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Little I, Bersie S, Redente EF, McCubbrey AL, Tarling EJ. Alveolar macrophages: guardians of the alveolar lipid galaxy. Curr Opin Lipidol 2025; 36:153-162. [PMID: 40183504 PMCID: PMC12043416 DOI: 10.1097/mol.0000000000000987] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 04/05/2025]
Abstract
PURPOSE OF REVIEW As the primary guardians at the air-surface interface, the functional profile of alveolar macrophages (AM) is wide-ranging from establishment of the alveolar niche, homeostatic maintenance of surfactant levels, to pathogen clearance and resolution and repair processes. Alveolar lipid homeostasis is disturbed in chronic lung diseases and contributes to disease pathogenesis through extracellular localization in the alveolar lumen or intracellular accumulation in AM. This review aims to provide a focused overview of the state of knowledge of AM, their ontogeny and development during health and disease, and how dysregulated AM lipids play a key role in disease processes, from initiation to resolution. RECENT FINDINGS While lipid-laden macrophages are observed across a broad spectrum of lung diseases, their occurrence has largely been considered consequential. Recent advances in lipidomic profiling of single cell types has revealed that disturbances to lipid homeostasis occur early in disease in tissue-resident cells. Comparisons between inflammatory and fibrotic injury models reveal specific alveolar macrophage subsets with different lipid utilization that contribute to the disease process. SUMMARY Understanding the intricate web of AM population seeding and development and how this niche is perturbed by lipid disturbances may help provide leverage for new interventions.
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Affiliation(s)
- Isaiah Little
- Division of Cardiology, Department of Medicine, David Geffen School of Medicine at UCLA, University of California Los Angeles, Los Angeles, California
| | - Stephanie Bersie
- Toxicology Graduate Program, Skaggs School of Pharmacy and Pharmaceutical Sciences
| | - Elizabeth F. Redente
- Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado
- Department of Pediatrics
| | - Alexandra L. McCubbrey
- Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado
- Department of Medicine, National Jewish Health, Denver, Colorado
| | - Elizabeth J. Tarling
- Division of Cardiology, Department of Medicine, David Geffen School of Medicine at UCLA, University of California Los Angeles, Los Angeles, California
- Molecular Biology Institute
- Johnsson Comprehensive Cancer Center (JCCC), University of California Los Angeles, Los Angeles, California, USA
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Sun P, Wang M, Chai X, Liu YX, Li L, Zheng W, Chen S, Zhu X, Zhao S. Disruption of tryptophan metabolism by high-fat diet-triggered maternal immune activation promotes social behavioral deficits in male mice. Nat Commun 2025; 16:2105. [PMID: 40025041 PMCID: PMC11873046 DOI: 10.1038/s41467-025-57414-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2024] [Accepted: 02/20/2025] [Indexed: 03/04/2025] Open
Abstract
Diet-related maternal obesity has been implicated in neurodevelopmental disorders in progeny. Although the precise mechanisms and effective interventions remain uncertain, our research elucidates some of these complexities. We established that a prenatal high-fat diet triggered maternal immune activation (MIA), marked by elevated serum lipopolysaccharide levels and inflammatory-cytokine overproduction, which dysregulated the maternal tryptophan metabolism promoting the accumulation of neurotoxic kynurenine metabolites in the embryonic brain. Interventions aimed at mitigating MIA or blocking the kynurenine pathway effectively rescued the male mice social performance. Furthermore, excessive kynurenine metabolites initiated oxidative stress response causing neuronal migration deficits in the fetal neocortex, an effect that was mitigated by administering the glutathione synthesis precursor N-Acetylcysteine, underscoring the central role of maternal immune-metabolic homeostasis in male mice behavioral outcomes. Collectively, our study accentuated the profound influence of maternal diet-induced immuno-metabolic dysregulation on fetal brain development and provided the preventive strategies for addressing neurodevelopmental disorders.
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Affiliation(s)
- Penghao Sun
- College of Veterinary Medicine, Northwest A&F University, Yangling, Shaanxi, China
| | - Mengli Wang
- College of Veterinary Medicine, Northwest A&F University, Yangling, Shaanxi, China
| | - Xuejun Chai
- College of Basic Medicine, Xi'an Medical University, Xi'an, Shaanxi, China.
| | - Yong-Xin Liu
- Shenzhen Branch, Guangdong Laboratory of Lingnan Modern Agriculture, Genome Analysis Laboratory of the Ministry of Agriculture and Rural Affairs, Agricultural Genomics Institute at Shenzhen, Chinese Academy of Agricultural Sciences, Shenzhen, Guangdong, China
| | - Luqi Li
- Life Science Research Core Services, Northwest A&F University, Yangling, Shaanxi, China
| | - Wei Zheng
- College of Resources and Environment Sciences, Northwest A&F University, Yangling, Shaanxi, China
| | - Shulin Chen
- College of Veterinary Medicine, Northwest A&F University, Yangling, Shaanxi, China
| | - Xiaoyan Zhu
- College of Veterinary Medicine, Northwest A&F University, Yangling, Shaanxi, China.
| | - Shanting Zhao
- College of Veterinary Medicine, Northwest A&F University, Yangling, Shaanxi, China.
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Wang MY, Mo XY, Yi MX, Lu HY. Visualization of the relationship between metabolism and lung diseases from the perspective of bibliometric analysis: research trends and future prospects. Front Med (Lausanne) 2024; 11:1443926. [PMID: 39664315 PMCID: PMC11631585 DOI: 10.3389/fmed.2024.1443926] [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: 06/04/2024] [Accepted: 11/15/2024] [Indexed: 12/13/2024] Open
Abstract
Background Extensive research has examined the role of metabolism in lung disease development, yet a comprehensive literature review remains absent despite numerous publications. Objective This study aims to visualize and assess the advancements in research on metabolism and its role in lung diseases. Methods Publications from January 1, 1991, to April 30, 2024, related to lung diseases and metabolism were sourced from the Web of Science Core Collection and analyzed using CiteSpace 6.2.R4, VOSviewer 1.6.19, Bibliometrix, R Studio, and various online tools. Results A total of 1,542 studies were collected and processed through these platforms for literature analysis and data visualization. The analysis revealed a sharp increase in annual publications on metabolism and lung diseases, with the United States and China emerging as leading contributors. Current research trends highlight a shift toward investigating metabolic reprogramming of immune cells in the context of lung diseases. Moreover, genes such as TNF, DIF, AKT1, INS, IL-6, CXCL8, IL-1β, TP53, NF-κB1, MTOR, IFNG, TGF-β1, HIF1α, VEGFA, IL-10, NFE2L2, PPARG, AKT, CRP, STAT3, and CD4 have received significant attention in this research domain. Employing a bibliometric approach, this study offers a comprehensive and objective examination of the knowledge landscape, shedding light on the evolving trends in this field. The findings serve as a valuable resource for researchers, offering a clearer perspective on the advancements in metabolism-related lung disease studies.
