outer mitochondrial membrane 20; TREM2: triggering receptor expressed on myeloid cells 2; WT: wild-type.
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Affiliation(s)
- Sangseob Kim
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Republic of Korea
| | - Cheoljun Choi
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Republic of Korea
| | - Yeonho Son
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Republic of Korea
| | - Junhyuck Lee
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Republic of Korea
| | - Sungug Joo
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Republic of Korea
| | - Yun-Hee Lee
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Republic of Korea
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Mirchandani AS, Sanchez-Garcia MA, Walmsley SR. How oxygenation shapes immune responses: emerging roles for physioxia and pathological hypoxia. Nat Rev Immunol 2025; 25:161-177. [PMID: 39349943 DOI: 10.1038/s41577-024-01087-5] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/23/2024] [Indexed: 03/04/2025]
Abstract
Most eukaryotes require oxygen for their survival and, with increasing multicellular complexity, oxygen availability and delivery rates vary across the tissues of complex organisms. In humans, healthy tissues have markedly different oxygen gradients, ranging from the hypoxic environment of the bone marrow (where our haematopoietic stem cells reside) to the lungs and their alveoli, which are among the most oxygenated areas of the body. Immune cells are therefore required to adapt to varying oxygen availability as they move from the bone marrow to peripheral organs to mediate their effector functions. These changing oxygen gradients are exaggerated during inflammation, where oxygenation is often depleted owing to alterations in tissue perfusion and increased cellular activity. As such, it is important to consider the effects of oxygenation on shaping the immune response during tissue homeostasis and disease conditions. In this Review, we address the relevance of both physiological oxygenation (physioxia) and disease-associated hypoxia (where cellular oxygen demand outstrips supply) for immune cell functions, discussing the relevance of hypoxia for immune responses in the settings of tissue homeostasis, inflammation, infection, cancer and disease immunotherapy.
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Affiliation(s)
- Ananda Shanti Mirchandani
- Centre for Inflammation Research, Institute for Regeneration and Repair, University of Edinburgh, Edinburgh, UK.
| | | | - Sarah Ruth Walmsley
- Centre for Inflammation Research, Institute for Regeneration and Repair, University of Edinburgh, Edinburgh, UK.
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Nisar A, Khan S, Li W, Hu L, Samarawickrama PN, Gold NM, Zi M, Mehmood SA, Miao J, He Y. Hypoxia and aging: molecular mechanisms, diseases, and therapeutic targets. MedComm (Beijing) 2024; 5:e786. [PMID: 39415849 PMCID: PMC11480526 DOI: 10.1002/mco2.786] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2024] [Revised: 09/26/2024] [Accepted: 09/26/2024] [Indexed: 10/19/2024] Open
Abstract
Aging is a complex biological process characterized by the gradual decline of cellular functions, increased susceptibility to diseases, and impaired stress responses. Hypoxia, defined as reduced oxygen availability, is a critical factor that influences aging through molecular pathways involving hypoxia-inducible factors (HIFs), oxidative stress, inflammation, and epigenetic modifications. This review explores the interconnected roles of hypoxia in aging, highlighting how hypoxic conditions exacerbate cellular damage, promote senescence, and contribute to age-related pathologies, including cardiovascular diseases, neurodegenerative disorders, cancer, metabolic dysfunctions, and pulmonary conditions. By examining the molecular mechanisms linking hypoxia to aging, we identify key pathways that serve as potential therapeutic targets. Emerging interventions such as HIF modulators, antioxidants, senolytics, and lifestyle modifications hold promise in mitigating the adverse effects of hypoxia on aging tissues. However, challenges such as the heterogeneity of aging, lack of reliable biomarkers, and safety concerns regarding hypoxia-targeted therapies remain. This review emphasizes the need for personalized approaches and advanced technologies to develop effective antiaging interventions. By integrating current knowledge, this review provides a comprehensive framework that underscores the importance of targeting hypoxia-induced pathways to enhance healthy aging and reduce the burden of age-related diseases.
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Affiliation(s)
- Ayesha Nisar
- Key Laboratory of Genetic Evolution & Animal Models, KIZ/CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Kunming Institute of ZoologyChinese Academy of SciencesKunmingYunnanChina
- Kunming College of Life ScienceUniversity of Chinese Academy of SciencesKunmingChina
- Key Laboratory of Healthy Aging Research of Yunnan Province, Kunming Institute of ZoologyChinese Academy of SciencesKunmingYunnanChina
| | - Sawar Khan
- Department of Cell Biology, School of Life SciencesCentral South UniversityChangshaHunanChina
- Institute of Molecular Biology and BiotechnologyThe University of LahoreLahorePakistan
| | - Wen Li
- Department of EndocrinologyThe Second Affiliated Hospital of Dali University (the Third People's Hospital of Yunnan Province)KunmingYunnanChina
| | - Li Hu
- Key Laboratory of Genetic Evolution & Animal Models, KIZ/CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Kunming Institute of ZoologyChinese Academy of SciencesKunmingYunnanChina
- Kunming College of Life ScienceUniversity of Chinese Academy of SciencesKunmingChina
- Key Laboratory of Healthy Aging Research of Yunnan Province, Kunming Institute of ZoologyChinese Academy of SciencesKunmingYunnanChina
| | - Priyadarshani Nadeeshika Samarawickrama
- Key Laboratory of Genetic Evolution & Animal Models, KIZ/CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Kunming Institute of ZoologyChinese Academy of SciencesKunmingYunnanChina
- Kunming College of Life ScienceUniversity of Chinese Academy of SciencesKunmingChina
- Key Laboratory of Healthy Aging Research of Yunnan Province, Kunming Institute of ZoologyChinese Academy of SciencesKunmingYunnanChina
| | - Naheemat Modupeola Gold
- Key Laboratory of Genetic Evolution & Animal Models, KIZ/CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Kunming Institute of ZoologyChinese Academy of SciencesKunmingYunnanChina
- Kunming College of Life ScienceUniversity of Chinese Academy of SciencesKunmingChina
- Key Laboratory of Healthy Aging Research of Yunnan Province, Kunming Institute of ZoologyChinese Academy of SciencesKunmingYunnanChina
| | - Meiting Zi
- Key Laboratory of Genetic Evolution & Animal Models, KIZ/CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Kunming Institute of ZoologyChinese Academy of SciencesKunmingYunnanChina
- Key Laboratory of Healthy Aging Research of Yunnan Province, Kunming Institute of ZoologyChinese Academy of SciencesKunmingYunnanChina
| | | | - Jiarong Miao
- Department of GastroenterologyThe First Affiliated Hospital of Kunming Medical UniversityKunmingYunnanChina
| | - Yonghan He
- Key Laboratory of Genetic Evolution & Animal Models, KIZ/CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Kunming Institute of ZoologyChinese Academy of SciencesKunmingYunnanChina
- Kunming College of Life ScienceUniversity of Chinese Academy of SciencesKunmingChina
- Key Laboratory of Healthy Aging Research of Yunnan Province, Kunming Institute of ZoologyChinese Academy of SciencesKunmingYunnanChina
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Beer HN, Lacey TA, Gibbs RL, Most MS, Hicks ZM, Grijalva PC, Marks-Nelson ES, Schmidt TB, Petersen JL, Yates DT. Daily Eicosapentaenoic Acid Infusion in IUGR Fetal Lambs Reduced Systemic Inflammation, Increased Muscle ADRβ2 Content, and Improved Myoblast Function and Muscle Growth. Metabolites 2024; 14:340. [PMID: 38921474 PMCID: PMC11205652 DOI: 10.3390/metabo14060340] [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: 05/14/2024] [Revised: 06/07/2024] [Accepted: 06/16/2024] [Indexed: 06/27/2024] Open
Abstract
Intrauterine growth-restricted (IUGR) fetuses exhibit systemic inflammation that contributes to programmed deficits in myoblast function and muscle growth. Thus, we sought to determine if targeting fetal inflammation improves muscle growth outcomes. Heat stress-induced IUGR fetal lambs were infused with eicosapentaenoic acid (IUGR+EPA; n = 9) or saline (IUGR; n = 8) for 5 days during late gestation and compared to saline-infused controls (n = 11). Circulating eicosapentaenoic acid was 42% less (p < 0.05) for IUGR fetuses but was recovered in IUGR+EPA fetuses. The infusion did not improve placental function or fetal O2 but resolved the 67% greater (p < 0.05) circulating TNFα observed in IUGR fetuses. This improved myoblast function and muscle growth, as the 23% reduction (p < 0.05) in the ex vivo differentiation of IUGR myoblasts was resolved in IUGR+EPA myoblasts. Semitendinosus, longissimus dorsi, and flexor digitorum superficialis muscles were 24-39% lighter (p < 0.05) for IUGR but not for IUGR+EPA fetuses. Elevated (p < 0.05) IL6R and reduced (p < 0.05) β2 adrenoceptor content in IUGR muscle indicated enhanced inflammatory sensitivity and diminished β2 adrenergic sensitivity. Although IL6R remained elevated, β2 adrenoceptor deficits were resolved in IUGR+EPA muscle, demonstrating a unique underlying mechanism for muscle dysregulation. These findings show that fetal inflammation contributes to IUGR muscle growth deficits and thus may be an effective target for intervention.
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Affiliation(s)
- Haley N. Beer
- Stress Physiology Laboratory, Department of Animal Science, University of Nebraska-Lincoln, Lincoln, NE 68583, USA
| | - Taylor A. Lacey
- Stress Physiology Laboratory, Department of Animal Science, University of Nebraska-Lincoln, Lincoln, NE 68583, USA
| | - Rachel L. Gibbs
- Stress Physiology Laboratory, Department of Animal Science, University of Nebraska-Lincoln, Lincoln, NE 68583, USA
| | - Micah S. Most
- Stress Physiology Laboratory, Department of Animal Science, University of Nebraska-Lincoln, Lincoln, NE 68583, USA
| | - Zena M. Hicks
- Stress Physiology Laboratory, Department of Animal Science, University of Nebraska-Lincoln, Lincoln, NE 68583, USA
| | - Pablo C. Grijalva
- Stress Physiology Laboratory, Department of Animal Science, University of Nebraska-Lincoln, Lincoln, NE 68583, USA
| | - Eileen S. Marks-Nelson
- Stress Physiology Laboratory, Department of Animal Science, University of Nebraska-Lincoln, Lincoln, NE 68583, USA
| | - Ty B. Schmidt
- Meat Science and Muscle Biology, Department of Animal Science, University of Nebraska-Lincoln, Lincoln, NE 68583, USA;
| | - Jessica L. Petersen
- Animal Breeding and Genetics, Department of Animal Science, University of Nebraska-Lincoln, Lincoln, NE 68583, USA;
| | - Dustin T. Yates
- Stress Physiology Laboratory, Department of Animal Science, University of Nebraska-Lincoln, Lincoln, NE 68583, USA
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Bjork S, Jain D, Marliere MH, Predescu SA, Mokhlesi B. Obstructive Sleep Apnea, Obesity Hypoventilation Syndrome, and Pulmonary Hypertension: A State-of-the-Art Review. Sleep Med Clin 2024; 19:307-325. [PMID: 38692755 DOI: 10.1016/j.jsmc.2024.02.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/03/2024]
Abstract
The pathophysiological interplay between sleep-disordered breathing (SDB) and pulmonary hypertension (PH) is complex and can involve a variety of mechanisms by which SDB can worsen PH. These mechanistic pathways include wide swings in intrathoracic pressure while breathing against an occluded upper airway, intermittent and/or sustained hypoxemia, acute and/or chronic hypercapnia, and obesity. In this review, we discuss how the downstream consequences of SDB can adversely impact PH, the challenges in accurately diagnosing and classifying PH in the severely obese, and review the limited literature assessing the effect of treating obesity, obstructive sleep apnea, and obesity hypoventilation syndrome on PH.
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Affiliation(s)
- Sarah Bjork
- Division of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, Rush University Medical Center, 1750 W. Harrison Street, Jelke 297, Chicago, IL 60612, USA
| | - Deepanjali Jain
- Division of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, Rush University Medical Center, 1750 W. Harrison Street, Jelke 297, Chicago, IL 60612, USA
| | - Manuel Hache Marliere
- Division of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, Rush University Medical Center, 1750 W. Harrison Street, Jelke 297, Chicago, IL 60612, USA
| | - Sanda A Predescu
- Division of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, Rush University Medical Center, 1750 W. Harrison Street, Jelke 297, Chicago, IL 60612, USA
| | - Babak Mokhlesi
- Division of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, Rush University Medical Center, 1750 W. Harrison Street, Jelke 297, Chicago, IL 60612, USA.
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6
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Zhang Y, Zhang B, Sun X. The molecular mechanism of macrophage-adipocyte crosstalk in maintaining energy homeostasis. Front Immunol 2024; 15:1378202. [PMID: 38650945 PMCID: PMC11033412 DOI: 10.3389/fimmu.2024.1378202] [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: 01/29/2024] [Accepted: 03/25/2024] [Indexed: 04/25/2024] Open
Abstract
Interactions between macrophages and adipocytes in adipose tissue are critical for the regulation of energy metabolism and obesity. Macrophage polarization induced by cold or other stimulations can drive metabolic reprogramming of adipocytes, browning, and thermogenesis. Accordingly, investigating the roles of macrophages and adipocytes in the maintenance of energy homeostasis is critical for the development of novel therapeutic approaches specifically targeting macrophages in metabolic disorders such as obesity. Current review outlines macrophage polarization not only regulates the release of central nervous system and inflammatory factors, but controls mitochondrial function, and other factor that induce metabolic reprogramming of adipocytes and maintain energy homeostasis. We also emphasized on how the adipocytes conversely motivate the polarization of macrophage. Exploring the interactions between adipocytes and macrophages may provide new therapeutic strategies for the management of obesity-related metabolic diseases.
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Affiliation(s)
- Yudie Zhang
- Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
- Guizhou University of Traditional Chinese Medicine, Guiyang, China
- Key Laboratory of Bioactive Substances and Resources Utilization of Chinese Herbal Medicine, Ministry of Education, Beijing, China
- Beijing Key Laboratory of Innovative Drug Discovery of Traditional Chinese Medicine (Natural Medicine) and Translational Medicine, Beijing, China
- Key Laboratory of Efficacy Evaluation of Chinese Medicine Against Glyeolipid Metabolism Disorder Disease, State Administration of Traditional Chinese Medicine, Beijing, China
| | - Bin Zhang
- Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
- Key Laboratory of Bioactive Substances and Resources Utilization of Chinese Herbal Medicine, Ministry of Education, Beijing, China
- Beijing Key Laboratory of Innovative Drug Discovery of Traditional Chinese Medicine (Natural Medicine) and Translational Medicine, Beijing, China
- Key Laboratory of Efficacy Evaluation of Chinese Medicine Against Glyeolipid Metabolism Disorder Disease, State Administration of Traditional Chinese Medicine, Beijing, China
| | - Xiaobo Sun
- Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
- Guizhou University of Traditional Chinese Medicine, Guiyang, China
- Key Laboratory of Bioactive Substances and Resources Utilization of Chinese Herbal Medicine, Ministry of Education, Beijing, China
- Beijing Key Laboratory of Innovative Drug Discovery of Traditional Chinese Medicine (Natural Medicine) and Translational Medicine, Beijing, China
- Key Laboratory of Efficacy Evaluation of Chinese Medicine Against Glyeolipid Metabolism Disorder Disease, State Administration of Traditional Chinese Medicine, Beijing, China
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7
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Wu Y, Ma Y. CCL2-CCR2 signaling axis in obesity and metabolic diseases. J Cell Physiol 2024; 239:e31192. [PMID: 38284280 DOI: 10.1002/jcp.31192] [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: 10/14/2023] [Revised: 12/10/2023] [Accepted: 12/29/2023] [Indexed: 01/30/2024]
Abstract
Obesity and metabolic diseases, such as insulin resistance, type 2 diabetes, nonalcoholic fatty liver disease, and cardiovascular ailments, represent formidable global health challenges, bearing considerable implications for both morbidity and mortality rates. It has become increasingly evident that chronic, low-grade inflammation plays a pivotal role in the genesis and advancement of these conditions. The involvement of C-C chemokine ligand 2 (CCL2) and its corresponding receptor, C-C chemokine receptor 2 (CCR2), has been extensively documented in numerous inflammatory maladies. Recent evidence indicates that the CCL2/CCR2 pathway extends beyond immune cell recruitment and inflammation, exerting a notable influence on the genesis and progression of metabolic syndrome. The present review seeks to furnish a comprehensive exposition of the CCL2-CCR2 signaling axis within the context of obesity and metabolic disorders, elucidating its molecular mechanisms, functional roles, and therapeutic implications.