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Affiliation(s)
| | | | | | - Hong-Yan Lu
- Department of Pediatrics, The Affiliated Hospital of Jiangsu University, Zhenjiang, China
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4
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Alassiri M, Alanazi A, Barhoumi T, Alrfaei B, Alanazi M, Rashid M, Alhazmi AS, Alasseiri M, AlMefleh A, Boudjelal M, Shaibah H, Almuhalhil K, Mansour FA, Alehaideb Z, Alghanem B. Preliminary findings on the absence of PEPITEM release in B cells isolated from Saudi donors: implications for expanded population studies. AMERICAN JOURNAL OF CLINICAL AND EXPERIMENTAL IMMUNOLOGY 2024; 13:215-225. [PMID: 39583342 PMCID: PMC11578804 DOI: 10.62347/xnno3661] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/08/2024] [Accepted: 10/08/2024] [Indexed: 11/26/2024]
Abstract
BACKGROUND Adiponectin (AQ) plays a role in regulating immune responses. Previous research indicates that B cells can affect T cell transmigration via the adiponectin-induced peptide PEPITEM in Caucasians. This study explores whether this mechanism is also applicable to Saudi populations, considering potential ethnic variations in immune response. METHODS We conducted unbiased peptidomic screen on B cells, NK cells, and monocytes isolated from the peripheral blood of male healthy Saudi donors. The cells were stimulated with AQ, and the secretion of PEPITEM and other peptides was assessed using liquid chromatography-mass spectrometry (LC-MS/MS). Flow cytometry was utilized to confirm the purity of isolated cell populations and to verify the expression of adiponectin receptors AR1 and AR2. RESULTS PEPITEM was not detected in the supernatants of AQ-stimulated B cells, NK cells, or monocytes. All three cell populations were isolated and purified with high purity, confirmed by flow cytometry showing AR1 and AR2 expression on the surface of these cells. Specifically, less than 47% of B cells expressed ARs, with AR1 at 12% and AR2 at 17%. AQ stimulation increased the number of identified peptides in B cells and monocytes but decreased peptide numbers in NK cells. Dimensionality reduction analysis demonstrated clear segregation of cell types, with strong reproducibility across technical replicates. CONCLUSION The inability of B cells to release PEPITEM in response to AQ stimulation is an interesting finding and it needs more confirmatory tests and experiments, however; a hypothesis about the impact of predisposing factors, such as ethnicity could be formulated and tested in the future.
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Affiliation(s)
- Mohammed Alassiri
- Department of Basic Sciences, College of Science and Health Professions, King Abdullah International Medical Research Center (KAIMRC), King Saud bin Abdulaziz University for Health Sciences (KSAU-HS)Riyadh, KSA
- Department of Pathology and Laboratory Medicine, King Abdulaziz Medical City (KAMC)Riyadh, KSA
| | - Asma Alanazi
- Department of Basic Medical Sciences, College of Medicine, King Abdullah International Medical Research Center (KAIMRC), King Saud bin Abdulaziz University for Health Sciences (KSAU-HS), King Abdulaziz Medical City (KAMC)Riyadh, KSA
| | - Tlili Barhoumi
- Medical Research Core Facility and Platforms, King Abdullah International Medical Research Center (KAIMRC), King Saud bin Abdulaziz University for Health Sciences (KSAU-HS), King Abdulaziz Medical City, Ministry of National Guard Health Affairs (MNGHA)Riyadh, KSA
| | - Bahauddeen Alrfaei
- Department of Basic Medical Sciences, College of Medicine, King Abdullah International Medical Research Center (KAIMRC), King Saud bin Abdulaziz University for Health Sciences (KSAU-HS), King Abdulaziz Medical City (KAMC)Riyadh, KSA
- Department of Cellular Therapy and Cancer Research, King Abdullah International Medical Research Center (KAIMRC), King Saud bin Abdulaziz University for Health Sciences (KSAU-HS), King Abdulaziz Medical City, Ministry of National Guard Health Affairs (MNGHA)Riyadh, KSA
| | - Maisa Alanazi
- Department of Cellular Therapy and Cancer Research, King Abdullah International Medical Research Center (KAIMRC), King Saud bin Abdulaziz University for Health Sciences (KSAU-HS), King Abdulaziz Medical City, Ministry of National Guard Health Affairs (MNGHA)Riyadh, KSA
| | - Mamoon Rashid
- Department of AI and Bioinformatics, King Abdullah International Medical Research Center (KAIMRC), King Saud bin Abdulaziz University for Health Sciences (KSAU-HS), King Abdulaziz Medical City, Ministry of National Guard Health Affairs (MNGHA)Riyadh, KSA
| | - Aiman S Alhazmi
- Department of Basic Sciences, College of Science and Health Professions, King Abdullah International Medical Research Center (KAIMRC), King Saud bin Abdulaziz University for Health Sciences (KSAU-HS)Riyadh, KSA
- Department of Pathology and Laboratory Medicine, King Abdulaziz Medical City (KAMC)Riyadh, KSA
| | - Mohammed Alasseiri
- Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, Prince Fahad Bin Sultan Chair for Biomedical Research, University of TabukTabuk, KSA
| | - Abdulrahman AlMefleh
- Department of Radiology, King Faisal Specialist Hospital and Research CenterRiyadh, Saudi Arabia
| | - Mohammad Boudjelal
- Medical Research Core Facility and Platforms, King Abdullah International Medical Research Center (KAIMRC), King Saud bin Abdulaziz University for Health Sciences (KSAU-HS), King Abdulaziz Medical City, Ministry of National Guard Health Affairs (MNGHA)Riyadh, KSA
| | - Hayat Shaibah
- Medical Research Core Facility and Platforms, King Abdullah International Medical Research Center (KAIMRC), King Saud bin Abdulaziz University for Health Sciences (KSAU-HS), King Abdulaziz Medical City, Ministry of National Guard Health Affairs (MNGHA)Riyadh, KSA
| | - Khawlah Almuhalhil
- Medical Research Core Facility and Platforms, King Abdullah International Medical Research Center (KAIMRC), King Saud bin Abdulaziz University for Health Sciences (KSAU-HS), King Abdulaziz Medical City, Ministry of National Guard Health Affairs (MNGHA)Riyadh, KSA
| | - Fatmah A Mansour
- Medical Research Core Facility and Platforms, King Abdullah International Medical Research Center (KAIMRC), King Saud bin Abdulaziz University for Health Sciences (KSAU-HS), King Abdulaziz Medical City, Ministry of National Guard Health Affairs (MNGHA)Riyadh, KSA
| | - Zeyad Alehaideb
- Medical Research Core Facility and Platforms, King Abdullah International Medical Research Center (KAIMRC), King Saud bin Abdulaziz University for Health Sciences (KSAU-HS), King Abdulaziz Medical City, Ministry of National Guard Health Affairs (MNGHA)Riyadh, KSA
| | - Bandar Alghanem
- Medical Research Core Facility and Platforms, King Abdullah International Medical Research Center (KAIMRC), King Saud bin Abdulaziz University for Health Sciences (KSAU-HS), King Abdulaziz Medical City, Ministry of National Guard Health Affairs (MNGHA)Riyadh, KSA
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5
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Zhang Y, Xu H, Tang Y, Li Y, Zheng F. The levels of amino acid metabolites in serum induce the pathogenesis of atopic dermatitis by mediating the inflammatory protein S100A12. Sci Rep 2024; 14:23435. [PMID: 39379513 PMCID: PMC11461510 DOI: 10.1038/s41598-024-74522-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2024] [Accepted: 09/26/2024] [Indexed: 10/10/2024] Open
Abstract