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Affiliation(s)
- Yue Wu
- Shandong Provincial Key Laboratory of Animal Resistance Biology, Center for Cell Structure and Function, Collaborative Innovation Center of Cell Biology in Universities of Shandong, College of Life Sciences, Shandong Normal University, Jinan, China
| | - Yanchun Ma
- Shandong Provincial Key Laboratory of Animal Resistance Biology, Center for Cell Structure and Function, Collaborative Innovation Center of Cell Biology in Universities of Shandong, College of Life Sciences, Shandong Normal University, Jinan, China
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Engin A. Adipose Tissue Hypoxia in Obesity: Clinical Reappraisal of Hypoxia Hypothesis. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2024; 1460:329-356. [PMID: 39287857 DOI: 10.1007/978-3-031-63657-8_11] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/19/2024]
Abstract
Obese subjects exhibit lower adipose tissue oxygen consumption in accordance with the lower adipose tissue blood flow. Thereby, compared to lean subjects, obese individuals have almost half lower capillary density and more than half lower vascular endothelial growth factor (VEGF). The VEGF expression together with hypoxia-inducible transcription factor-1 alpha (HIF-1α) activity also requires phosphatidylinositol 3-kinase (PI3K) and mammalian target of rapamycin (mTOR)-mediated signaling. Especially HIF-1α is an important signaling molecule for hypoxia to induce the inflammatory responses. Hypoxia contributes to several biological functions, such as angiogenesis, cell proliferation, apoptosis, inflammation, and insulin resistance (IR). Pathogenesis of obesity-related comorbidities is attributed to intermittent hypoxia (IH), which is mostly observed in visceral obesity. Proinflammatory phenotype of the adipose tissue is a crucial link between IH and the development of IR. Inhibition of adaptive unfolded protein response (UPR) in hypoxia increases β cell death. Moreover, deletion of HIF-1α worsens β cell function. Oxidative stress, as well as the release of proinflammatory cytokines/adipokines in obesity, is proportional to the severity of IH. Reactive oxygen species (ROS) generation at mitochondria is responsible for propagation of the hypoxic signal; however, mitochondrial ROS production is required for hypoxic HIF-1α protein stabilization. Alterations in oxygen availability of adipose tissue directly affect the macrophage polarization and are responsible for the dysregulated adipocytokines production in obesity. Hypoxia both inhibits adipocyte differentiation from preadipocytes and macrophage migration from the hypoxic adipose tissue. Upon reaching a hypertrophic threshold beyond the adipocyte fat loading capacity, excess extracellular matrix (ECM) components are deposited, causing fibrosis. HIF-1α initiates the whole pathological process of fibrosis and inflammation in the obese adipose tissue. In addition to stressed adipocytes, hypoxia contributes to immune cell migration and activation which further aggravates adipose tissue fibrosis. Therefore, targeting HIF-1α might be an efficient way to suppress hypoxia-induced pathological changes in the ECM. The fibrosis score of adipose tissue correlates negatively with the body mass index and metabolic parameters. Inducers of browning/beiging adipocytes and adipokines, as well as modulations of matrix remodeling enzyme inhibitors, and associated gene regulators, are potential pharmacological targets for treating obesity.
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Affiliation(s)
- Atilla Engin
- Faculty of Medicine, Department of General Surgery, Gazi University, Besevler, Ankara, Turkey.
- Mustafa Kemal Mah. 2137. Sok. 8/14, 06520, Cankaya, Ankara, Turkey.
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Engin AB. Message Transmission Between Adipocyte and Macrophage in Obesity. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2024; 1460:273-295. [PMID: 39287855 DOI: 10.1007/978-3-031-63657-8_9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/19/2024]
Abstract
Obesity is characterized by the chronic low-grade activation of the innate immune system. In this respect, macrophage-elicited metabolic inflammation and adipocyte-macrophage interaction have primary importance in obesity. Large quantity of macrophages is accumulated by different mechanisms in obese adipose tissue. Hypertrophic adipocyte-derived chemotactic monocyte chemoattractant protein-1 (MCP-1)/C-C chemokine receptor 2 (CCR2) pathway promotes more macrophage accumulation into the obese adipose tissue. However, obesity-induced changes in adipose tissue macrophage density are mainly dependent on increases in the triple-positive cluster of differentiation (CD)11b+ F4/80+ CD11c+ adipose tissue macrophage subpopulation. As epigenetic regulators, microRNAs (miRNAs) are one of the most important mediators of obesity. miRNAs are expressed by adipocytes as well as macrophages and regulate inflammation with the expression of target genes. A paracrine loop involving free fatty acids and tumor necrosis factor-alpha (TNF-α) between adipocytes and macrophages establishes a vicious cycle that aggravates inflammatory changes in the adipose tissue. Adipocyte-specific caspase-1 and production of interleukin-1beta (IL-1β) by macrophages; both adipocyte and macrophage induction by toll-like receptor-4 (TLR4) through nuclear factor-kappaB (NF-κB) activation; free fatty acid-induced and TLR-mediated activation of c-Jun N-terminal kinase (JNK)-related pro-inflammatory pathways in CD11c+ immune cells; are effective in mutual message transmission between adipocyte and macrophage and in the development of adipose tissue inflammation. Thus, the metabolic status of adipocytes and their released exosomes are important determinants of macrophage inflammatory output. However, old adipocytes are removed by macrophages through trogocytosis or sending an "eat me" signal. As a single miRNA can be able to regulate a variety of target genes and signaling pathways, reciprocal transfer of miRNAs between adipocytes and macrophages via miRNA-loaded exosomes reorganizes the different stages of obesity. Changes in the expression of circulating miRNAs because of obesity progression or anti-obesity treatment indicate that miRNAs could be used as potential biomarkers. Therefore, it is believed that targeting macrophage-associated miRNAs with anti-obesity miRNA-loaded nano-carriers may be successful in the attenuation of both obesity and adipose tissue inflammation in clinical practice. Moreover, miRNA-containing exosomes and transferable mitochondria between the adipocyte and macrophage are investigated as new therapeutic targets for obesity-related metabolic disorders.
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Affiliation(s)
- Ayse Basak Engin
- Faculty of Pharmacy, Department of Toxicology, Gazi University, Hipodrom, Ankara, Turkey.
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de Castro RJA, Marina CL, Sturny-Leclère A, Hoffmann C, Bürgel PH, Wong SSW, Aimanianda V, Varet H, Agrawal R, Bocca AL, Alanio A. Kicking sleepers out of bed: Macrophages promote reactivation of dormant Cryptococcus neoformans by extracellular vesicle release and non-lytic exocytosis. PLoS Pathog 2023; 19:e1011841. [PMID: 38033163 PMCID: PMC10715671 DOI: 10.1371/journal.ppat.1011841] [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: 06/16/2023] [Revised: 12/12/2023] [Accepted: 11/18/2023] [Indexed: 12/02/2023] Open
Abstract
Macrophages play a key role in disseminated cryptococcosis, a deadly fungal disease caused by Cryptococcus neoformans. This opportunistic infection can arise following the reactivation of a poorly characterized latent infection attributed to dormant C. neoformans. Here, we investigated the mechanisms underlying reactivation of dormant C. neoformans using an in vitro co-culture model of viable but non-culturable (VBNC; equivalent of dormant) yeast cells with bone marrow-derived murine macrophages (BMDMs). Comparative transcriptome analysis of BMDMs incubated with log, stationary phase or VBNC cells of C. neoformans showed that VBNC cells elicited a reduced transcriptional modification of the macrophage but retaining the ability to regulate genes important for immune response, such as NLRP3 inflammasome-related genes. We further confirmed the maintenance of the low immunostimulatory capacity of VBNC cells using multiplex cytokine profiling, and analysis of cell wall composition and dectin-1 ligands exposure. In addition, we evaluated the effects of classic (M1) or alternative (M2) macrophage polarization on VBNC cells. We observed that intracellular residence sustained dormancy, regardless of the polarization state of macrophages and despite indirect detection of pantothenic acid (or its derivatives), a known reactivator for VBNC cells, in the C. neoformans-containing phagolysosome. Notably, M0 and M2, but not M1 macrophages, induced extracellular reactivation of VBNC cells by the secretion of extracellular vesicles and non-lytic exocytosis. Our results indicate that VBNC cells retain the low immunostimulatory profile required for persistence of C. neoformans in the host. We also describe a pro-pathogen role of macrophage-derived extracellular vesicles in C. neoformans infection and reinforce the impact of non-lytic exocytosis and the macrophage profile on the pathophysiology of cryptococcosis.
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Affiliation(s)
- Raffael Júnio Araújo de Castro
- Translational Mycology Research Group, National Reference Center for Invasive Mycoses and Antifungals, Mycology Department, Institut Pasteur, Université Paris Cité, Paris, France
- Laboratory of Applied Immunology, Department of Cell Biology, Institute of Biological Sciences, University of Brasilia, Brasília, Distrito Federal, Brazil
| | - Clara Luna Marina
- Laboratory of Applied Immunology, Department of Cell Biology, Institute of Biological Sciences, University of Brasilia, Brasília, Distrito Federal, Brazil
| | - Aude Sturny-Leclère
- Translational Mycology Research Group, National Reference Center for Invasive Mycoses and Antifungals, Mycology Department, Institut Pasteur, Université Paris Cité, Paris, France
| | - Christian Hoffmann
- Food Research Center, Department of Food Sciences and Experimental Nutrition, Faculty of Pharmaceutical Sciences, University of São Paulo, São Paulo, São Paulo, Brazil
| | - Pedro Henrique Bürgel
- Laboratory of Applied Immunology, Department of Cell Biology, Institute of Biological Sciences, University of Brasilia, Brasília, Distrito Federal, Brazil
| | - Sarah Sze Wah Wong
- Immunobiology of Aspergillus, Institut Pasteur, Université Paris Cité, Paris, France
| | - Vishukumar Aimanianda
- Immunobiology of Aspergillus, Institut Pasteur, Université Paris Cité, Paris, France
| | - Hugo Varet
- Plate-forme Technologique Biomics, Institut Pasteur, Université Paris Cité, Paris, France
| | - Ruchi Agrawal
- Translational Mycology Research Group, National Reference Center for Invasive Mycoses and Antifungals, Mycology Department, Institut Pasteur, Université Paris Cité, Paris, France
| | - Anamélia Lorenzetti Bocca
- Laboratory of Applied Immunology, Department of Cell Biology, Institute of Biological Sciences, University of Brasilia, Brasília, Distrito Federal, Brazil
| | - Alexandre Alanio
- Translational Mycology Research Group, National Reference Center for Invasive Mycoses and Antifungals, Mycology Department, Institut Pasteur, Université Paris Cité, Paris, France
- Laboratoire de parasitologie-mycologie, AP-HP, Hôpital Saint-Louis, Paris, France
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11
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Deng Y, Adam V, Nepovimova E, Heger Z, Valko M, Wu Q, Wei W, Kuca K. c-Jun N-terminal kinase signaling in cellular senescence. Arch Toxicol 2023; 97:2089-2109. [PMID: 37335314 DOI: 10.1007/s00204-023-03540-1] [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: 03/28/2023] [Accepted: 06/06/2023] [Indexed: 06/21/2023]
Abstract
Cellular senescence leads to decreased tissue regeneration and inflammation and is associated with diabetes, neurodegenerative diseases, and tumorigenesis. However, the mechanisms of cellular senescence are not fully understood. Emerging evidence has indicated that c-Jun N-terminal kinase (JNK) signaling is involved in the regulation of cellular senescence. JNK can downregulate hypoxia inducible factor-1α to accelerate hypoxia-induced neuronal cell senescence. The activation of JNK inhibits mTOR activity and triggers autophagy, which promotes cellular senescence. JNK can upregulate the expression of p53 and Bcl-2 and accelerates cancer cell senescence; however, this signaling also mediates the expression of amphiregulin and PD-LI to achieve cancer cell immune evasion and prevents their senescence. The activation of JNK further triggers forkhead box O expression and its target gene Jafrac1 to extend the lifespan of Drosophila. JNK can also upregulate the expression of DNA repair protein poly ADP-ribose polymerase 1 and heat shock protein to delay cellular senescence. This review discusses recent advances in understanding the function of JNK signaling in cellular senescence and includes a comprehensive analysis of the molecular mechanisms underlying JNK-mediated senescence evasion and oncogene-induced cellular senescence. We also summarize the research progress in anti-aging agents that target JNK signaling. This study will contribute to a better understanding of the molecular targets of cellular senescence and provides insights into anti-aging, which may be used to develop drugs for the treatment of aging-related diseases.
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Affiliation(s)
- Ying Deng
- College of Life Science, Yangtze University, Jingzhou, 434025, China
| | - Vojtech Adam
- Department of Chemistry and Biochemistry, Mendel University in Brno, Brno, 613 00, Czech Republic
- Central European Institute of Technology, Brno University of Technology, Brno, 602 00, Czech Republic
| | - Eugenie Nepovimova
- Department of Chemistry, Faculty of Science, University of Hradec Králové, 500 03, Hradec Králové, Czech Republic
| | - Zbynek Heger
- Department of Chemistry and Biochemistry, Mendel University in Brno, Brno, 613 00, Czech Republic
- Central European Institute of Technology, Brno University of Technology, Brno, 602 00, Czech Republic
| | - Marian Valko
- Faculty of Chemical and Food Technology, Slovak University of Technology, 812 37, Bratislava, Slovakia
| | - Qinghua Wu
- College of Life Science, Yangtze University, Jingzhou, 434025, China.
- Department of Chemistry, Faculty of Science, University of Hradec Králové, 500 03, Hradec Králové, Czech Republic.
| | - Wei Wei
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-Products, Key Laboratory of Traceability for Agricultural Genetically Modified Organisms, Ministry of Agriculture and Rural Affairs, Zhejiang Academy of Agricultural Sciences, Hangzhou, 310021, China.
| | - Kamil Kuca
- Department of Chemistry, Faculty of Science, University of Hradec Králové, 500 03, Hradec Králové, Czech Republic.
- Andalusian Research Institute in Data Science and Computational Intelligence (DaSCI), University of Granada, Granada, Spain.
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12
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Ohtake T, Itaba S, Salybekov AA, Sheng Y, Sato T, Yanai M, Imagawa M, Fujii S, Kumagai H, Harata M, Asahara T, Kobayashi S. Repetitive administration of cultured human CD34+ cells improve adenine-induced kidney injury in mice. World J Stem Cells 2023; 15:268-280. [PMID: 37181001 PMCID: PMC10173816 DOI: 10.4252/wjsc.v15.i4.268] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/13/2022] [Revised: 02/24/2023] [Accepted: 03/21/2023] [Indexed: 04/26/2023] Open
Abstract
BACKGROUND There is no established treatment to impede the progression or restore kidney function in human chronic kidney disease (CKD).
AIM To examine the efficacy of cultured human CD34+ cells with enhanced proliferating potential in kidney injury in mice.
METHODS Human umbilical cord blood (UCB)-derived CD34+ cells were incubated for one week in vasculogenic conditioning medium. Vasculogenic culture significantly increased the number of CD34+ cells and their ability to form endothelial progenitor cell colony-forming units. Adenine-induced tubulointerstitial injury of the kidney was induced in immunodeficient non-obese diabetic/severe combined immunodeficiency mice, and cultured human UCB-CD34+ cells were administered at a dose of 1 × 106/mouse on days 7, 14, and 21 after the start of adenine diet.
RESULTS Repetitive administration of cultured UCB-CD34+ cells significantly improved the time-course of kidney dysfunction in the cell therapy group compared with that in the control group. Both interstitial fibrosis and tubular damage were significantly reduced in the cell therapy group compared with those in the control group (P < 0.01). Microvasculature integrity was significantly preserved (P < 0.01) and macrophage infiltration into kidney tissue was dramatically decreased in the cell therapy group compared with those in the control group (P < 0.001).
CONCLUSION Early intervention using human cultured CD34+ cells significantly improved the progression of tubulointerstitial kidney injury. Repetitive administration of cultured human UCB-CD34+ cells significantly improved tubulointerstitial damage in adenine-induced kidney injury in mice via vasculoprotective and anti-inflammatory effects.
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Affiliation(s)
- Takayasu Ohtake
- Regenerative Medicine, The Center for Cell Therapy & Regenerative Medicine, Shonan Kamakura General Hospital, Kamakura 247-8533, Kanagawa, Japan
- Kidney Disease and Transplant center, Shonan Kamakura General Hospital, Kamakura 247-8533, Kanagawa, Japan
- Regenerative Medicine, Shonan Research Institute of Innovative Medicine, Kamakura 247-8533, Kanagawa, Japan
| | - Shoichi Itaba
- Kamakura Techno-science Inc., Kamakura 248-0036, Japan
| | - Amankeldi A Salybekov
- Regenerative Medicine, Shonan Research Institute of Innovative Medicine, Kamakura 247-8533, Kanagawa, Japan
| | - Yin Sheng
- Advanced Medicine Science, Tokai University School of Medicine, Isehara 259-1193, Japan
| | - Tsutomu Sato
- Regenerative Medicine, Shonan Research Institute of Innovative Medicine, Kamakura 247-8533, Kanagawa, Japan
| | - Mitsuru Yanai
- Department of Pathology, Sapporo Tokushukai Hospital, Sapporo 004-0041, Japan
| | - Makoto Imagawa
- Department of Pathology, Sapporo Medical Center, Sapporo 004-0041, Japan
| | - Shigeo Fujii
- Kamakura Techno-science Inc., Kamakura 248-0036, Japan
| | | | | | - Takayuki Asahara
- Regenerative Medicine, Shonan Research Institute of Innovative Medicine, Kamakura 247-8533, Kanagawa, Japan
- Cell Processing and Cell/Genome Analysis Center, The Center for Cell Therapy & Regenerative Medicine, Shonan Kamakura General Hospital, Kamakura 247-8533, Kanagawa, Japan
| | - Shuzo Kobayashi
- Regenerative Medicine, Shonan Research Institute of Innovative Medicine, Kamakura 247-8533, Kanagawa, Japan
- Kidney Disease and Transplant Center, Shonan Kamakura General Hospital, Kamakura 247-8533, Kanazawa, Japan
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13
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Hancková M, Miháliková L, Pastoreková S, Betáková T. Hypoxia alters the immune response in mouse peritoneal macrophages infected with influenza a virus with truncated NS1 protein. Cytokine 2023; 164:156138. [PMID: 36796258 DOI: 10.1016/j.cyto.2023.156138] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2022] [Revised: 11/30/2022] [Accepted: 01/19/2023] [Indexed: 02/16/2023]
Abstract
Macrophages are the most abundant cells in infected tissue and are involved in the clearing infection, and immunomodulation of the innate and adaptive immune response. NS80 virus of influenza A virus, which encodes only the first 80 aa of the NS1 protein, suppresses the immune host response and is associated with enhanced pathogenicity. Hypoxia promotes infiltration of peritoneal macrophages into the adipose tissue and production of cytokines. To understand the role of hypoxia in the regulation of immune response, macrophages were infected with A/WSN/33 (WSN) and NS80 virus, and transcriptional profiles of the RIG-I-like receptor signalling pathway and expression of cytokines were evaluated in normoxia and hypoxia. Hypoxia inhibited the proliferation of IC-21 cells, downregulated the RIG-I-like receptor signalling pathway, and inhibited transcriptional activity of IFN-α, IFN-β, IFN-ε, and IFN-λ mRNA in infected macrophages. While transcription of IL-1β and Casp-1 mRNAs were increased in infected macrophages in normoxia, hypoxia resulted in decreased transcription activity of IL-1β and Casp-1 mRNAs. Hypoxia significantly affected expression of the translation factors IRF4, IFN-γ, and CXCL10 involved in regulation of immune response and polarization of the macrophages. The expression of pro-inflammatory cytokines such as sICAM-1, IL-1α, TNF-α, CCL2, CCL3, CXCL12, and M-CSF was to a large extent affected in uninfected and infected macrophages cultivated in hypoxia. The NS80 virus increased the expression of M-CSF, IL-16, CCL2, CCL3, and CXCL12, especially under hypoxia. The results show that hypoxia may play an important role in peritoneal macrophage activation, regulates the innate and adaptive immune response, changes production of pro-inflammatory cytokines, promotes macrophage polarization, and could affect the function of other immune cells.
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Affiliation(s)
- Miriam Hancková
- Biomedical Research Center, Slovak Academy of Sciences, Institute of Virology, Bratislava, Slovak Republic
| | - Lucia Miháliková
- Biomedical Research Center, Slovak Academy of Sciences, Institute of Virology, Bratislava, Slovak Republic
| | - Silvia Pastoreková
- Biomedical Research Center, Slovak Academy of Sciences, Institute of Virology, Bratislava, Slovak Republic
| | - Tatiana Betáková
- Biomedical Research Center, Slovak Academy of Sciences, Institute of Virology, Bratislava, Slovak Republic; Comenius University in Bratislava, Faculty of Natural Sciences, Department of Microbiology and Virology, Bratislava, Slovak Republic.
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14
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Warmink K, Vinod P, Korthagen NM, Weinans H, Rios JL. Macrophage-Driven Inflammation in Metabolic Osteoarthritis: Implications for Biomarker and Therapy Development. Int J Mol Sci 2023; 24:ijms24076112. [PMID: 37047082 PMCID: PMC10094694 DOI: 10.3390/ijms24076112] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2023] [Revised: 03/19/2023] [Accepted: 03/21/2023] [Indexed: 04/14/2023] Open
Abstract
Osteoarthritis (OA) is a common and debilitating joint disorder that leads to progressive joint breakdown and loss of articular cartilage. Accompanied by a state of low-grade inflammation, its etiology extends beyond that of a wear-and-tear disease, and the immune system might have a role in its initiation and progression. Obesity, which is directly associated with an increased incidence of OA, alters adipokine release, increases pro-inflammatory macrophage activity, and affects joint immune regulation. Studying inflammatory macrophage expression and strategies to inhibit inflammatory macrophage phenotype polarization might provide insights into disease pathogenesis and therapeutic applications. In pre-clinical studies, the detection of OA in its initial stages was shown to be possible using imaging techniques such as SPECT-CT, and advances are made to detect OA through blood-based biomarker analysis. In this review, obesity-induced osteoarthritis and its mechanisms in inducing joint degeneration are summarized, along with an analysis of the current developments in patient imaging and biomarker use for diagnostic and therapeutic strategies.
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Affiliation(s)
- Kelly Warmink
- Department of Orthopedics, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands
| | - Prateeksha Vinod
- Department of Orthopedics, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands
| | - Nicoline M Korthagen
- Department of Orthopedics, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands
- Department of Equine Sciences, Faculty of Veterinary Medicine, Utrecht University, 3584 CL Utrecht, The Netherlands
| | - Harrie Weinans
- Department of Orthopedics, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands
- Department of Biomechanical Engineering, TU Delft, 2628 CD Delft, The Netherlands
| | - Jaqueline L Rios
- Department of Orthopedics, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands
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15
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Patra D, Roy S, Arora L, Kabeer SW, Singh S, Dey U, Banerjee D, Sinha A, Dasgupta S, Tikoo K, Kumar A, Pal D. miR-210-3p Promotes Obesity-Induced Adipose Tissue Inflammation and Insulin Resistance by Targeting SOCS1-Mediated NF-κB Pathway. Diabetes 2023; 72:375-388. [PMID: 36469307 DOI: 10.2337/db22-0284] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Accepted: 11/29/2022] [Indexed: 12/12/2022]
Abstract
Under the condition of chronic obesity, an increased level of free fatty acids along with low oxygen tension in the adipose tissue creates a pathophysiological adipose tissue microenvironment (ATenv), leading to the impairment of adipocyte function and insulin resistance. Here, we found the synergistic effect of hypoxia and lipid (H + L) surge in fostering adipose tissue macrophage (ATM) inflammation and polarization. ATenv significantly increased miR-210-3p expression in ATMs which promotes NF-κB activation-dependent proinflammatory cytokine expression along with the downregulation of anti-inflammatory cytokine expression. Interestingly, delivery of miR-210-3p mimic significantly increased macrophage inflammation in the absence of H + L co-stimulation, while miR-210-3p inhibitor notably compromised H + L-induced macrophage inflammation through increased production of suppressor of cytokine signaling 1 (SOCS1), a negative regulator of the NF-κB inflammatory signaling pathway. Mechanistically, miR-210 directly binds to the 3'-UTR of SOCS1 mRNA and silences its expression, thus preventing proteasomal degradation of NF-κB p65. Direct delivery of anti-miR-210-3p LNA in the ATenv markedly rescued mice from obesity-induced adipose tissue inflammation and insulin resistance. Thus, miR-210-3p inhibition in ATMs could serve as a novel therapeutic strategy for managing obesity-induced type 2 diabetes.
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Affiliation(s)
- Debarun Patra
- Department of Biomedical Engineering, Indian Institute of Technology Ropar, Punjab, India
| | - Soumyajit Roy
- Department of Biomedical Engineering, Indian Institute of Technology Ropar, Punjab, India
| | - Leena Arora
- Department of Biomedical Engineering, Indian Institute of Technology Ropar, Punjab, India
| | - Shaheen Wasil Kabeer
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, Sahibzada Ajit Singh Nagar, Punjab, India
| | - Satpal Singh
- Department of Gastro Surgery, Dayanand Medical College and Hospital, Ludhiana, Punjab, India
| | - Upalabdha Dey
- Department of Molecular Biology and Biotechnology, Tezpur University, Assam, India
| | - Dipanjan Banerjee
- Department of Molecular Biology and Biotechnology, Tezpur University, Assam, India
| | - Archana Sinha
- Department of Molecular Biology and Biotechnology, Tezpur University, Assam, India
| | - Suman Dasgupta
- Department of Molecular Biology and Biotechnology, Tezpur University, Assam, India
| | - Kulbhushan Tikoo
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, Sahibzada Ajit Singh Nagar, Punjab, India
| | - Aditya Kumar
- Department of Molecular Biology and Biotechnology, Tezpur University, Assam, India
| | - Durba Pal
- Department of Biomedical Engineering, Indian Institute of Technology Ropar, Punjab, India
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16
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Kolb H. Obese visceral fat tissue inflammation: from protective to detrimental? BMC Med 2022; 20:494. [PMID: 36575472 PMCID: PMC9795790 DOI: 10.1186/s12916-022-02672-y] [Citation(s) in RCA: 107] [Impact Index Per Article: 35.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/16/2022] [Accepted: 11/21/2022] [Indexed: 12/28/2022] Open
Abstract
Obesity usually is accompanied by inflammation of fat tissue, with a prominent role of visceral fat. Chronic inflammation in obese fat tissue is of a lower grade than acute immune activation for clearing the tissue from an infectious agent. It is the loss of adipocyte metabolic homeostasis that causes activation of resident immune cells for supporting tissue functions and regaining homeostasis. Initially, the excess influx of lipids and glucose in the context of overnutrition is met by adipocyte growth and proliferation. Eventual lipid overload of hypertrophic adipocytes leads to endoplasmic reticulum stress and the secretion of a variety of signals causing increased sympathetic tone, lipolysis by adipocytes, lipid uptake by macrophages, matrix remodeling, angiogenesis, and immune cell activation. Pro-inflammatory signaling of adipocytes causes the resident immune system to release increased amounts of pro-inflammatory and other mediators resulting in enhanced tissue-protective responses. With chronic overnutrition, these protective actions are insufficient, and death of adipocytes as well as senescence of several tissue cell types is seen. This structural damage causes the expression or release of immunostimulatory cell components resulting in influx and activation of monocytes and many other immune cell types, with a contribution of stromal cells. Matrix remodeling and angiogenesis is further intensified as well as possibly detrimental fibrosis. The accumulation of senescent cells also may be detrimental via eventual spread of senescence state from affected to neighboring cells by the release of microRNA-containing vesicles. Obese visceral fat inflammation can be viewed as an initially protective response in order to cope with excess ambient nutrients and restore tissue homeostasis but may contribute to tissue damage at a later stage.
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Affiliation(s)
- Hubert Kolb
- Faculty of Medicine, University of Düsseldorf, Moorenstr. 5, 40225, Düsseldorf, Germany. .,West-German Centre of Diabetes and Health, Düsseldorf Catholic Hospital Group, Hohensandweg 37, 40591, Düsseldorf, Germany.