Atopic dermatitis (AD) is a chronic inflammatory skin disease affecting tens of millions of people globally. The causal relationship between metabolites and AD pathology has not yet been formally indicated, and the mediating mechanism by which metabolites affect AD has not yet been explored. This study aimed to determine the genetic relationship between metabolites and AD and to determine the pathways through which amino acid metabolites affect AD. Meta-analysis integrates the results of multiple GWAS analyses using METAL software. Using bidirectional two-sample Mendelian randomization (MR), we analyzed the causal relationships between metabolites and AD. The principal MR test of causal effects was conducted using inverse-variance weighted regression, and we used reverse MR analysis to exclude reverse causality. We also performed the MR-PRESSO test to detect and correct for possible pleiotropic effects, and used the Cochran Q test to assess heterogeneity. Two-step MR was utilized to analyze the mediating factors between amino acid metabolites and the onset of AD. The correlation between mediating factors (inflammatory protein S100A12) and immune cell infiltration was analyzed using the edgeR and GSVA software packages. Using single-cell sequencing data from skin tissues of patients with AD, we studied the regulatory role of the S100A12 gene in immune cells. Multiple drug databases and macromolecular docking were used to search for S100A12-targeting drugs. Bidirectional two-sample MR analyses indicated that twenty-two metabolites and one inflammatory protein (S100A12) were significantly associated with AD pathogenesis. S100A12 is a mediator of amino acid metabolites (N6-methyllysine; N2-acetyl,N6,N6-dimethyllysine and N6,N6-dimethyllysine) that are genetically associated with AD. S100A12 was positively correlated with the infiltration of multiple immune cell types in lesional AD skin. The amino acid metabolites N6-methyllysine; N2-acetyl,N6,N6-dimethyllysine and N6,N6-dimethyllysine influence AD pathogenesis by mediating S100A12 expression.
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Affiliation(s)
- Yaqi Zhang
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
| | - Heng Xu
- School of Life Sciences, Beijing University of Chinese Medicine, Beijing, China
| | - Yang Tang
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
| | - Yuhang Li
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China.
| | - Fengjie Zheng
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China.
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6
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Zhang T, Chen L, Kueth G, Shao E, Wang X, Ha T, Williams DL, Li C, Fan M, Yang K. Lactate's impact on immune cells in sepsis: unraveling the complex interplay. Front Immunol 2024; 15:1483400. [PMID: 39372401 PMCID: PMC11449721 DOI: 10.3389/fimmu.2024.1483400] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2024] [Accepted: 09/05/2024] [Indexed: 10/08/2024] Open
Abstract
Lactate significantly impacts immune cell function in sepsis and septic shock, transcending its traditional view as just a metabolic byproduct. This review summarizes the role of lactate as a biomarker and its influence on immune cell dynamics, emphasizing its critical role in modulating immune responses during sepsis. Mechanistically, key lactate transporters like MCT1, MCT4, and the receptor GPR81 are crucial in mediating these effects. HIF-1α also plays a significant role in lactate-driven immune modulation. Additionally, lactate affects immune cell function through post-translational modifications such as lactylation, acetylation, and phosphorylation, which alter enzyme activities and protein functions. These interactions between lactate and immune cells are central to understanding sepsis-associated immune dysregulation, offering insights that can guide future research and improve therapeutic strategies to enhance patient outcomes.
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Affiliation(s)
- Tao Zhang
- Department of Biomedical Sciences, James H Quillen College of Medicine, East Tennessee State University, Johnson City, TN, United States
| | - Linjian Chen
- Department of Surgery, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN, United States
| | - Gatkek Kueth
- James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN, United States
| | - Emily Shao
- Program in Neuroscience, College of Arts and Science, Vanderbilt University, Nashville, TN, United States
| | - Xiaohui Wang
- Department of Surgery, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN, United States
- Center of Excellence in Inflammation, Infectious Disease and Immunity, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN, United States
| | - Tuanzhu Ha
- Department of Biomedical Sciences, James H Quillen College of Medicine, East Tennessee State University, Johnson City, TN, United States
- Center of Excellence in Inflammation, Infectious Disease and Immunity, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN, United States
| | - David L. Williams
- Department of Biomedical Sciences, James H Quillen College of Medicine, East Tennessee State University, Johnson City, TN, United States
- Center of Excellence in Inflammation, Infectious Disease and Immunity, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN, United States
| | - Chuanfu Li
- Department of Biomedical Sciences, James H Quillen College of Medicine, East Tennessee State University, Johnson City, TN, United States
- Center of Excellence in Inflammation, Infectious Disease and Immunity, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN, United States
| | - Min Fan
- Department of Biomedical Sciences, James H Quillen College of Medicine, East Tennessee State University, Johnson City, TN, United States
- Center of Excellence in Inflammation, Infectious Disease and Immunity, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN, United States
| | - Kun Yang
- Department of Biomedical Sciences, James H Quillen College of Medicine, East Tennessee State University, Johnson City, TN, United States
- Center of Excellence in Inflammation, Infectious Disease and Immunity, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN, United States
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7
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Ting KKY. Revisiting the role of hypoxia-inducible factors and nuclear factor erythroid 2-related factor 2 in regulating macrophage inflammation and metabolism. Front Cell Infect Microbiol 2024; 14:1403915. [PMID: 39119289 PMCID: PMC11306205 DOI: 10.3389/fcimb.2024.1403915] [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: 03/20/2024] [Accepted: 07/11/2024] [Indexed: 08/10/2024] Open
Abstract
The recent birth of the immunometabolism field has comprehensively demonstrated how the rewiring of intracellular metabolism is critical for supporting the effector functions of many immune cell types, such as myeloid cells. Among all, the transcriptional regulation mediated by Hypoxia-Inducible Factors (HIFs) and Nuclear factor erythroid 2-related factor 2 (NRF2) have been consistently shown to play critical roles in regulating the glycolytic metabolism, redox homeostasis and inflammatory responses of macrophages (Mφs). Although both of these transcription factors were first discovered back in the 1990s, new advances in understanding their function and regulations have been continuously made in the context of immunometabolism. Therefore, this review attempts to summarize the traditionally and newly identified functions of these transcription factors, including their roles in orchestrating the key events that take place during glycolytic reprogramming in activated myeloid cells, as well as their roles in mediating Mφ inflammatory responses in various bacterial infection models.
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Affiliation(s)
- Kenneth K. Y. Ting
- Department of Immunology, University of Toronto, Toronto, ON, Canada
- Toronto General Hospital Research Institute, University Health Network, Toronto, ON, Canada
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8
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Meng XY, Yang D, Zhang B, Zhang T, Zheng ZC, Zhao Y. Glycolysis-related five-gene signature correlates with prognosis and immune infiltration in gastric cancer. World J Gastrointest Oncol 2024; 16:3097-3117. [PMID: 39072176 PMCID: PMC11271787 DOI: 10.4251/wjgo.v16.i7.3097] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/09/2024] [Revised: 05/14/2024] [Accepted: 06/13/2024] [Indexed: 07/12/2024] Open
Abstract
BACKGROUND Gastric cancer (GC) is one of the most common malignancies worldwide. Glycolysis has been demonstrated to be pivotal for the carcinogenesis of GC. AIM To develop a glycolysis-based gene signature for prognostic evaluation in GC patients. METHODS Differentially expressed genes correlated with glycolysis were identified in stomach adenocarcinoma data (STAD). A risk score was established through a univariate Cox and least absolute shrinkage and selection operator analysis. The model was evaluated using the area under the receiver operating characteristic curves. RNA-sequencing data from high- and low-glycolysis groups of STAD patients were analyzed using Cibersort algorithm and Spearman correlation to analyze the interaction of immune cell infiltration and glycolysis. Multiomics characteristics in different glycolysis status were also analyzed. RESULTS A five-gene signature comprising syndecan 2, versican, malic enzyme 1, pyruvate carboxylase and SRY-box transcription factor 9 was constructed. Patients were separated to high- or low-glycolysis groups according to risk scores. Overall survival of patients with high glycolysis was poorer. The sensitivity and specificity of the model in prediction of survival of GC patients were also observed by receiver operating characteristic curves. A nomogram including clinicopathological characteristics and the risk score also showed good prediction for 3- and 5-year overall survival. Gene set variation analysis showed that high-glycolysis patients were related to dysregulation of pancreas beta cells and estrogen late pathways, and low-glycolysis patients were related to Myc targets, oxidative phosphorylation, mechanistic target of rapamycin complex 1 signaling and G2M checkpoint pathways. Tumor-infiltrating immune cells and multiomics analysis suggested that the different glycolysis status was significantly correlated with multiple immune cell infiltration. The patients with high glycolysis had lower tumor mutational burden and neoantigen load, higher incidence of microsatellite instability and lower chemosensitivity. High glycolysis status was often found among patients with grade 2/3 cancer or poor prognosis. CONCLUSION The genetic characteristics revealed by glycolysis could predict the prognosis of GC. High glycolysis significantly affects GC phenotype, but the detailed mechanism needs to be further studied.
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Affiliation(s)
- Xiang-Yu Meng
- Department of Gastric Surgery, Cancer Hospital of China Medical University/Liaoning Cancer Hospital & Institute/The Liaoning Provincial Key Laboratory of Interdisciplinary Research on Gastrointestinal Tumor Combining Medicine with Engineering, Shenyang 110042, Liaoning Province, China
| | - Dong Yang
- Department of Gastric Surgery, Cancer Hospital of China Medical University/Liaoning Cancer Hospital & Institute/The Liaoning Provincial Key Laboratory of Interdisciplinary Research on Gastrointestinal Tumor Combining Medicine with Engineering, Shenyang 110042, Liaoning Province, China
| | - Bao Zhang
- Department of Gastric Surgery, Cancer Hospital of China Medical University/Liaoning Cancer Hospital & Institute/The Liaoning Provincial Key Laboratory of Interdisciplinary Research on Gastrointestinal Tumor Combining Medicine with Engineering, Shenyang 110042, Liaoning Province, China
| | - Tao Zhang
- Department of Gastric Surgery, Cancer Hospital of China Medical University/Liaoning Cancer Hospital & Institute/The Liaoning Provincial Key Laboratory of Interdisciplinary Research on Gastrointestinal Tumor Combining Medicine with Engineering, Shenyang 110042, Liaoning Province, China
| | - Zhi-Chao Zheng
- Department of Gastric Surgery, Cancer Hospital of China Medical University/Liaoning Cancer Hospital & Institute/The Liaoning Provincial Key Laboratory of Interdisciplinary Research on Gastrointestinal Tumor Combining Medicine with Engineering, Shenyang 110042, Liaoning Province, China
| | - Yan Zhao
- Department of Gastric Surgery, Cancer Hospital of China Medical University/Liaoning Cancer Hospital & Institute/The Liaoning Provincial Key Laboratory of Interdisciplinary Research on Gastrointestinal Tumor Combining Medicine with Engineering, Shenyang 110042, Liaoning Province, China
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9
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Nanoff C, Yang Q, Hellinger R, Hermann M. Activation of the Calcium-Sensing Receptor by a Subfraction of Amino Acids Contained in Thyroid Drainage Fluid. ACS Pharmacol Transl Sci 2024; 7:1937-1950. [PMID: 39022353 PMCID: PMC11249632 DOI: 10.1021/acsptsci.3c00350] [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: 12/06/2023] [Revised: 06/03/2024] [Accepted: 06/17/2024] [Indexed: 07/20/2024]
Abstract
Hypoparathyroidism is a common sequela of thyroid surgery; in this study, we aimed at exploring the pathogenesis behind it. The following premises suggest that wound fluid might be a causative agent. (i) Parathyroid hormone secretion is under feedback control by the calcium-sensing receptor, which responds to a diverse array of activating ligands. (ii) Postoperative hypoparathyroidism arises from a secretory deficiency of the parathyroid glands. Even in patients later unaffected by hypoparathyroidism, parathyroid hormone levels drop within hours after surgery. (iii) Wound fluid is bound to enter the tissue around the thyroid bed, where the parathyroid glands are located. Its composition is shaped by a series of proteolytic reactions triggered by wounding. Using thyroid drainage as a surrogate, we addressed the possibility that wound fluid contains compounds activating the calcium-sensing receptor. Drainage fluid ultrafiltrate was found to be rich in amino acids, and on separation by HPLC, compounds activating the calcium-sensing receptor partitioned with hydrophilic matter that rendered buffer acidic. The data show that glutamate and aspartate at millimolar concentrations supported activation of the calcium-sensing receptor, an effect contingent on low pH. In the presence of glutamate/aspartate, protons activated the calcium-sensing receptor with a pH50 of 6.1, and at pH 5, produced maximal activation. This synergistic mode of action was exclusive; glutamine/asparagine did not substitute for the acidic amino acids, nor did Ca2+ substitute for protons. NPS-2143, a negative allosteric receptor modulator completely blocked receptor activation by glutamate/aspartate and by fractionated drainage fluid. Thus, wound fluid may be involved in suppressing parathyroid hormone secretion.