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17
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O’Farrell M, Duke G, Crowley R, Buckley D, Martins EB, Bhattacharya D, Friedman SL, Kemble G. FASN inhibition targets multiple drivers of NASH by reducing steatosis, inflammation and fibrosis in preclinical models. Sci Rep 2022; 12:15661. [PMID: 36123383 PMCID: PMC9485253 DOI: 10.1038/s41598-022-19459-z] [Citation(s) in RCA: 40] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2022] [Accepted: 08/30/2022] [Indexed: 01/05/2023] Open
Abstract
Fatty acid synthase (FASN) is an attractive therapeutic target in non-alcoholic steatohepatitis (NASH) because it drives de novo lipogenesis and mediates pro-inflammatory and fibrogenic signaling. We therefore tested pharmacological inhibition of FASN in human cell culture and in three diet induced mouse models of NASH. Three related FASN inhibitors were used; TVB-3664, TVB-3166 and clinical stage TVB-2640 (denifanstat). In human primary liver microtissues, FASN inhibiton (FASNi) decreased triglyceride (TG) content, consistent with direct anti-steatotic activity. In human hepatic stellate cells, FASNi reduced markers of fibrosis including collagen1α (COL1α1) and α-smooth muscle actin (αSMA). In CD4+ T cells exposed to NASH-related cytokines, FASNi decreased production of Th17 cells, and reduced IL-1β release in LPS-stimulated PBMCs. In mice with diet induced NASH l, FASNi prevented development of hepatic steatosis and fibrosis, and reduced circulating IL-1β. In mice with established diet-induced NASH, FASNi reduced NAFLD activity score, fibrosis score, ALT and TG levels. In the CCl4-induced FAT-NASH mouse model, FASN inhibition decreased hepatic fibrosis and fibrosis markers, and development of hepatocellular carcinoma (HCC) tumors by 85%. These results demonstrate that FASN inhibition attenuates inflammatory and fibrotic drivers of NASH by direct inhibition of immune and stellate cells, beyond decreasing fat accumulation in hepatocytes. FASN inhibition therefore provides an opportunity to target three key hallmarks of NASH.
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Affiliation(s)
- Marie O’Farrell
- Sagimet Biosciences Inc., 155 Bovet Rd, San Mateo, CA 94402 USA
| | - Greg Duke
- Sagimet Biosciences Inc., 155 Bovet Rd, San Mateo, CA 94402 USA
| | - Richard Crowley
- Sagimet Biosciences Inc., 155 Bovet Rd, San Mateo, CA 94402 USA
| | - Douglas Buckley
- Sagimet Biosciences Inc., 155 Bovet Rd, San Mateo, CA 94402 USA
| | | | - Dipankar Bhattacharya
- grid.59734.3c0000 0001 0670 2351Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, NY USA
| | - Scott L. Friedman
- grid.59734.3c0000 0001 0670 2351Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, NY USA
| | - George Kemble
- Sagimet Biosciences Inc., 155 Bovet Rd, San Mateo, CA 94402 USA
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18
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Fan Y, Dong W, Wang Y, Zhu S, Chai R, Xu Z, Zhang X, Yan Y, Yang L, Bian Y. Glycyrrhetinic acid regulates impaired macrophage autophagic flux in the treatment of non-alcoholic fatty liver disease. Front Immunol 2022; 13:959495. [PMID: 35967372 PMCID: PMC9365971 DOI: 10.3389/fimmu.2022.959495] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2022] [Accepted: 07/01/2022] [Indexed: 11/13/2022] Open
Abstract
Macrophages are involved in hepatocyte steatosis and necroinflammation and play an important role in the pathogenesis of non-alcoholic fatty liver disease (NAFLD). Impaired autophagy function (decreased autophagy or blocked autophagic flow) leads to cell damage and death and promotes NAFLD progression. The experimental and clinical research of glycyrrhetinic acid (GA) in the treatment of NAFLD has gradually attracted attention with clear pharmacological activities such as immune regulation, antiviral, antitumor, antioxidant, liver protection, and anti-inflammatory. However, the effects of GA on the STAT3-HIF-1α pathway and autophagy in macrophages are still unclear, and its mechanism of action in the treatment of NAFLD remains to be further elucidated. We constructed a NAFLD mouse model through a high-fat and high-sugar diet to investigate the therapeutic effects of GA. The results showed that GA reduced weight, improved the pathological changes and hepatic lipid deposition of liver, and abnormally elevated the levels of serum biochemical (AST, ALT, TG, T-CHO, LDL-C, and HDL-C) and inflammatory indexes (IL-1β, IL-4, IL-6, MCP-1, and TNF-α) in NAFLD mice. Further examination revealed that GA ameliorates excessive hepatic macrophage infiltration and hepatocyte apoptosis. The results of the cell experiments further elaborated that GA modulated the PA-induced macrophage STAT3-HIF-1α pathway and ameliorated impaired autophagic flux (blockade of autophagosome–lysosome fusion) and overactivation of inflammation. Excessive hepatocyte apoptosis caused by the uncontrolled release of inflammatory cytokines was also suppressed by GA.ConclusionThis study demonstrated that GA could regulate the STAT3-HIF-1α pathway of macrophages, ameliorate the impaired autophagy flux, and reduce the excessive production of inflammatory cytokines to improve the excessive apoptosis of liver cells, thus playing a therapeutic role on NAFLD.
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Affiliation(s)
- Yadong Fan
- School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Wenjin Dong
- Department of Science and Education, Tianjin Union Medical Center, Tianjin, China
| | - Ying Wang
- School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Shan Zhu
- State Key Laboratory of Component Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Rundong Chai
- School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Zhe Xu
- School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Xiaoyu Zhang
- The Reproductive Center, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Yiqi Yan
- State Key Laboratory of Component Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Long Yang
- School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
- Research Center for Infectious Diseases, Tianjin University of Traditional Chinese Medicine, Tianjin, China
- *Correspondence: Long Yang, ; Yuhong bian,
| | - Yuhong Bian
- School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
- *Correspondence: Long Yang, ; Yuhong bian,
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19
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Wei Y, Giunta S, Xia S. Hypoxia in Aging and Aging-Related Diseases: Mechanism and Therapeutic Strategies. Int J Mol Sci 2022; 23:8165. [PMID: 35897741 PMCID: PMC9330578 DOI: 10.3390/ijms23158165] [Citation(s) in RCA: 32] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2022] [Revised: 07/12/2022] [Accepted: 07/14/2022] [Indexed: 01/27/2023] Open
Abstract
As the global aging process continues to lengthen, aging-related diseases (e.g., chronic obstructive pulmonary disease (COPD), heart failure) continue to plague the elderly population. Aging is a complex biological process involving multiple tissues and organs and is involved in the development and progression of multiple aging-related diseases. At the same time, some of these aging-related diseases are often accompanied by hypoxia, chronic inflammation, oxidative stress, and the increased secretion of the senescence-associated secretory phenotype (SASP). Hypoxia seems to play an important role in the process of inflammation and aging, but is often neglected in advanced clinical research studies. Therefore, we have attempted to elucidate the role played by different degrees and types of hypoxia in aging and aging-related diseases and their possible pathways, and propose rational treatment options based on such mechanisms for reference.
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Affiliation(s)
- Yaqin Wei
- Department of Geriatrics, Shanghai Institute of Geriatrics, Huadong Hospital, Fudan University, Shanghai 200000, China;
| | - Sergio Giunta
- Casa di Cura Prof. Nobili–GHC Garofalo Health Care, 40035 Bologna, Italy;
| | - Shijin Xia
- Department of Geriatrics, Shanghai Institute of Geriatrics, Huadong Hospital, Fudan University, Shanghai 200000, China;
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20
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Khan MM. Disrupted leptin-fatty acid biosynthesis is an early manifestation of metabolic abnormalities in schizophrenia. World J Psychiatry 2022; 12:827-842. [PMID: 35978970 PMCID: PMC9258274 DOI: 10.5498/wjp.v12.i6.827] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/31/2021] [Revised: 04/03/2022] [Accepted: 05/22/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Insulin resistance (IR) and impaired energy expenditure (IEE) are irreparable metabolic comorbidities in schizophrenia. Although mechanism(s) underlying IR and IEE remains unclear, leptin and fatty acid signaling, which has profound influence on insulin secretion/sensitivity, glucose metabolism and energy expenditure, could be disrupted. However, no association of plasma leptin with erythrocyte membrane fatty acids, body mass index (BMI), and psychotic symptoms in the same cohort of untreated patients with first-episode psychosis (FEP) or medicated patients with chronic schizophrenia (CSZ) is presented before. These studies are crucial for deciphering the role of leptin and fatty acids in the development of IR and IEE in schizophrenia. AIM To determine the association between plasma leptin, erythrocyte membrane fatty acids, particularly, saturated fatty acids (SFAs), BMI and psychotic symptoms in patients with FEP and CSZ. METHODS In this study, twenty-two drug naive patients with FEP, twenty-one CSZ patients treated with atypical antipsychotic drugs, and fourteen healthy control (CNT) subjects were analyzed. Plasma leptin was measured using sandwich mode enzyme-linked immunosorbent assay. Erythrocyte membrane SFAs were measured using ultrathin capillary gas chromatography. BMI was calculated by using the formula: weight (kg)/height (m2). Psychiatric symptoms were evaluated at baseline using brief psychiatric rating scale (BPRS), and positive and negative syndrome scale (PANSS). The total BPRS scores, positive and negative symptom scores (PANSS-PSS and PANSS-NSS, respectively) were recorded. Pearson correlation coefficient (r) analyses were performed to find the nature and strength of association between plasma leptin, PANSS scores, BMI and SFAs, particularly, palmitic acid (PA). RESULTS In patients with FEP, plasma leptin not BMI was significantly lower (P = 0.034), whereas, erythrocyte membrane SFAs were significantly higher (P < 0.005) compared to the CNT subjects. Further, plasma leptin showed negative correlation with erythrocyte membrane SFAs-PA (r = -0.4972, P = 0.001), PANSS-PSS (r = -0.4034, P = 0.028), and PANSS-NSS (r = -0.3487, P = 0.048). However, erythrocyte membrane SFAs-PA showed positive correlation with PANSS-PSS (r = 0.5844, P = 0.0034) and PANSS-NSS (r = 0.5380, P = 0.008). In CSZ patients, plasma leptin, BMI, and erythrocyte membrane SFAs, all were significantly higher (P < 0.05) compared to the CNT subjects. Plasma leptin showed positive correlation with BMI (r = 0.312, P = 0.032) but not with PANSS scores or erythrocyte membrane SFAs-PA. However, erythrocyte membrane SFAs-PA showed positive correlation with PANSS-NSS only (r = 0.4729, P = 0.031). Similar changes in the plasma leptin and erythrocyte membrane SFAs have also been reported in individuals at ultra-high risk of developing psychosis; therefore, the above findings suggest that leptin-fatty acid biosynthesis could be disrupted before the onset of psychosis in schizophrenia. CONCLUSION Disrupted leptin-fatty acid biosynthesis/signaling could be an early manifestation of metabolic comorbidities in schizophrenia. Large-scale studies are warranted to validate the above findings.
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Affiliation(s)
- Mohammad M Khan
- Laboratory of Translational Neurology and Molecular Psychiatry, Department of Biotechnology, Era's Lucknow Medical College and Hospital, and Faculty of Science, Era University, Lucknow 226003, India
- Department of Psychiatry and Health Behavior, Medical College of Georgia, Augusta University, Augusta, GA 30912, United States
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21
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Jiang X, Tian W, Kim D, McQuiston AS, Vinh R, Rockson SG, Semenza GL, Nicolls MR. Hypoxia and Hypoxia-Inducible Factors in Lymphedema. Front Pharmacol 2022; 13:851057. [PMID: 35450048 PMCID: PMC9017680 DOI: 10.3389/fphar.2022.851057] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2022] [Accepted: 03/14/2022] [Indexed: 12/19/2022] Open
Abstract
Lymphedema is a chronic inflammatory disorder characterized by edema, fat deposition, and fibrotic tissue remodeling. Despite significant advances in lymphatic biology research, our knowledge of lymphedema pathology is incomplete. Currently, there is no approved pharmacological therapy for this debilitating disease. Hypoxia is a recognized feature of inflammation, obesity, and fibrosis. Understanding hypoxia-regulated pathways in lymphedema may provide new insights into the pathobiology of this chronic disorder and help develop new medicinal treatments.
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Affiliation(s)
- Xinguo Jiang
- VA Palo Alto Health Care System, Palo Alto, CA, United States.,Stanford University School of Medicine, Stanford, CA, United States
| | - Wen Tian
- VA Palo Alto Health Care System, Palo Alto, CA, United States.,Stanford University School of Medicine, Stanford, CA, United States
| | - Dongeon Kim
- VA Palo Alto Health Care System, Palo Alto, CA, United States.,Stanford University School of Medicine, Stanford, CA, United States
| | - Alexander S McQuiston
- VA Palo Alto Health Care System, Palo Alto, CA, United States.,Stanford University School of Medicine, Stanford, CA, United States
| | - Ryan Vinh
- VA Palo Alto Health Care System, Palo Alto, CA, United States.,Stanford University School of Medicine, Stanford, CA, United States
| | | | - Gregg L Semenza
- Departments of Pediatrics, Medicine, Oncology, Radiation Oncology, and Biological Chemistry, and McKusick-Nathans Institute of Genetic Medicine, Vascular Program, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, United States
| | - Mark R Nicolls
- VA Palo Alto Health Care System, Palo Alto, CA, United States.,Stanford University School of Medicine, Stanford, CA, United States
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22
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Sun L, Li FH, Han C, Wang ZZ, Gao KK, Qiao YB, Ma S, Xie T, Wang J. Alterations in mitochondrial biogenesis and respiratory activity, inflammation of the senescence-associated secretory phenotype, and lipolysis in the perirenal fat and liver of rats following lifelong exercise and detraining. FASEB J 2021; 35:e21890. [PMID: 34460990 DOI: 10.1096/fj.202100868r] [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: 05/26/2021] [Revised: 08/04/2021] [Accepted: 08/16/2021] [Indexed: 12/25/2022]
Abstract
The primary aims of this study were to determine the effects of lifelong exercise and detraining on age-related alterations in mitochondrial function, inflammation associated with senescence-associated secretory phenotype (SASP), and lipolysis in the perirenal fat and liver of rats. Female Sprague-Dawley rats were randomly assigned to four groups: young control (n = 12), old control (n = 12), detraining (n = 12), and lifelong exercise (n = 12). We then investigated mitochondrial function, SASP-associated inflammation, and lipolysis in the perirenal fat and liver using qRT-PCR and western blotting to assess the expression of AKT, hypoxia-inducible factor 1α (HIF-1α), nuclear factor-kappa B (NF-κB), c-jun kinase (JNK), and p38 mitogen-activated protein kinase (p38MAPK). In the tissues of both the perirenal fat and liver, lifelong exercise significantly improved mitochondrial function, SASP-associated inflammation, and lipolysis. Meanwhile, pathways associated with inflammatory regulation were inhibited, predominantly via the activation of phosphorylated-AKT (p-AKT) and suppression of HIF-1α in both tissues, and via JNK in the perirenal fat and p38MAPK in the liver. Furthermore, detraining activated NF-κB expression in both tissues and induced the upregulation of serum high-sensitivity C-reactive protein (hsCRP) levels. Collectively, lifelong exercise was found to exert beneficial effects by ameliorating age-related alterations in mitochondrial function, SASP-associated inflammation, and lipolysis in perirenal fat and liver tissues, potentially inhibiting inflammation via the JNK and p38 MAPK pathways, respectively, as well as the HIF-1α and AKT pathways in both tissues. In contrast, detraining induced high levels of circulating hsCRP by activating the NF-κB signaling pathway in both tissues.