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Affiliation(s)
- Christian Nanoff
- Centre
for Physiology and Pharmacology, Gaston H. Glock Laboratories for
Exploratory Drug Research, Medizinische
Universität Wien, Währinger Straße 13A, Vienna 1090, Austria
| | - Qiong Yang
- Centre
for Physiology and Pharmacology, Gaston H. Glock Laboratories for
Exploratory Drug Research, Medizinische
Universität Wien, Währinger Straße 13A, Vienna 1090, Austria
| | - Roland Hellinger
- Centre
for Physiology and Pharmacology, Gaston H. Glock Laboratories for
Exploratory Drug Research, Medizinische
Universität Wien, Währinger Straße 13A, Vienna 1090, Austria
| | - Michael Hermann
- Department
of Surgery, Vienna Hospital Association,
Klinik Landstraße, Juchgasse 25, Vienna 1030, Austria
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Parasar P, Kaur N, Singh J. Pathophysiology of X-Linked Adrenoleukodystrophy: Updates on Molecular Mechanisms. JOURNAL OF BIOTECHNOLOGY AND BIOMEDICINE 2024; 7:277-288. [PMID: 39056013 PMCID: PMC11271253 DOI: 10.26502/jbb.2642-91280151] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Indexed: 07/28/2024]
Abstract
X-ALD, an inherited monogenic metabolic disorder affecting the CNS and adrenal white matter, is caused by mutations in ABCD1 gene leading to defective fatty acid oxidation in the peroxisomes. This results in accumulation of very long-chain fatty acids, VLCFA, into brain, spinal cord, and body fluids. A single ABCD1mutation does not clearly explain the severity and diverse clinical spectrum of X-ALD phenotypes which suggests that not only genetic but also other modifier genes, epigenetic factors, and environmental factors play a role and contribute to neuroinflammation, mitochondrial dysfunctions, oxidative stress, and metabolic defects seen in phenotypes of ALD. In this review we discuss genotype and phenotype correlation and clinical spectra of X-ALD, previous and recent modifier genetic factors of X-ALD, including novel role of microRNAs (miRNAs) in pathology and as biomarkers. We also discuss the mechanistic interplay of miRNAs and metabolic pathways and potential of targeting miRNAs for X-ALD.
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Affiliation(s)
- Parveen Parasar
- Department of Neurology, Henry Ford Health, Detroit, MI 48202, USA
| | - Navtej Kaur
- Department of Neurology, Henry Ford Health, Detroit, MI 48202, USA
| | - Jaspreet Singh
- Department of Neurology, Henry Ford Health, Detroit, MI 48202, USA
- Department of Physiology, Michigan State University, Lansing, MI 48824, USA
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11
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Kim J, Choi JY, Min H, Hwang KW. Exploring the Potential of Glycolytic Modulation in Myeloid-Derived Suppressor Cells for Immunotherapy and Disease Management. Immune Netw 2024; 24:e26. [PMID: 38974210 PMCID: PMC11224668 DOI: 10.4110/in.2024.24.e26] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2024] [Revised: 04/25/2024] [Accepted: 04/29/2024] [Indexed: 07/09/2024] Open
Abstract
Recent advancements in various technologies have shed light on the critical role of metabolism in immune cells, paving the way for innovative disease treatment strategies through immunometabolism modulation. This review emphasizes the glucose metabolism of myeloid-derived suppressor cells (MDSCs), an emerging pivotal immunosuppressive factor especially within the tumor microenvironment. MDSCs, an immature and heterogeneous myeloid cell population, act as a double-edged sword by exacerbating tumors or mitigating inflammatory diseases through their immune-suppressive functions. Numerous recent studies have centered on glycolysis of MDSC, investigating the regulation of altered glycolytic pathways to manage diseases. However, the specific changes in MDSC glycolysis and their exact functions continue to be areas of ongoing discussion yet. In this paper, we review a range of current findings, including the latest research on the alteration of glycolysis in MDSCs, the consequential functional alterations in these cells, and the outcomes of attempts to modulate MDSC functions by regulating glycolysis. Ultimately, we will provide insights into whether these research efforts could be translated into clinical applications.
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Affiliation(s)
- Jisu Kim
- College of Pharmacy, Chung-Ang University, Seoul 06974, Korea
| | - Jee Yeon Choi
- College of Pharmacy, Chung-Ang University, Seoul 06974, Korea
| | - Hyeyoung Min
- College of Pharmacy, Chung-Ang University, Seoul 06974, Korea
| | - Kwang Woo Hwang
- College of Pharmacy, Chung-Ang University, Seoul 06974, Korea
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12
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Jie XL, Tong ZR, Xu XY, Wu JH, Jiang XL, Tao Y, Feng PS, Yu J, Lan JP, Wang P. Mechanic study based on untargeted metabolomics of Pi-pa-run-fei-tang on pepper combined with ammonia induced chronic cough model mice. JOURNAL OF ETHNOPHARMACOLOGY 2024; 326:117905. [PMID: 38364934 DOI: 10.1016/j.jep.2024.117905] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/25/2024] [Revised: 02/05/2024] [Accepted: 02/08/2024] [Indexed: 02/18/2024]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Pi-pa-run-fei-tang (PPRFT), a traditional Chinese medicine formula with long-standing history, demonstrated beneficial effect on chronic cough. However, the mechanism underlying efficacy unclear. In current research, we explored the impact and molecular mechanism of chronic cough mouse stimulating with capsaicin combined with ammonia. AIM OF THE STUDY To investigate the metabolic modulating effects, and potential mechanisms underlying the therapeutic effect of PPRFT in chronic cough. MATERIALS AND METHODS Chronic cough mouse models were created by stimulating mice by capsaicin combined with ammonia. Number of coughs and cough latency within 2 min were recorded. With lung tissue and serum samples collected for histopathology, metabolomics, RT-qPCR, immunohistochemistry, and WB analysis. Lymphocytes were isolated and flow cytometric assays were conducted to evaluate the differentiation between Th17 and Treg cell among CD4+ cells. RESULTS Results indicated that PPRFT obviously reduced the number of coughs, prolonged cough latency, reduced inflammatory cell infiltration and lung tissues damage, and decreased the serum level of IL-6, IL-1β, TNF-α, and IL-17 while increasing IL-10 levels. Notably, PPRFT suppressed Th17 cell divergence and promoted Treg cell divergence. Furthermore, serum metabolomic assays showed that 46 metabolites differed significantly between group, with 35 pathways involved. Moreover, mRNA levels of IL-6, NF-κB, IL-17, RORγT, JAK2, STAT3, PI3K and AKT in lung tissues remarkably reduced and mRNA levels of IL-10 and FOXP3 were elevated after PPRFT pretreatment. Additionally, PPRFT treatments decreased the protein levels of IL-6, NF-κB, IL-17, RORγT, p-JAK2, p-STAT3, p-PI3K, and p-AKT and increased the protein levels of IL-10 and FOXP3, but no significantly effects to the levels on JAK2, STAT3, PI3K, and AKT in the lungs. CONCLUSION Conclusively, our result suggested the effect with PPRFT on chronic cough may be mediated through IL-6/JAK2/STAT3 and PI3K/AKT/NF-κB pathway, which regulate the differentiation between Th17 and Treg cell. This beneficial effect of PPRFT in capsaicin and ammonia-stimulated chronic cough mice indicates its potential application in treating chronic cough.
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Affiliation(s)
- Xiao-Lu Jie
- The Affiliated Hospital of Hangzhou Normal University, Hangzhou, China; College of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou, China
| | - Zhe-Ren Tong
- College of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou, China
| | - Xin-Yue Xu
- College of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou, China
| | - Jia-Hui Wu
- College of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou, China
| | - Xing-Liang Jiang
- College of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou, China
| | - Yi Tao
- College of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou, China
| | - Pei-Shi Feng
- College of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou, China
| | - Jin Yu
- Hangzhou Zhongmei Huadong Pharmaceutical Co., Ltd., Hangzhou, China.
| | - Ji-Ping Lan
- School of Integrative Medicine Shanghai University of Traditional Chinese Medicine (SHUTCM), Shanghai 201203, China.
| | - Ping Wang
- College of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou, China.
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Peng C, Xiao P, Li N. Does oncolytic viruses-mediated metabolic reprogramming benefit or harm the immune microenvironment? FASEB J 2024; 38:e23450. [PMID: 38294796 DOI: 10.1096/fj.202301947rr] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2023] [Revised: 12/11/2023] [Accepted: 01/11/2024] [Indexed: 02/01/2024]
Abstract
Oncolytic virus immunotherapy as a new tumor therapy has made remarkable achievements in clinical practice. And metabolic reprogramming mediated by oncolytic virus has a significant impact on the immune microenvironment. This review summarized the reprogramming of host cell glucose metabolism, lipid metabolism, oxidative phosphorylation, and glutamine metabolism by oncolytic virus and illustrated the effects of metabolic reprogramming on the immune microenvironment. It was found that oncolytic virus-induced reprogramming of glucose metabolism in tumor cells has both beneficial and detrimental effects on the immune microenvironment. In addition, oncolytic virus can promote fatty acid synthesis in tumor cells, inhibit oxidative phosphorylation, and promote glutamine catabolism, which facilitates the anti-tumor immune function of immune cells. Therefore, targeted metabolic reprogramming is a new direction to improve the efficacy of oncolytic virus immunotherapy.
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Affiliation(s)
- Chengcheng Peng
- Institute of Virology, Wenzhou University, Wenzhou, China
- Key Laboratory of Virology and Immunology of Wenzhou, Wenzhou University, Wenzhou, China
| | - Pengpeng Xiao
- Institute of Virology, Wenzhou University, Wenzhou, China
- Key Laboratory of Virology and Immunology of Wenzhou, Wenzhou University, Wenzhou, China
| | - Nan Li
- Institute of Virology, Wenzhou University, Wenzhou, China
- Key Laboratory of Virology and Immunology of Wenzhou, Wenzhou University, Wenzhou, China
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14
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Gupta T, Najumuddin, Rajendran D, Gujral A, Jangra A. Metabolism configures immune response across multi-systems: Lessons from COVID-19. Adv Biol Regul 2023; 90:100977. [PMID: 37690286 DOI: 10.1016/j.jbior.2023.100977] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2023] [Revised: 07/19/2023] [Accepted: 08/16/2023] [Indexed: 09/12/2023]
Abstract
Several studies over the last decade demonstrate the recruitment of immune cells, increased inflammatory cytokines, and chemokine in patients with metabolic diseases, including heart failure, parenchymal inflammation, obesity, tuberculosis, and diabetes mellitus. Metabolic rewiring of immune cells is associated with the severity and prevalence of these diseases. The risk of developing COVID-19/SARS-CoV-2 infection increases in patients with metabolic dysfunction (heart failure, diabetes mellitus, and obesity). Several etiologies, including fatigue, dyspnea, and dizziness, persist even months after COVID-19 infection, commonly known as Post-Acute Sequelae of CoV-2 (PASC) or long COVID. A chronic inflammatory state and metabolic dysfunction are the factors that contribute to long COVID. Here, this study explores the potential link between pathogenic metabolic and immune alterations across different organ systems that could underlie COVID-19 and PASC. These interactions could be utilized for targeted future therapeutic approaches.
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Affiliation(s)
- Tinku Gupta
- Department of Pharmacognosy & Phytochemistry, School of Pharmaceutical Education and Research, Jamia Hamdard (Deemed University), M. B. Road, New Delhi 110062, India
| | - Najumuddin
- Program of Biotechnology, Department of Applied Sciences, Faculty of Engineering, Science and Technology, Hamdard University, Karachi, Pakistan
| | - Dhanya Rajendran
- Rajiv Gandhi Centre for Biotechnology, Trivandrum, Kerala, 695014, India
| | - Akash Gujral
- Department of Medicine, Nyu Grossman School of Medicine, NY, USA
| | - Ashok Jangra
- Department of Pharmaceutical Sciences, Central University of Haryana, Mahendergarh, Haryana, India.
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Ryan DG, Peace CG, Hooftman A. Basic Mechanisms of Immunometabolites in Shaping the Immune Response. J Innate Immun 2023; 15:925-943. [PMID: 37995666 PMCID: PMC10730108 DOI: 10.1159/000535452] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2023] [Accepted: 11/21/2023] [Indexed: 11/25/2023] Open
Abstract
BACKGROUND Innate immune cells play a crucial role in responding to microbial infections, but their improper activation can also drive inflammatory disease. For this reason, their activation state is governed by a multitude of factors, including the metabolic state of the cell and, more specifically, the individual metabolites which accumulate intracellularly and extracellularly. This relationship is bidirectional, as innate immune cell activation by pathogen-associated molecular patterns causes critical changes in cellular metabolism. SUMMARY In this review, we describe the emergence of various "immunometabolites." We outline the general characteristics of these immunometabolites, the conditions under which they accumulate, and their subsequent impact on immune cells. We delve into well-studied metabolites of recent years, such as succinate and itaconate, as well as newly emerging immunometabolites, such as methylglyoxal. KEY MESSAGES We hope that this review may be used as a framework for further studies dissecting the mechanisms by which immunometabolites regulate the immune system and provide an outlook to harnessing these mechanisms in the treatment of inflammatory diseases.