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Affiliation(s)
- Lei Sun
- School of Sport Sciences, Nanjing Normal University, Nanjing, P.R. China
| | - Fang-Hui Li
- School of Sport Sciences, Nanjing Normal University, Nanjing, P.R. China
| | - Chong Han
- School of Sport Sciences, Nanjing Normal University, Nanjing, P.R. China
| | - Zhuang-Zhi Wang
- School of Sport Sciences, Nanjing Normal University, Nanjing, P.R. China
| | - Ke-Ke Gao
- School of Sport Sciences, Nanjing Normal University, Nanjing, P.R. China
| | - Yi-Bo Qiao
- School of Sport Sciences, Nanjing Normal University, Nanjing, P.R. China
| | - Song Ma
- School of Sport Sciences, Nanjing Normal University, Nanjing, P.R. China
| | - Tian Xie
- School of Sport Sciences, Nanjing Normal University, Nanjing, P.R. China
| | - Jing Wang
- School of Sport Sciences, Nanjing Normal University, Nanjing, P.R. China
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23
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Lipid metabolism, inflammation, and foam cell formation in health and metabolic disorders: targeting mTORC1. J Mol Med (Berl) 2021; 99:1497-1509. [PMID: 34312684 DOI: 10.1007/s00109-021-02117-8] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2020] [Revised: 07/12/2021] [Accepted: 07/14/2021] [Indexed: 02/07/2023]
Abstract
Metabolic homeostasis is important for maintaining a healthy lifespan. Lipid metabolism is particularly necessary for the maintenance of metabolic energy sources and their storage, and the structure and function of cell membranes, as well as for the regulation of nutrition through lipogenesis, lipolysis, and lipophagy. Dysfunctional lipid metabolism leads to the development of metabolic disorders, such as atherosclerosis, diabetes mellitus, and non-alcoholic fatty liver disease (NAFLD). Furthermore, dyslipidaemia causes inflammatory responses and foam cell formation. Mechanistic target of rapamycin (mTOR) signalling is a key regulator of diverse cellular processes, including cell metabolism and cell fate. mTOR complex 1 (mTORC1) is involved in lipid metabolism and immune responses in the body. Therefore, the mTORC1 signalling pathway has been suggested as a potential therapeutic target for the treatment of metabolic disorders. In this review, we focus on the roles of mTORC1 in lipid metabolism and inflammation, and present current evidence on its involvement in the development and progression of metabolic disorders.
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24
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Gusev E, Sarapultsev A, Hu D, Chereshnev V. Problems of Pathogenesis and Pathogenetic Therapy of COVID-19 from the Perspective of the General Theory of Pathological Systems (General Pathological Processes). Int J Mol Sci 2021; 22:7582. [PMID: 34299201 PMCID: PMC8304657 DOI: 10.3390/ijms22147582] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2021] [Revised: 06/30/2021] [Accepted: 07/12/2021] [Indexed: 01/18/2023] Open
Abstract
The COVID-19 pandemic examines not only the state of actual health care but also the state of fundamental medicine in various countries. Pro-inflammatory processes extend far beyond the classical concepts of inflammation. They manifest themselves in a variety of ways, beginning with extreme physiology, then allostasis at low-grade inflammation, and finally the shockogenic phenomenon of "inflammatory systemic microcirculation". The pathogenetic core of critical situations, including COVID-19, is this phenomenon. Microcirculatory abnormalities, on the other hand, lie at the heart of a specific type of general pathological process known as systemic inflammation (SI). Systemic inflammatory response, cytokine release, cytokine storm, and thrombo-inflammatory syndrome are all terms that refer to different aspects of SI. As a result, the metabolic syndrome model does not adequately reflect the pathophysiology of persistent low-grade systemic inflammation (ChSLGI). Diseases associated with ChSLGI, on the other hand, are risk factors for a severe COVID-19 course. The review examines the role of hypoxia, metabolic dysfunction, scavenger receptors, and pattern-recognition receptors, as well as the processes of the hemophagocytic syndrome, in the systemic alteration and development of SI in COVID-19.
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Affiliation(s)
- Evgenii Gusev
- Institute of Immunology and Physiology, Ural Branch of the Russian Academy of Science, 620049 Ekaterinburg, Russia; (E.G.); (V.C.)
| | - Alexey Sarapultsev
- Institute of Immunology and Physiology, Ural Branch of the Russian Academy of Science, 620049 Ekaterinburg, Russia; (E.G.); (V.C.)
- School of Medical Biology, South Ural State University, 454080 Chelyabinsk, Russia
| | - Desheng Hu
- Department of Integrated Traditional Chinese and Western Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 200092, China;
| | - Valeriy Chereshnev
- Institute of Immunology and Physiology, Ural Branch of the Russian Academy of Science, 620049 Ekaterinburg, Russia; (E.G.); (V.C.)
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25
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Tsai YW, Lu CH, Chang RCA, Hsu YP, Ho LT, Shih KC. Palmitoleic acid ameliorates palmitic acid-induced proinflammation in J774A.1 macrophages via TLR4-dependent and TNF-α-independent signallings. Prostaglandins Leukot Essent Fatty Acids 2021; 169:102270. [PMID: 33930845 DOI: 10.1016/j.plefa.2021.102270] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/17/2020] [Revised: 02/17/2021] [Accepted: 03/22/2021] [Indexed: 12/27/2022]
Abstract
Adipose tissue resident macrophages play an important role in the regulation of the inflammatory response. Monounsaturated fatty acids assist in the prevention of cardiovascular diseases via an anti-inflammatory effect. However, the mechanisms by which monounsaturated fatty acids, such as palmitoleic acid, regulate the inflammatory response has not been well investigated. In this study, we found that a high concentration of palmitic acid induced J774A.1 murine macrophages toward a pro-inflammatory state, possibly through the activation of the TLR2 or TLR4 genes, and their downstream signaling pathways. In contrast, palmitoleic acid induced a protective effect against inflammation in macrophage of non-obese rodents by inducing an alternative activation pathway via reducing TLR2 or TLR4 signaling. This study indicates that the balance of palmitic acid (saturated fatty acid) and palmitoleic acid (monounsaturated fatty acid) effects macrophage activation. The potential therapeutic impact of palmitoleic acid to ameliorate non-obese-mediated inflammation warrants further investigation.
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Affiliation(s)
- Yi-Wen Tsai
- Department of Family Medicine, Chang Gung Memorial Hospital, Keelung, and Chang Gung University College of Medicine, No.259, Wenhua 1st Rd., Guishan Dist., Taoyuan City 33302, Taiwan; Graduate Institute of Medical Sciences, National Defence Medical Canter, No.161, Sec. 6, Minquan E. Rd., Neihu Dist., Taipei City 11490, Taiwan
| | - Chieh-Hua Lu
- Division of Endocrinology and Metabolism, Department of Medicine, Tri-Service General Hospital, School of Medicine, National Defense Medical Center, No.325, Sec.2, Chenggong Rd., Neihu District, Taipei City 11490, Taiwan
| | - Richard Cheng-An Chang
- Department of Developmental and Cell Biology, University of California, University of California, Irvine, CA 92697-2300, United States
| | - Yung-Pei Hsu
- Departments of Medical Research, and Internal Medicine, Taipei Veterans General Hospital, No.201, Sec. 2, Shipai Rd., Beitou District, Taipei City 11217, Taiwan
| | - Low-Tone Ho
- Departments of Medical Research, and Internal Medicine, Taipei Veterans General Hospital, No.201, Sec. 2, Shipai Rd., Beitou District, Taipei City 11217, Taiwan; School of Medicine, National Yang-Ming University, No.155, Sec.2, Linong Street, Taipei, 112 Taiwan
| | - Kuang-Chung Shih
- Division of Endocrinology and Metabolism, Department of Medicine, Tri-Service General Hospital, School of Medicine, National Defense Medical Center, No.325, Sec.2, Chenggong Rd., Neihu District, Taipei City 11490, Taiwan; School of Medicine, National Yang-Ming University, No.155, Sec.2, Linong Street, Taipei, 112 Taiwan; Division of Endocrinology and Metabolism, Department of Medicine, Cheng-Hsin General Hospital, No.45, Cheng Hsin St., Beitou, Taipei 112, Taiwan.
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26
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Ren J, Wu NN, Wang S, Sowers JR, Zhang Y. Obesity cardiomyopathy: evidence, mechanisms, and therapeutic implications. Physiol Rev 2021; 101:1745-1807. [PMID: 33949876 PMCID: PMC8422427 DOI: 10.1152/physrev.00030.2020] [Citation(s) in RCA: 207] [Impact Index Per Article: 51.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
The prevalence of heart failure is on the rise and imposes a major health threat, in part, due to the rapidly increased prevalence of overweight and obesity. To this point, epidemiological, clinical, and experimental evidence supports the existence of a unique disease entity termed “obesity cardiomyopathy,” which develops independent of hypertension, coronary heart disease, and other heart diseases. Our contemporary review evaluates the evidence for this pathological condition, examines putative responsible mechanisms, and discusses therapeutic options for this disorder. Clinical findings have consolidated the presence of left ventricular dysfunction in obesity. Experimental investigations have uncovered pathophysiological changes in myocardial structure and function in genetically predisposed and diet-induced obesity. Indeed, contemporary evidence consolidates a wide array of cellular and molecular mechanisms underlying the etiology of obesity cardiomyopathy including adipose tissue dysfunction, systemic inflammation, metabolic disturbances (insulin resistance, abnormal glucose transport, spillover of free fatty acids, lipotoxicity, and amino acid derangement), altered intracellular especially mitochondrial Ca2+ homeostasis, oxidative stress, autophagy/mitophagy defect, myocardial fibrosis, dampened coronary flow reserve, coronary microvascular disease (microangiopathy), and endothelial impairment. Given the important role of obesity in the increased risk of heart failure, especially that with preserved systolic function and the recent rises in COVID-19-associated cardiovascular mortality, this review should provide compelling evidence for the presence of obesity cardiomyopathy, independent of various comorbid conditions, underlying mechanisms, and offer new insights into potential therapeutic approaches (pharmacological and lifestyle modification) for the clinical management of obesity cardiomyopathy.
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Affiliation(s)
- Jun Ren
- Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital Fudan University, Shanghai, China.,Department of Laboratory Medicine and Pathology, University of Washington, Seattle, Washington
| | - Ne N Wu
- Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital Fudan University, Shanghai, China
| | - Shuyi Wang
- School of Medicine, Shanghai University, Shanghai, China.,University of Wyoming College of Health Sciences, Laramie, Wyoming
| | - James R Sowers
- Dalton Cardiovascular Research Center, Diabetes and Cardiovascular Research Center, University of Missouri-Columbia, Columbia, Missouri
| | - Yingmei Zhang
- Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital Fudan University, Shanghai, China
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27
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Almeida L, Everts B. Fa(c)t checking: How fatty acids shape metabolism and function of macrophages and dendritic cells. Eur J Immunol 2021; 51:1628-1640. [PMID: 33788250 PMCID: PMC8359938 DOI: 10.1002/eji.202048944] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2020] [Revised: 03/04/2021] [Accepted: 03/25/2021] [Indexed: 12/24/2022]
Abstract
In recent years there have been major advances in our understanding of the role of free fatty acids (FAs) and their metabolism in shaping the functional properties of macrophages and DCs. This review presents the most recent insights into how cell intrinsic FA metabolism controls DC and macrophage function, as well as the current evidence of the importance of various exogenous FAs (such as polyunsaturated FAs and their oxidation products—prostaglandins, leukotrienes, and proresolving lipid mediators) in affecting DC and macrophage biology, by modulating their metabolic properties. Finally, we explore whether targeted modulation of FA metabolism of myeloid cells to steer their function could hold promise in therapeutic settings.
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Affiliation(s)
- Luís Almeida
- Department of Parasitology, Leiden University Medical Centre, Leiden, The Netherlands
| | - Bart Everts
- Department of Parasitology, Leiden University Medical Centre, Leiden, The Netherlands
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28
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Deng L, He K, Pan Y, Wang H, Luo Y, Xia Q. The role of tumor-associated macrophages in primary hepatocellular carcinoma and its related targeting therapy. Int J Med Sci 2021; 18:2109-2116. [PMID: 33859517 PMCID: PMC8040428 DOI: 10.7150/ijms.56003] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/16/2020] [Accepted: 03/03/2021] [Indexed: 12/12/2022] Open
Abstract
Liver macrophages consist of ontogenically distinct populations termed Kupffer cells and monocyte-derived macrophages. Tumor-associated macrophages (TAMs) inhepatocellularcarcinoma (HCC) play a prominent role in tumormicroenvironment by presenting M1(induced by IFN γ along with LPS) and M2(induced by IL-4 and IL13) polarization. Although TAMs are involved in tumor immune surveillance during the course of HCC, they contribute to tumour progression at different levels by inhibiting the anti-tumor immune response, promoting the generation of blood vessels and lymphatic vessels, and supporting the proliferation and survival of tumor cells. In this paper, the multiple functions of TAMs in HCC were reviewed to provide assistance for future researches about therapeutic approaches.
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Affiliation(s)
- Lu Deng
- Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Kang He
- Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Yixiao Pan
- Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Hai Wang
- Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Yi Luo
- Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Qiang Xia
- Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
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29
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Kawai T, Autieri MV, Scalia R. Adipose tissue inflammation and metabolic dysfunction in obesity. Am J Physiol Cell Physiol 2020; 320:C375-C391. [PMID: 33356944 DOI: 10.1152/ajpcell.00379.2020] [Citation(s) in RCA: 900] [Impact Index Per Article: 180.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Several lines of preclinical and clinical research have confirmed that chronic low-grade inflammation of adipose tissue is mechanistically linked to metabolic disease and organ tissue complications in the overweight and obese organism. Despite this widely confirmed paradigm, numerous open questions and knowledge gaps remain to be investigated. This is mainly due to the intricately intertwined cross-talk of various pro- and anti-inflammatory signaling cascades involved in the immune response of expanding adipose depots, particularly the visceral adipose tissue. Adipose tissue inflammation is initiated and sustained over time by dysfunctional adipocytes that secrete inflammatory adipokines and by infiltration of bone marrow-derived immune cells that signal via production of cytokines and chemokines. Despite its low-grade nature, adipose tissue inflammation negatively impacts remote organ function, a phenomenon that is considered causative of the complications of obesity. The aim of this review is to broadly present an overview of adipose tissue inflammation by highlighting the most recent reports in the scientific literature and summarizing our overall understanding of the field. We also discuss key endogenous anti-inflammatory mediators and analyze their mechanistic role(s) in the pathogenesis and treatment of adipose tissue inflammation. In doing so, we hope to stimulate studies to uncover novel physiological, cellular, and molecular targets for the treatment of obesity.
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Affiliation(s)
- Tatsuo Kawai
- The Cardiovascular Research Center and The Limole Center for Integrated Lymphatic Research, Lewis Katz School of Medicine, Temple University, Philadelphia, Pennsylvania
| | - Michael V Autieri
- The Cardiovascular Research Center and The Limole Center for Integrated Lymphatic Research, Lewis Katz School of Medicine, Temple University, Philadelphia, Pennsylvania
| | - Rosario Scalia
- The Cardiovascular Research Center and The Limole Center for Integrated Lymphatic Research, Lewis Katz School of Medicine, Temple University, Philadelphia, Pennsylvania
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30
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Guo S, Zhang F, Chen Y, Chen Y, Shushakova N, Yao Y, Zeng R, Li J, Lu X, Chen R, Haller H, Gueler F, Xu G, Rong S. Pre-ischemic renal lavage protects against renal ischemia-reperfusion injury by attenuation of local and systemic inflammatory responses. FASEB J 2020; 34:16307-16318. [PMID: 33089923 DOI: 10.1096/fj.201902943r] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2019] [Revised: 09/30/2020] [Accepted: 10/02/2020] [Indexed: 01/04/2023]
Abstract
Postischemic acute kidney injury (AKI) is a common clinical complication and often fatal, with no effective treatment available. Little is known about the role of leukocytes trapped in renal vessels during ischemia-reperfusion injury (IRI) in the postischemic AKI. We designed a new animal model in rats with preforming renal artery lavage prior to IRI to investigate the effect of diminishing the residual circulating leukocytes on kidney damage and inflammation. Moreover, the functional changes of macrophages in hypoxia reoxygenation condition were also analyzed. We found pre-ischemic renal lavage significantly decreased the serum creatinine and blood urea nitrogen levels, and downregulated the mRNA and protein expressions in kidneys and urinary secretion of kidney injury molecule-1 of rats after IRI. The renal pathological damage caused by IRI was also ameliorated by pre-ischemic renal lavage, as evidenced by fewer cast formation, diminished morphological signs of AKI in the tissue at 24 hours after IRI. Pre-ischemic renal lavage reduced the numbers of infiltrating CD68+ macrophages and MPO+ neutrophils. The mRNA expression of pro-inflammatory mediator in IRI kidneys and the levels of pro-inflammatory cytokines in circulatory system and urine were also reduced due to pre-ischemic lavage. Compared with nontreated rats with IRI, pre-ischemic renal lavage significantly reduced the phosphorylation levels of ERK and p65 subunit of NF-κB in the kidney after IRI. In addition, we found hypoxia/reoxygenation could promote the expression of pro-inflammatory mediators and inhibit the expression of anti-inflammatory factors by regulating ERK/NF-κB signaling pathway. Thus, pre-ischemic renal lavage could clearly reduce the renal damage after IRI by attenuating inflammation, and macrophages trapped in renal vessels during IRI could be important pathogenic factors driving tissue injury.
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Affiliation(s)
- Shuiming Guo
- Department of Nephrology, Division of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Fuxiang Zhang
- ICU, Shandong Provincial Qianfoshan Hospital, The First Hospital Affiliated with Shandong First Medical University, Jinan, China
| | - Ying Chen
- Department of Nephrology, The First People's Hospital of Yichang, Yichang, China
| | - Yuetao Chen
- Department of Respiratory, Division of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Nelli Shushakova
- Department of Nephrology, Hannover Medical School, Hannover, Germany
| | - Ying Yao
- Department of Nephrology, Division of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Rui Zeng
- Department of Nephrology, Division of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Junhua Li
- Department of Nephrology, Division of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xia Lu
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Rongjun Chen
- Department of Pediatric Kidney, Liver, and Metabolic Diseases, Hannover Medical School, Hannover, Germany
| | - Hermann Haller
- Department of Nephrology, Hannover Medical School, Hannover, Germany
| | - Faikah Gueler
- Department of Nephrology, Hannover Medical School, Hannover, Germany
| | - Gang Xu
- Department of Nephrology, Division of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Song Rong
- Department of Nephrology, Hannover Medical School, Hannover, Germany
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31
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Skuratovskaia D, Vulf M, Khaziakhmatova O, Malashchenko V, Komar A, Shunkin E, Shupletsova V, Goncharov A, Urazova O, Litvinova L. Tissue-Specific Role of Macrophages in Noninfectious Inflammatory Disorders. Biomedicines 2020; 8:E400. [PMID: 33050138 PMCID: PMC7600904 DOI: 10.3390/biomedicines8100400] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2020] [Revised: 09/30/2020] [Accepted: 10/07/2020] [Indexed: 12/11/2022] Open
Abstract
Chronic inflammation may not begin with local tissue disorders, such as hypoxia, but with the accumulation of critically activated macrophages in one site. The purpose of this review is to analyze the data reported in the scientific literature on the features of the functions of macrophages and their contributions to the development of pathology in various tissues during aseptic inflammation in obese subjects. In individuals with obesity, increased migration of monocytes from the peripheral blood to various tissues, the proliferation of resident macrophages and a change in the balance between alternatively activated anti-inflammatory macrophages (M2) and pro-inflammatory classically activated macrophages (M1) towards the latter have been observed. The primary cause of some metabolic pathologies has been precisely identified as the recruitment of macrophages with an altered phenotype, which is probably typical for many other pathologies. Recent studies have identified phenotypes, such as metabolically activated M (MMe), oxidized (Mox), hemoglobin-related macrophages (Mhem and MHb), M4 and neuroimmunological macrophages (NAM, SAM), which directly and indirectly affect energy metabolism. The high heterogeneity of macrophages in tissues contributes to the involvement of these cells in the development of a wide range of immune responses, including pathological ones. The replenishment of tissue-specific macrophages occurs at the expense of infiltrating monocyte-derived macrophages (MoMFs) in the pathological process. The origin of MoMFs from a general precursor retains their common regulatory mechanisms and similar sensitivity to regulatory stimuli. This makes it possible to find universal approaches to the effect on these cells and, as a consequence, universal approaches for the treatment of various pathological conditions.
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Affiliation(s)
- Daria Skuratovskaia
- Center for Immunology and Cellular Biotechnology, Immanuel Kant Baltic Federal University, 236001 Kaliningrad, Russia; (M.V.); (O.K.); (V.M.); (A.K.); (E.S.); (V.S.); (A.G.); (L.L.)
| | - Maria Vulf
- Center for Immunology and Cellular Biotechnology, Immanuel Kant Baltic Federal University, 236001 Kaliningrad, Russia; (M.V.); (O.K.); (V.M.); (A.K.); (E.S.); (V.S.); (A.G.); (L.L.)
| | - Olga Khaziakhmatova
- Center for Immunology and Cellular Biotechnology, Immanuel Kant Baltic Federal University, 236001 Kaliningrad, Russia; (M.V.); (O.K.); (V.M.); (A.K.); (E.S.); (V.S.); (A.G.); (L.L.)
| | - Vladimir Malashchenko
- Center for Immunology and Cellular Biotechnology, Immanuel Kant Baltic Federal University, 236001 Kaliningrad, Russia; (M.V.); (O.K.); (V.M.); (A.K.); (E.S.); (V.S.); (A.G.); (L.L.)
| | - Aleksandra Komar
- Center for Immunology and Cellular Biotechnology, Immanuel Kant Baltic Federal University, 236001 Kaliningrad, Russia; (M.V.); (O.K.); (V.M.); (A.K.); (E.S.); (V.S.); (A.G.); (L.L.)
| | - Egor Shunkin
- Center for Immunology and Cellular Biotechnology, Immanuel Kant Baltic Federal University, 236001 Kaliningrad, Russia; (M.V.); (O.K.); (V.M.); (A.K.); (E.S.); (V.S.); (A.G.); (L.L.)
| | - Valeriya Shupletsova
- Center for Immunology and Cellular Biotechnology, Immanuel Kant Baltic Federal University, 236001 Kaliningrad, Russia; (M.V.); (O.K.); (V.M.); (A.K.); (E.S.); (V.S.); (A.G.); (L.L.)
| | - Andrei Goncharov
- Center for Immunology and Cellular Biotechnology, Immanuel Kant Baltic Federal University, 236001 Kaliningrad, Russia; (M.V.); (O.K.); (V.M.); (A.K.); (E.S.); (V.S.); (A.G.); (L.L.)
| | - Olga Urazova
- Pathophysiology Division, Siberian State Medical University, 634050 Tomsk, Russia;
| | - Larisa Litvinova
- Center for Immunology and Cellular Biotechnology, Immanuel Kant Baltic Federal University, 236001 Kaliningrad, Russia; (M.V.); (O.K.); (V.M.); (A.K.); (E.S.); (V.S.); (A.G.); (L.L.)
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Kiernan EA, Ewald AC, Ouellette JN, Wang T, Agbeh A, Knutson AO, Roopra AS, Watters JJ. Prior Hypoxia Exposure Enhances Murine Microglial Inflammatory Gene Expression in vitro Without Concomitant H3K4me3 Enrichment. Front Cell Neurosci 2020; 14:535549. [PMID: 33132843 PMCID: PMC7575929 DOI: 10.3389/fncel.2020.535549] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2020] [Accepted: 09/09/2020] [Indexed: 12/19/2022] Open
Abstract
Hypoxia (Hx) is a component of multiple disorders, including stroke and sleep-disordered breathing, which often precede or are comorbid with neurodegenerative diseases. However, little is known about how hypoxia affects the ability of microglia, resident CNS macrophages, to respond to subsequent inflammatory challenges that are often present during neurodegenerative processes. We, therefore, tested the hypothesis that hypoxia would enhance or "prime" microglial pro-inflammatory gene expression in response to a later inflammatory challenge without programmatically increasing basal levels of pro-inflammatory cytokine expression. To test this, we pre-exposed immortalized N9 and primary microglia to hypoxia (1% O2) for 16 h and then challenged them with pro-inflammatory lipopolysaccharide (LPS) either immediately or 3-6 days following hypoxic exposure. We used RNA sequencing coupled with chromatin immunoprecipitation sequencing to analyze primed microglial inflammatory gene expression and modifications to histone H3 lysine 4 trimethylation (H3K4me3) at the promoters of primed genes. We found that microglia exhibited enhanced responses to LPS 3 days and 6 days post-hypoxia. Surprisingly, however, the majority of primed genes were not enriched for H3K4me3 acutely following hypoxia exposure. Using the bioinformatics tool MAGICTRICKS and reversible pharmacological inhibition, we found that primed genes required the transcriptional activities of NF-κB. These findings provide evidence that hypoxia pre-exposure could lead to persistent and aberrant inflammatory responses in the context of CNS disorders.
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Affiliation(s)
- Elizabeth A. Kiernan
- Department of Neuroscience Training Program, University of Wisconsin-Madison, Madison, WI, United States
- Department of Comparative Biosciences, University of Wisconsin-Madison, Madison, WI, United States
| | - Andrea C. Ewald
- Department of Comparative Biosciences, University of Wisconsin-Madison, Madison, WI, United States
| | - Jonathan N. Ouellette
- Department of Comparative Biosciences, University of Wisconsin-Madison, Madison, WI, United States
| | - Tao Wang
- Department of Comparative Biosciences, University of Wisconsin-Madison, Madison, WI, United States
| | - Abiye Agbeh
- Department of Comparative Biosciences, University of Wisconsin-Madison, Madison, WI, United States
| | - Andrew O. Knutson
- Department of Comparative Biosciences, University of Wisconsin-Madison, Madison, WI, United States
- Molecular and Environmental Toxicology Training Program, University of Wisconsin-Madison, Madison, WI, United States
| | - Avtar S. Roopra
- Department of Neuroscience Training Program, University of Wisconsin-Madison, Madison, WI, United States
- Department of Neuroscience, University of Wisconsin-Madison, Madison, WI, United States
| | - Jyoti J. Watters
- Department of Neuroscience Training Program, University of Wisconsin-Madison, Madison, WI, United States
- Department of Comparative Biosciences, University of Wisconsin-Madison, Madison, WI, United States
- Molecular and Environmental Toxicology Training Program, University of Wisconsin-Madison, Madison, WI, United States
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Skuratovskaia D, Komar A, Vulf M, Litvinova L. Mitochondrial destiny in type 2 diabetes: the effects of oxidative stress on the dynamics and biogenesis of mitochondria. PeerJ 2020; 8:e9741. [PMID: 32904391 PMCID: PMC7453922 DOI: 10.7717/peerj.9741] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2020] [Accepted: 07/26/2020] [Indexed: 12/28/2022] Open
Abstract
Background One reason for the development of insulin resistance is the chronic inflammation in obesity. Materials & Methods Scientific articles in the field of knowledge on the involvement of mitochondria and mitochondrial DNA (mtDNA) in obesity and type 2 diabetes were analyzed. Results Oxidative stress developed during obesity contributes to the formation of peroxynitrite, which causes cytochrome C-related damage in the mitochondrial electron transfer chain and increases the production of reactive oxygen species (ROS), which is associated with the development of type 2 diabetes. Oxidative stress contributes to the nuclease activity of the mitochondrial matrix, which leads to the accumulation of cleaved fragments and an increase in heteroplasmy. Mitochondrial dysfunction and mtDNA variations during insulin resistance may be connected with a change in ATP levels, generation of ROS, mitochondrial division/fusion and mitophagy. This review discusses the main role of mitochondria in the development of insulin resistance, which leads to pathological processes in insulin-dependent tissues, and considers potential therapeutic directions based on the modulation of mitochondrial biogenesis. In this regard, the development of drugs aimed at the regulation of these processes is gaining attention. Conclusion Changes in the mtDNA copy number can help to protect mitochondria from severe damage during conditions of increased oxidative stress. Mitochondrial proteome studies are conducted to search for potential therapeutic targets. The use of mitochondrial peptides encoded by mtDNA also represents a promising new approach to therapy.
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Affiliation(s)
| | - Alexandra Komar
- Immanuel Kant Baltic Federal University, Kaliningrad, Russian Federation
| | - Maria Vulf
- Immanuel Kant Baltic Federal University, Kaliningrad, Russian Federation
| | - Larisa Litvinova
- Immanuel Kant Baltic Federal University, Kaliningrad, Russian Federation
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Rodgers LC, Cole J, Rattigan KM, Barrett MP, Kurian N, McInnes IB, Goodyear CS. The rheumatoid synovial environment alters fatty acid metabolism in human monocytes and enhances CCL20 secretion. Rheumatology (Oxford) 2020; 59:869-878. [PMID: 31497857 DOI: 10.1093/rheumatology/kez378] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2018] [Revised: 07/05/2019] [Accepted: 08/02/2019] [Indexed: 01/24/2023] Open
Abstract
OBJECTIVES Fatty acid oxidation (FAO) and glycolysis have been implicated in immune regulation and activation of macrophages. However, investigation of human monocyte intracellular metabolism in the context of the hypoxic and inflammatory rheumatoid arthritis (RA) synovium is lacking. We hypothesized that exposure of monocytes to the hypoxic and inflammatory RA environment would have a profound impact on their metabolic state, and potential to contribute to disease pathology. METHODS Human monocytes were isolated from buffy coats and exposed to hypoxia. Metabolic profiling of monocytes was carried out by LC-MS metabolomics. Inflammatory mediator release after LPS or RA-synovial fluid (RA-SF) stimulation was analysed by ELISA. FAO was inhibited by etomoxir or enhanced with exogenous carnitine supplementation. Transcriptomics of RA blood monocytes and RA-SF macrophages was carried out by microarray. RESULTS Hypoxia exacerbated monocyte-derived CCL20 and IL-1β release in response to LPS, and increased glycolytic intermediates at the expense of carnitines. Modulation of carnitine identified a novel role for FAO in the production of CCL20 in response to LPS. Transcriptional analysis of RA blood monocytes and RA-SF macrophages revealed that fatty acid metabolism was altered and CCL20 increased when monocytes enter the synovial environment. In vitro analysis of monocytes showed that RA-SF increases carnitine abundance and CCL20 production in hypoxia, which was exacerbated by exogenous carnitine. CONCLUSION This work has revealed a novel inflammatory mechanism in RA that links FAO to CCL20 production in human monocytes, which could subsequently contribute to RA disease pathogenesis by promoting the recruitment of Th17 cells and osteoclastogenesis.