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Affiliation(s)
- Dylan Gerard Ryan
- MRC Mitochondrial Biology Unit, University of Cambridge, Cambridge, UK
| | - Christian Graham Peace
- School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland
| | - Alexander Hooftman
- Global Health Institute, Swiss Federal Institute of Technology Lausanne (EPFL), Lausanne, Switzerland
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16
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LIU D, ZHANG Y, YU T, LIU Z, JIAO Y, WANG H, XU Y, GUAN Q, CHEN L, HU H. Protective mechanisms of Tuina therapy against lipopolysaccharide-induced fever in young rabbits based on untargeted metabolomics analysis. J TRADIT CHIN MED 2023; 43:725-733. [PMID: 37454257 PMCID: PMC10320445 DOI: 10.19852/j.cnki.jtcm.2023.04.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2022] [Accepted: 11/15/2022] [Indexed: 07/18/2023]
Abstract
OBJECTIVE To investigate the effect of Tuina on the plasma metabolites of lipopolysaccharide-induced febrile in infant rabbits. METHODS Twenty-four infant New Zealand rabbits were selected and randomly divided into three groups: saline, model, and Tuina. The fever model was established by injecting LPS intravenously through the ear margin vein in the model group and Tuina group, respectively. The modeling was considered successful when the anal temperature increased by 0.5℃ or above within 1 h. In the Tuina group, six Tuina techniques (i.e., opening Tianmen / the heaven gate, pushing Kangong / the superciliary arch, kneading Taiyang and the prominent bone behind the ears, clearing Tianheshui, spine pinching) that alleviate fever were performed on the young rabbits 1 h after the modeling, whereas the model and saline groups were not given Tuina treatment, with the real-time anal temperature monitored during the experiment. The plasma was taken 3 h after the modeling for liquid chromatography-mass spectrometry (LC-MS) untargeted metabolomics study. RESULTS Our results showed a fever-reducing effects of Tuina therapy on lipopolysaccharide-induced fever in young rabbits, as indicated by a significantly lower anal temperature, maximum rise in body temperature, and body response index at 2 and 3 h after modeling in the Tuina group compared to the model group, with reductions in the PGE2 expression observed in the blood and hypothalamus. The differential metabolites including riboflavin, nicotinamide N-oxide, porphobilinogen, 5-hydroxyindoleacetic acid, gamma-aminobutyric acid, and lysoPC (16:1 (9Z)/0:0) were found following the Tuina intervention. Tuina primarily involves glycine-serine-threonine, arginine-proline, porphyrin-chlorophyll, pyrimidine, primary bile acid biosynthesis, and cyanoamino acid metabolic pathways. CONCLUSION Tuina therapy has proven to be effective in reducing body temperature and down-regulating PGE2 expression in LPS-induced febrile young rabbits, with its mechanism of fever-reducing action possibly associated with the changes in plasma metabolites and metabolic pathways.
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Affiliation(s)
- Di LIU
- 1 School of Acupuncture-Moxibustion and Tuina, Beijing University of Chinese Medicine, Beijing 102401, China
| | - Yingqi ZHANG
- 1 School of Acupuncture-Moxibustion and Tuina, Beijing University of Chinese Medicine, Beijing 102401, China
| | - Tianyuan YU
- 1 School of Acupuncture-Moxibustion and Tuina, Beijing University of Chinese Medicine, Beijing 102401, China
| | - Zhifeng LIU
- 1 School of Acupuncture-Moxibustion and Tuina, Beijing University of Chinese Medicine, Beijing 102401, China
| | - Yi JIAO
- 1 School of Acupuncture-Moxibustion and Tuina, Beijing University of Chinese Medicine, Beijing 102401, China
| | - Hourong WANG
- 1 School of Acupuncture-Moxibustion and Tuina, Beijing University of Chinese Medicine, Beijing 102401, China
| | - Yajing XU
- 1 School of Acupuncture-Moxibustion and Tuina, Beijing University of Chinese Medicine, Beijing 102401, China
| | - Qian GUAN
- 1 School of Acupuncture-Moxibustion and Tuina, Beijing University of Chinese Medicine, Beijing 102401, China
| | - Lulu CHEN
- 2 Department of Acupuncture-Moxibustion, Beijing Massage Hospital, Beijing 100035, China
| | - Hui HU
- 3 Department of Acupuncture-Moxibustion, Dongfang Hospital, Beijing University of Chinese Medicine, Beijing 100078, China
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Shouhui Tongbian Capsules induce regression of inflammation to improve intestinal barrier in mice with constipation by targeted binding to Prkaa1: With no obvious toxicity. Biomed Pharmacother 2023; 161:114495. [PMID: 36906969 DOI: 10.1016/j.biopha.2023.114495] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2023] [Revised: 02/26/2023] [Accepted: 03/07/2023] [Indexed: 03/12/2023] Open
Abstract
Constipation arising from the poor bowel movement is a rife enteric health problem. Shouhui Tongbian Capsule (SHTB) is a traditional Chinese medicine (TCM) which effectively improve the symptoms of constipation. However, the mechanism has not been fully evaluated. The purpose of this study was to evaluate the effect of SHTB on the symptoms and intestinal barrier of mice with constipation. Our data showed that SHTB effectively improved the constipation induced by diphenoxylate, which was confirmed by shorter first defecation time, higher internal propulsion rate and fecal water content. Additionally, SHTB improved the intestinal barrier function, which was manifested by inhibiting the leakage of Evans blue in intestinal tissues and increasing the expression of occludin and ZO-1. SHTB inhibited NLRP3 inflammasome signaling pathway and TLR4/NF-κB signaling pathway, reduced the number of proinflammatory cell subsets and increased the number of immunosuppressive cell subsets to relieve inflammation. The photochemically induced reaction coupling system combined with cellular thermal shift assay and central carbon metabolomics technology confirmed that SHTB activated AMPKα through targeted binding to Prkaa1 to regulate Glycolysis/Gluconeogenesis and Pentose Phosphate Pathway, and finally inhibited intestinal inflammation. Finally, no obvious toxicity related to SHTB was found in a repeated drug administration toxicity test for consecutive 13 weeks. Collectively, we reported SHTB as a TCM targeting Prkaa1 for anti-inflammation to improve intestinal barrier in mice with constipation. These findings broaden our knowledge of Prkaa1 as a druggable target protein for inflammation inhibition, and open a new avenue to novel therapy strategy for constipation injury.