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Affiliation(s)
- Lewis C Rodgers
- Centre of Immunobiology, University of Glasgow, Glasgow, UK.,GLAZgo Discovery Centre, Glasgow, UK
| | - John Cole
- GLAZgo Discovery Centre, Glasgow, UK
| | - Kevin M Rattigan
- Wellcome Centre for Molecular Parasitology, Institute of Infection, Immunity and Inflammation, Glasgow, UK
| | - Michael P Barrett
- Wellcome Centre for Molecular Parasitology, Institute of Infection, Immunity and Inflammation, Glasgow, UK.,Glasgow Polyomics, Wolfson Wohl Cancer Research Centre, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK
| | - Nisha Kurian
- Respiratory Inflammation and Autoimmune (RIA) Precision Medicine Unit, Precision Medicine, Oncology R&D, AstraZeneca, Gothenburg, Sweden
| | - Iain B McInnes
- Centre of Immunobiology, University of Glasgow, Glasgow, UK
| | - Carl S Goodyear
- Centre of Immunobiology, University of Glasgow, Glasgow, UK.,GLAZgo Discovery Centre, Glasgow, UK
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Claycombe-Larson KJ, Alvine T, Wu D, Kalupahana NS, Moustaid-Moussa N, Roemmich JN. Nutrients and Immunometabolism: Role of Macrophage NLRP3. J Nutr 2020; 150:1693-1704. [PMID: 32271912 DOI: 10.1093/jn/nxaa085] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2019] [Revised: 01/27/2020] [Accepted: 03/10/2020] [Indexed: 12/19/2022] Open
Abstract
Inflammation is largely mediated by immune cells responding to invading pathogens, whereas metabolism is oriented toward producing usable energy for vital cell functions. Immunometabolic alterations are considered key determinants of chronic inflammation, which leads to the development of chronic diseases. Studies have demonstrated that macrophages and the NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome are activated in key metabolic tissues to contribute to increased risk for type 2 diabetes mellitus, Alzheimer disease, and liver diseases. Thus, understanding the tissue-/cell-type-specific regulation of the NLRP3 inflammasome is crucial for developing intervention strategies. Currently, most of the nutrients and bioactive compounds tested to determine their inflammation-reducing effects are limited to animal models. Future studies need to address how dietary compounds regulate immune and metabolic cell reprograming in humans.
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Affiliation(s)
- Kate J Claycombe-Larson
- Grand Forks Human Nutrition Research Center, USDA Agricultural Research Service, Grand Forks, ND, USA
| | - Travis Alvine
- Grand Forks Human Nutrition Research Center, USDA Agricultural Research Service, Grand Forks, ND, USA
| | - Dayong Wu
- The Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, Boston, MA, USA
| | | | - Naima Moustaid-Moussa
- Nutritional Science Department and Obesity Research Institute, Texas Tech University, Lubbock, TX, USA
| | - James N Roemmich
- Grand Forks Human Nutrition Research Center, USDA Agricultural Research Service, Grand Forks, ND, USA
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Abstract
Obesity is becoming an epidemic in the United States and worldwide and increases risk for many diseases, particularly insulin resistance, type 2 diabetes mellitus, and cardiovascular disease. The mechanisms linking obesity with these diseases remain incompletely understood. Over the past 2 to 3 decades, it has been recognized that in obesity, inflammation, with increased accumulation and inflammatory polarization of immune cells, takes place in various tissues, including adipose tissue, skeletal muscle, liver, gut, pancreatic islet, and brain and may contribute to obesity-linked metabolic dysfunctions, leading to insulin resistance and type 2 diabetes mellitus. Therapies targeting inflammation have shed light on certain obesity-linked diseases, including type 2 diabetes mellitus and atherosclerotic cardiovascular disease, but remain to be tested further and confirmed in clinical trials. This review focuses on inflammation in adipose tissue and its potential role in insulin resistance associated with obesity.
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Affiliation(s)
- Huaizhu Wu
- From the Department of Medicine (H.W., C.M.B.), Baylor College of Medicine, Houston, TX.,Department of Pediatrics (H.W.), Baylor College of Medicine, Houston, TX
| | - Christie M Ballantyne
- From the Department of Medicine (H.W., C.M.B.), Baylor College of Medicine, Houston, TX.,Department of Molecular and Human Genetics (C.M.B.), Baylor College of Medicine, Houston, TX.,Center for Cardiometabolic Disease Prevention (C.M.B.), Baylor College of Medicine, Houston, TX
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Gao W, Guo X, Wang Y, Jian D, Li M. Monocyte-derived extracellular vesicles upon treated by palmitate promote endothelial migration and monocytes attachment to endothelial cells. Biochem Biophys Res Commun 2020; 523:685-691. [PMID: 31948757 DOI: 10.1016/j.bbrc.2019.12.095] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2019] [Accepted: 12/28/2019] [Indexed: 11/17/2022]
Abstract
AIM High circulating free fatty acid (FFA) concentration has a critical role in the development of obesity associated vascular comorbidities. Ample previous findings revealed that FFA, especially saturated, induce endothelial dysfunction throught multiple mechanisms (summarized as lipotoxicity). As a mediator that transfers information among cells, extracellular vesicles(EVs) participate in pathologic processes of many diseases, including angiocardiopathy, insulin resistance, autoimmunity disease. However, how lipotoxicity changed the proportion of EVs secreted from monocytes, furthermore, the effect of the EVs exerts on endothelial cells, haven't been demonstrated. METHOD In our experience, differential ultracentrifugation was used to extract EVs from condition medium (CM) of THP-1 monocytes under given treatments. Then we co-incubated the EVs derived from palmitate-treated monocytes with HUVECs for 24 h, after which molecular and phenotypic assays were conducted. RESULT Palmitate-treated monocytes EVs promote the production of adhesion associated proteins of endothelial cells, such as VCAM-1, ICAM-1. Meanwhile, palmitate-stimulation may play a promoter role in the pro-migration capacity of monocytes-EVs. In brief, EVs could be the new pathological junction between FFA and endothelial damage.
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Affiliation(s)
- Wanhao Gao
- Department of Cardiology, People's Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China.
| | - Xingchen Guo
- Department of Cardiology, People's Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China.
| | - Ying Wang
- Department of Cardiology, People's Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China.
| | - Dongdong Jian
- Department of Cardiology, People's Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China.
| | - Muwei Li
- Department of Cardiology, People's Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China.
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Li S, Ren X, Wang Y, Hu J, Wu H, Song S, Yan C. Fucoxanthin alleviates palmitate-induced inflammation in RAW 264.7 cells through improving lipid metabolism and attenuating mitochondrial dysfunction. Food Funct 2020; 11:3361-3370. [DOI: 10.1039/d0fo00442a] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Fucoxanthin mitigated palmitate-induced inflammation in macrophages through promoting fatty acid oxidation and ameliorating mitochondrial dysfunction.
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Affiliation(s)
- Siyu Li
- School of Food Science and Technology
- National Engineering Research Center of Seafood
- Collaborative Innovation Center of Seafood Deep Processing
- Dalian Polytechnic University
- Dalian
| | - Xiaomeng Ren
- School of Food Science and Technology
- National Engineering Research Center of Seafood
- Collaborative Innovation Center of Seafood Deep Processing
- Dalian Polytechnic University
- Dalian
| | - Yuandong Wang
- School of Food Science and Technology
- National Engineering Research Center of Seafood
- Collaborative Innovation Center of Seafood Deep Processing
- Dalian Polytechnic University
- Dalian
| | - Jiangning Hu
- School of Food Science and Technology
- National Engineering Research Center of Seafood
- Collaborative Innovation Center of Seafood Deep Processing
- Dalian Polytechnic University
- Dalian
| | - Haitao Wu
- School of Food Science and Technology
- National Engineering Research Center of Seafood
- Collaborative Innovation Center of Seafood Deep Processing
- Dalian Polytechnic University
- Dalian
| | - Shuang Song
- School of Food Science and Technology
- National Engineering Research Center of Seafood
- Collaborative Innovation Center of Seafood Deep Processing
- Dalian Polytechnic University
- Dalian
| | - Chunhong Yan
- School of Food Science and Technology
- National Engineering Research Center of Seafood
- Collaborative Innovation Center of Seafood Deep Processing
- Dalian Polytechnic University
- Dalian
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DiGiacomo JW, Gilkes DM. Tumor Hypoxia As an Enhancer of Inflammation-Mediated Metastasis: Emerging Therapeutic Strategies. Target Oncol 2019; 13:157-173. [PMID: 29423593 DOI: 10.1007/s11523-018-0555-4] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Metastasis is the leading cause of cancer-related deaths. Recent research has implicated tumor inflammation as a promoter of metastasis. Myeloid, lymphoid, and mesenchymal cells in the tumor microenvironment promote inflammatory signaling amongst each other and together with cancer cells to modulate sustained inflammation, which may enhance cancer invasiveness. Tumor hypoxia, a state of reduced available oxygen present in the majority of solid tumors, acts as a prognostic factor for a worse outcome and is known to have a role in tumor inflammation through the regulation of inflammatory mediator signals in both cancer and neighboring cells in the microenvironment. Multiple methods to target tumor hypoxia have been developed and tested in clinical trials, and still more are emerging as the impacts of hypoxia become better understood. These strategies include mechanistic inhibition of the hypoxia inducible factor signaling pathway and hypoxia activated pro-drugs, leading to both anti-tumor and anti-inflammatory effects. This prompts a need for further research on the prevention of hypoxia-mediated inflammation in cancer. Hypoxia-targeting strategies seem to have the most potential for therapeutic benefit when combined with traditional chemotherapy agents. This paper will serve to summarize the role of the inflammatory response in metastasis, to discuss how hypoxia can enable or enhance inflammatory signaling, and to review established and emerging strategies to target the hypoxia-inflammation-metastasis axis.
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Affiliation(s)
- Josh W DiGiacomo
- Department of Chemical & Biomolecular Engineering, Johns Hopkins University, Baltimore, MD, 21218, USA.,Breast & Ovarian Cancer Program, Department of Oncology, Johns Hopkins School of Medicine, Baltimore, MD, 21287, USA
| | - Daniele M Gilkes
- Department of Chemical & Biomolecular Engineering, Johns Hopkins University, Baltimore, MD, 21218, USA. .,Breast & Ovarian Cancer Program, Department of Oncology, Johns Hopkins School of Medicine, Baltimore, MD, 21287, USA.
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ER-Mitochondria Communication in Cells of the Innate Immune System. Cells 2019; 8:cells8091088. [PMID: 31540165 PMCID: PMC6770024 DOI: 10.3390/cells8091088] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2019] [Revised: 09/11/2019] [Accepted: 09/13/2019] [Indexed: 01/06/2023] Open
Abstract
In cells the interorganelle communication comprises vesicular and non-vesicular mechanisms. Non-vesicular material transfer predominantly takes place at regions of close organelle apposition termed membrane contact sites and is facilitated by a growing number of specialized proteins. Contacts of the endoplasmic reticulum (ER) and mitochondria are now recognized to be essential for diverse biological processes such as calcium homeostasis, phospholipid biosynthesis, apoptosis, and autophagy. In addition to these universal roles, ER-mitochondria communication serves also cell type-specific functions. In this review, we summarize the current knowledge on ER-mitochondria contacts in cells of the innate immune system, especially in macrophages. We discuss ER- mitochondria communication in the context of macrophage fatty acid metabolism linked to inflammatory and ER stress responses, its roles in apoptotic cell engulfment, activation of the inflammasome, and antiviral defense.
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Kimura H, Ota H, Kimura Y, Takasawa S. Effects of Intermittent Hypoxia on Pulmonary Vascular and Systemic Diseases. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2019; 16:ijerph16173101. [PMID: 31455007 PMCID: PMC6747246 DOI: 10.3390/ijerph16173101] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/07/2019] [Revised: 08/19/2019] [Accepted: 08/21/2019] [Indexed: 12/21/2022]
Abstract
Obstructive sleep apnea (OSA) causes many systemic disorders via mechanisms related to sympathetic nerve activation, systemic inflammation, and oxidative stress. OSA typically shows repeated sleep apnea followed by hyperventilation, which results in intermittent hypoxia (IH). IH is associated with an increase in sympathetic activity, which is a well-known pathophysiological mechanism in hypertension and insulin resistance. In this review, we show the basic and clinical significance of IH from the viewpoint of not only systemic regulatory mechanisms focusing on pulmonary circulation, but also cellular mechanisms causing lifestyle-related diseases. First, we demonstrate how IH influences pulmonary circulation to cause pulmonary hypertension during sleep in association with sleep state-specific change in OSA. We also clarify how nocturnal IH activates circulating monocytes to accelerate the infiltration ability to vascular wall in OSA. Finally, the effects of IH on insulin secretion and insulin resistance are elucidated by using an in vitro chamber system that can mimic and manipulate IH. The obtained data implies that glucose-induced insulin secretion (GIS) in pancreatic β cells is significantly attenuated by IH, and that IH increases selenoprotein P, which is one of the hepatokines, as well as TNF-α, CCL-2, and resistin, members of adipokines, to induce insulin resistance via direct cellular mechanisms. Clinical and experimental findings concerning IH give us productive new knowledge of how lifestyle-related diseases and pulmonary hypertension develop during sleep.
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Affiliation(s)
- Hiroshi Kimura
- Department of Advanced Medicine for Pulmonary Circulation and Respiratory Failure, Graduate School of Medicine, Nippon Medical School, Bunkyo, Tokyo 113-8603, Japan.
| | - Hiroyo Ota
- Department of Respiratory Medicine, Nara Medical University, Kashihara, Nara 634-8522, Japan
| | - Yuya Kimura
- Center for Pulmonary Diseases, NHO Tokyo National Hospital, Kiyose, Tokyo 204-0023, Japan
| | - Shin Takasawa
- Department of Biochemistry, Nara Medical University, Kashihara, Nara 634-8521, Japan
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Korbecki J, Bajdak-Rusinek K. The effect of palmitic acid on inflammatory response in macrophages: an overview of molecular mechanisms. Inflamm Res 2019; 68:915-932. [PMID: 31363792 PMCID: PMC6813288 DOI: 10.1007/s00011-019-01273-5] [Citation(s) in RCA: 299] [Impact Index Per Article: 49.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2019] [Revised: 07/22/2019] [Accepted: 07/23/2019] [Indexed: 02/06/2023] Open
Abstract
Palmitic acid is a saturated fatty acid whose blood concentration is elevated in obese patients. This causes inflammatory responses, where toll-like receptors (TLR), TLR2 and TLR4, play an important role. Nevertheless, palmitic acid is not only a TLR agonist. In the cell, this fatty acid is converted into phospholipids, diacylglycerol and ceramides. They trigger the activation of various signaling pathways that are common for LPS-mediated TLR4 activation. In particular, metabolic products of palmitic acid affect the activation of various PKCs, ER stress and cause an increase in ROS generation. Thanks to this, palmitic acid also strengthens the TLR4-induced signaling. In this review, we discuss the mechanisms of inflammatory response induced by palmitic acid. In particular, we focus on describing its effect on ER stress and IRE1α, and the mechanisms of NF-κB activation. We also present the mechanisms of inflammasome NLRP3 activation and the effect of palmitic acid on enhanced inflammatory response by increasing the expression of FABP4/aP2. Finally, we focus on the consequences of inflammatory responses, in particular, the effect of TNF-α, IL-1β and IL-6 on insulin resistance. Due to the high importance of macrophages and the production of proinflammatory cytokines by them, this work mainly focuses on these cells.
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Affiliation(s)
- Jan Korbecki
- Department of Molecular Biology, School of Medicine in Katowice, Medical University of Silesia, Medyków 18 St., 40-752, Katowice, Poland.
| | - Karolina Bajdak-Rusinek
- Department of Medical Genetics, School of Medicine in Katowice, Medical University of Silesia, Medyków 18 St., 40-752, Katowice, Poland
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Bogomolova AM, Shavva VS, Nikitin AA, Nekrasova EV, Dizhe EB, Larionova EE, Kudriavtsev IV, Orlov SV. Hypoxia as a Factor Involved in the Regulation of the apoA-1, ABCA1, and Complement C3 Gene Expression in Human Macrophages. BIOCHEMISTRY (MOSCOW) 2019; 84:529-539. [DOI: 10.1134/s0006297919050079] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
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Engin AB, Engin A, Gonul II. The effect of adipocyte-macrophage crosstalk in obesity-related breast cancer. J Mol Endocrinol 2019; 62:R201-R222. [PMID: 30620711 DOI: 10.1530/jme-18-0252] [Citation(s) in RCA: 42] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/31/2018] [Accepted: 01/07/2019] [Indexed: 12/11/2022]
Abstract
Adipose tissue is the primary source of many pro-inflammatory cytokines in obesity. Macrophage numbers and pro-inflammatory gene expression are positively associated with adipocyte size. Free fatty acid and tumor necrosis factor-α involve in a vicious cycle between adipocytes and macrophages aggravating inflammatory changes. Thereby, M1 macrophages form a characteristic 'crown-like structure (CLS)' around necrotic adipocytes in obese adipose tissue. In obese women, CLSs of breast adipose tissue are responsible for both increase in local aromatase activity and aggressive behavior of breast cancer cells. Interlinked molecular mechanisms between adipocyte-macrophage-breast cancer cells in obesity involve seven consecutive processes: Excessive release of adipocyte- and macrophage-derived inflammatory cytokines, TSC1-TSC2 complex-mTOR crosstalk, insulin resistance, endoplasmic reticulum (ER) stress and excessive oxidative stress generation, uncoupled respiration and hypoxia, SIRT1 controversy, the increased levels of aromatase activity and estrogen production. Considering elevated risks of estrogen receptor (E2R)-positive postmenopausal breast cancer growth in obesity, adipocyte-macrophage crosstalk is important in the aforementioned issues. Increased mTORC1 signaling in obesity ensures the strong activation of oncogenic signaling in E2Rα-positive breast cancer cells. Since insulin and insulin-like growth factors have been identified as tumor promoters, hyperinsulinemia is an independent risk factor for poor prognosis in breast cancer despite peripheral insulin resistance. The unpredictable effects of adipocyte-derived leptin-estrogen-macrophage axis, and sirtuin 1 (SIRT1)-adipose-resident macrophage axis in obese postmenopausal patients with breast cancer are unresolved mechanistic gaps in the molecular links between the tumor growth and adipocytokines.
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Affiliation(s)
- Ayse Basak Engin
- Department of Toxicology, Faculty of Pharmacy, Gazi University, Ankara, Turkey
| | - Atilla Engin
- Department of General Surgery, Faculty of Medicine, Gazi University, Ankara, Turkey
| | - Ipek Isik Gonul
- Department of Pathology, Faculty of Medicine, Gazi University, Ankara, Turkey
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Chen DM, Zhang ML, Shi ZQ, Li CQ, Wang Q, Song JP, Xu Q, Li H, Zeng QP. Anti-inflammatory and Anti-infectious Dietary Paradigms May Be Crucial for Visceral Weight Reduction. Front Immunol 2019; 10:422. [PMID: 30906298 PMCID: PMC6418406 DOI: 10.3389/fimmu.2019.00422] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2018] [Accepted: 02/18/2019] [Indexed: 01/01/2023] Open
Affiliation(s)
- Dong-Mei Chen
- Institute of Tropical Medicine, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Meng-Le Zhang
- School of Basic Course, Guangdong Pharmaceutical University, Guangzhou, China
| | - Zhu-Qing Shi
- Science and Technology Industrial Park, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Chang-Qing Li
- Institute of Tropical Medicine, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Qi Wang
- Institute of Clinical Pharmacology, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Jian-Ping Song
- Institute of Tropical Medicine, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Qin Xu
- Institute of Tropical Medicine, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - He Li
- School of Basic Course, Guangdong Pharmaceutical University, Guangzhou, China
| | - Qing-Ping Zeng
- Institute of Tropical Medicine, Guangzhou University of Chinese Medicine, Guangzhou, China
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Skuratovskaia D, Zatolokin P, Vulf M, Mazunin I, Litvinova L. Interrelation of chemerin and TNF-α with mtDNA copy number in adipose tissues and blood cells in obese patients with and without type 2 diabetes. BMC Med Genomics 2019; 12:40. [PMID: 30871547 PMCID: PMC6416837 DOI: 10.1186/s12920-019-0485-8] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023] Open
Abstract
BACKGROUND Inflammatory response plays a key role in the development of insulin resistance (IR) in obesity. Oxidative stress triggers the replication of the mitochondrial genome and division of the organelle. The purpose of this study was to identify the relationship of chemerin and TNF-α with mitochondrial DNA (mtDNA) copy number in subcutaneous adipose tissue (SAT) and visceral adipose tissue (mesentery of the small intestine (Mes), greater omentum (GO) and blood mononuclear cells (MNCs)) in patients with obesity with/without type 2 diabetes mellitus (T2DM). METHODS The study included 142 obese patients and 34 healthy donors. The samples used for the study were peripheral venous blood (MNCs) and ATs (SAT, Mes and GO). The measurement of mtDNA copy number was done by droplet digital PCR. Quantitative determination of insulin, adiponectin, TNF-α and chemerin in serum/plasma was performed by flow-through fluorometry and commercial ELISA kit. Statistical analysis and graphs were obtained in R Statistical Software (version 3.3.1). RESULTS The increase in body mass index (BMI) was accompanied by an increase in TNF-α production, an increase in mtDNA copy number in SAT and a decrease in mtDNA copy number in MNCs. The negative association between plasma chemerin and mtDNA copy number in the Mes, as well as between mtDNA copy number and chemerin expression in the Mes, in the group with BMI > 40 kg/m2 without T2DM demonstrates the protective effect of chemerin against the development of IR via the regulation of mtDNA copy number in adipose tissues. CONCLUSIONS We thus speculated the existence of a compensatory mechanism in which leads to the increased number of mtDNA copies under the influence of proinflammatory factors. Based on the obtained data, we propose that reducing mtDNA copy number in cases of morbid obesity without T2DM has a positive effect on carbohydrate metabolism, which may help maintain glucose levels within reference values. Obesity, type 2 diabetes, mtDNA, cytokines, TNF-a, chemerin.
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Affiliation(s)
- Daria Skuratovskaia
- Immanuel Kant Baltic Federal University, Russian Federation Kaliningrad, Gaidara 6 st, Russia
| | - Pavel Zatolokin
- Department of Reconstructive and Endoscopic Surgery, Kaliningrad Regional Hospital Kaliningrad, Russia
| | - Maria Vulf
- Immanuel Kant Baltic Federal University, Russian Federation Kaliningrad, Gaidara 6 st, Russia
| | - Ilia Mazunin
- Immanuel Kant Baltic Federal University, Russian Federation Kaliningrad, Gaidara 6 st, Russia
| | - Larisa Litvinova
- Immanuel Kant Baltic Federal University, Russian Federation Kaliningrad, Gaidara 6 st, Russia
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Metabolic response of longitudinal muscles to acute hypoxia in sea cucumber Apostichopus japonicus (Selenka): A metabolome integrated analysis. COMPARATIVE BIOCHEMISTRY AND PHYSIOLOGY D-GENOMICS & PROTEOMICS 2019; 29:235-244. [DOI: 10.1016/j.cbd.2018.12.007] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/27/2018] [Revised: 12/23/2018] [Accepted: 12/23/2018] [Indexed: 01/16/2023]
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Wang X, Ribeiro M, Iracheta-Vellve A, Lowe P, Ambade A, Satishchandran A, Bukong T, Catalano D, Kodys K, Szabo G. Macrophage-Specific Hypoxia-Inducible Factor-1α Contributes to Impaired Autophagic Flux in Nonalcoholic Steatohepatitis. Hepatology 2019; 69:545-563. [PMID: 30102772 PMCID: PMC6351177 DOI: 10.1002/hep.30215] [Citation(s) in RCA: 89] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/24/2017] [Accepted: 08/07/2018] [Indexed: 12/11/2022]
Abstract
Inflammatory cell activation drives diverse cellular programming during hepatic diseases. Hypoxia-inducible factors (HIFs) have recently been identified as important regulators of immunity and inflammation. In nonalcoholic steatohepatitis (NASH), HIF-1α is upregulated in hepatocytes, where it induces steatosis; however, the role of HIF-1α in macrophages under metabolic stress has not been explored. In this study, we found increased HIF-1α levels in hepatic macrophages in methionine-choline-deficient (MCD) diet-fed mice and in macrophages of patients with NASH compared with controls. The HIF-1α increase was concomitant with elevated levels of autophagy markers BNIP3, Beclin-1, LC3-II, and p62 in both mouse and human macrophages. LysMCre HIFdPA fl/fl mice, which have HIF-1α levels stabilized in macrophages, showed higher steatosis and liver inflammation compared with HIFdPA fl/fl mice on MCD diet. In vitro and ex vivo experiments reveal that saturated fatty acid, palmitic acid (PA), both induces HIF-1α and impairs autophagic flux in macrophages. Using small interfering RNA-mediated knock-down and overexpression of HIF-1α in macrophages, we demonstrated that PA impairs autophagy via HIF-1α. We found that HIF-1α mediates NF-κB activation and MCP-1 production and that HIF-1α-mediated impairment of macrophage autophagy increases IL-1β production, contributing to MCD diet-induced NASH. Conclusion: Palmitic acid impairs autophagy via HIF-1α activation in macrophages. HIF-1α and impaired autophagy are present in NASH in vivo in mouse macrophages and in human blood monocytes. We identified that HIF-1α activation and decreased autophagic flux stimulate inflammation in macrophages through upregulation of NF-κB activation. These results suggest that macrophage activation in NASH involves a complex interplay between HIF-1α and autophagy as these pathways promote proinflammatory overactivation in MCD diet-induced NASH.
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Affiliation(s)
- Xiaojing Wang
- Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA,Institute and Department of Infectious Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Marcelle Ribeiro
- Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA
| | - Arvin Iracheta-Vellve
- Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA
| | - Patrick Lowe
- Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA
| | - Aditya Ambade
- Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA
| | - Abhishek Satishchandran
- Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA
| | - Terence Bukong
- Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA
| | - Donna Catalano
- Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA
| | - Karen Kodys
- Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA
| | - Gyongyi Szabo
- Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA
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Hypoxia potentiates monocyte-derived dendritic cells for release of tumor necrosis factor α via MAP3K8. Biosci Rep 2018; 38:BSR20182019. [PMID: 30463908 PMCID: PMC6294625 DOI: 10.1042/bsr20182019] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2018] [Revised: 11/20/2018] [Accepted: 11/20/2018] [Indexed: 01/22/2023] Open
Abstract
Dendritic cells (DCs) constantly sample peripheral tissues for antigens, which are subsequently ingested to derive peptides for presentation to T cells in lymph nodes. To do so, DCs have to traverse many different tissues with varying oxygen tensions. Additionally, DCs are often exposed to low oxygen tensions in tumors, where vascularization is lacking, as well as in inflammatory foci, where oxygen is rapidly consumed by inflammatory cells during the respiratory burst. DCs respond to oxygen levels to tailor immune responses to such low-oxygen environments. In the present study, we identified a mechanism of hypoxia-mediated potentiation of release of tumor necrosis factor α (TNF-α), a pro-inflammatory cytokine with important roles in both anti-cancer immunity and autoimmune disease. We show in human monocyte-derived DCs (moDCs) that this potentiation is controlled exclusively via the p38/mitogen-activated protein kinase (MAPK) pathway. We identified MAPK kinase kinase 8 (MAP3K8) as a target gene of hypoxia-induced factor (HIF), a transcription factor controlled by oxygen tension, upstream of the p38/MAPK pathway. Hypoxia increased expression of MAP3K8 concomitant with the potentiation of TNF-α secretion. This potentiation was no longer observed upon siRNA silencing of MAP3K8 or with a small molecule inhibitor of this kinase, and this also decreased p38/MAPK phosphorylation. However, expression of DC maturation markers CD83, CD86, and HLA-DR were not changed by hypoxia. Since DCs play an important role in controlling T-cell activation and differentiation, our results provide novel insight in understanding T-cell responses in inflammation, cancer, autoimmune disease and other diseases where hypoxia is involved.
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Burhans MS, Hagman DK, Kuzma JN, Schmidt KA, Kratz M. Contribution of Adipose Tissue Inflammation to the Development of Type 2 Diabetes Mellitus. Compr Physiol 2018; 9:1-58. [PMID: 30549014 DOI: 10.1002/cphy.c170040] [Citation(s) in RCA: 172] [Impact Index Per Article: 24.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
The objective of this comprehensive review is to summarize and discuss the available evidence of how adipose tissue inflammation affects insulin sensitivity and glucose tolerance. Low-grade, chronic adipose tissue inflammation is characterized by infiltration of macrophages and other immune cell populations into adipose tissue, and a shift toward more proinflammatory subtypes of leukocytes. The infiltration of proinflammatory cells in adipose tissue is associated with an increased production of key chemokines such as C-C motif chemokine ligand 2, proinflammatory cytokines including tumor necrosis factor α and interleukins 1β and 6 as well as reduced expression of the key insulin-sensitizing adipokine, adiponectin. In both rodent models and humans, adipose tissue inflammation is consistently associated with excess fat mass and insulin resistance. In humans, associations with insulin resistance are stronger and more consistent for inflammation in visceral as opposed to subcutaneous fat. Further, genetic alterations in mouse models of obesity that reduce adipose tissue inflammation are-almost without exception-associated with improved insulin sensitivity. However, a dissociation between adipose tissue inflammation and insulin resistance can be observed in very few rodent models of obesity as well as in humans following bariatric surgery- or low-calorie-diet-induced weight loss, illustrating that the etiology of insulin resistance is multifactorial. Taken together, adipose tissue inflammation is a key factor in the development of insulin resistance and type 2 diabetes in obesity, along with other factors that likely include inflammation and fat accumulation in other metabolically active tissues. © 2019 American Physiological Society. Compr Physiol 9:1-58, 2019.
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Affiliation(s)
- Maggie S Burhans
- Cancer Prevention Program, Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.,Department of Epidemiology, University of Washington, Seattle, Washington, USA
| | - Derek K Hagman
- Cancer Prevention Program, Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA
| | - Jessica N Kuzma
- Cancer Prevention Program, Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA
| | - Kelsey A Schmidt
- Cancer Prevention Program, Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.,Department of Epidemiology, University of Washington, Seattle, Washington, USA
| | - Mario Kratz
- Cancer Prevention Program, Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.,Department of Epidemiology, University of Washington, Seattle, Washington, USA.,Department of Medicine, University of Washington, Seattle, Washington, USA
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