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18
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New Insights into the Identification of Metabolites and Cytokines Predictive of Outcome for Patients with Severe SARS-CoV-2 Infection Showed Similarity with Cancer. Int J Mol Sci 2023; 24:ijms24054922. [PMID: 36902351 PMCID: PMC10003544 DOI: 10.3390/ijms24054922] [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: 11/05/2022] [Revised: 02/20/2023] [Accepted: 02/22/2023] [Indexed: 03/08/2023] Open
Abstract
SARS-CoV-2 infection is characterized by several clinical manifestations, ranging from the absence of symptoms to severe forms that necessitate intensive care treatment. It is known that the patients with the highest rate of mortality develop increased levels of proinflammatory cytokines, called the "cytokine storm", which is similar to inflammatory processes that occur in cancer. Additionally, SARS-CoV-2 infection induces modifications in host metabolism leading to metabolic reprogramming, which is closely linked to metabolic changes in cancer. A better understanding of the correlation between perturbed metabolism and inflammatory responses is necessary. We evaluated untargeted plasma metabolomics and cytokine profiling via 1H-NMR (proton nuclear magnetic resonance) and multiplex Luminex assay, respectively, in a training set of a limited number of patients with severe SARS-CoV-2 infection classified on the basis of their outcome. Univariate analysis and Kaplan-Meier curves related to hospitalization time showed that lower levels of several metabolites and cytokines/growth factors, correlated with a good outcome in these patients and these data were confirmed in a validation set of patients with similar characteristics. However, after the multivariate analysis, only the growth factor HGF, lactate and phenylalanine retained a significant prediction of survival. Finally, the combined analysis of lactate and phenylalanine levels correctly predicted the outcome of 83.3% of patients in both the training and the validation set. We highlighted that the cytokines and metabolites involved in COVID-19 patients' poor outcomes are similar to those responsible for cancer development and progression, suggesting the possibility of targeting them by repurposing anticancer drugs as a therapeutic strategy against severe SARS-CoV-2 infection.
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Alba G, Dakhaoui H, Santa-Maria C, Palomares F, Cejudo-Guillen M, Geniz I, Sobrino F, Montserrat-de la Paz S, Lopez-Enriquez S. Nutraceuticals as Potential Therapeutic Modulators in Immunometabolism. Nutrients 2023; 15:411. [PMID: 36678282 PMCID: PMC9865834 DOI: 10.3390/nu15020411] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2022] [Revised: 01/04/2023] [Accepted: 01/06/2023] [Indexed: 01/14/2023] Open
Abstract
Nutraceuticals act as cellular and functional modulators, contributing to the homeostasis of physiological processes. In an inflammatory microenvironment, these functional foods can interact with the immune system by modulating or balancing the exacerbated proinflammatory response. In this process, immune cells, such as antigen-presenting cells (APCs), identify danger signals and, after interacting with T lymphocytes, induce a specific effector response. Moreover, this conditions their change of state with phenotypical and functional modifications from the resting state to the activated and effector state, supposing an increase in their energy requirements that affect their intracellular metabolism, with each immune cell showing a unique metabolic signature. Thus, nutraceuticals, such as polyphenols, vitamins, fatty acids, and sulforaphane, represent an active option to use therapeutically for health or the prevention of different pathologies, including obesity, metabolic syndrome, and diabetes. To regulate the inflammation associated with these pathologies, intervention in metabolic pathways through the modulation of metabolic energy with nutraceuticals is an attractive strategy that allows inducing important changes in cellular properties. Thus, we provide an overview of the link between metabolism, immune function, and nutraceuticals in chronic inflammatory processes associated with obesity and diabetes, paying particular attention to nutritional effects on APC and T cell immunometabolism, as well as the mechanisms required in the change in energetic pathways involved after their activation.
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Affiliation(s)
- Gonzalo Alba
- Department of Medical Biochemistry and Molecular Biology, and Immunology, School of Medicine, University of Seville. Av. Sanchez Pizjuan s/n, 41009 Seville, Spain
| | - Hala Dakhaoui
- Department of Medical Biochemistry and Molecular Biology, and Immunology, School of Medicine, University of Seville. Av. Sanchez Pizjuan s/n, 41009 Seville, Spain
| | - Consuelo Santa-Maria
- Department of Biochemistry and Molecular Biology, School of Pharmacy, University of Seville, 41012 Seville, Spain
| | - Francisca Palomares
- Department of Medical Biochemistry and Molecular Biology, and Immunology, School of Medicine, University of Seville. Av. Sanchez Pizjuan s/n, 41009 Seville, Spain
| | - Marta Cejudo-Guillen
- Department of Pharmacology, Pediatry, and Radiology, School of Medicine, University of Seville. Av. Sanchez Pizjuan s/n, 41009 Seville, Spain
| | - Isabel Geniz
- Distrito Sanitario Seville Norte y Aljarafe, Servicio Andaluz de Salud, 41008 Seville, Spain
| | - Francisco Sobrino
- Department of Medical Biochemistry and Molecular Biology, and Immunology, School of Medicine, University of Seville. Av. Sanchez Pizjuan s/n, 41009 Seville, Spain
| | - Sergio Montserrat-de la Paz
- Department of Medical Biochemistry and Molecular Biology, and Immunology, School of Medicine, University of Seville. Av. Sanchez Pizjuan s/n, 41009 Seville, Spain
| | - Soledad Lopez-Enriquez
- Department of Medical Biochemistry and Molecular Biology, and Immunology, School of Medicine, University of Seville. Av. Sanchez Pizjuan s/n, 41009 Seville, Spain
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Liu J, Zhou G, Wang X, Liu D. Metabolic reprogramming consequences of sepsis: adaptations and contradictions. Cell Mol Life Sci 2022; 79:456. [PMID: 35904600 PMCID: PMC9336160 DOI: 10.1007/s00018-022-04490-0] [Citation(s) in RCA: 40] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2022] [Revised: 07/14/2022] [Accepted: 07/15/2022] [Indexed: 12/19/2022]
Abstract
During sepsis, the importance of alterations in cell metabolism is underappreciated. The cellular metabolism, which has a variable metabolic profile in different cells and disease stages, is largely responsible for the immune imbalance and organ failure associated with sepsis. Metabolic reprogramming, in which glycolysis replaces OXPHOS as the main energy-producing pathway, is both a requirement for immune cell activation and a cause of immunosuppression. Meanwhile, the metabolites produced by OXPHOS and glycolysis can act as signaling molecules to control the immune response during sepsis. Sepsis-induced "energy shortage" leads to stagnated cell function and even organ dysfunction. Metabolic reprogramming can alleviate the energy crisis to some extent, enhance host tolerance to maintain cell survival functions, and ultimately increase the adaptation of cells during sepsis. However, a switch from glycolysis to OXPHOS is essential for restoring cell function. This review summarized the crosstalk between metabolic reprogramming and immune cell activity as well as organ function during sepsis, discussed the benefits and drawbacks of metabolic reprogramming to show the contradictions of metabolic reprogramming during sepsis, and assessed the feasibility of treating sepsis through targeted metabolism. Using metabolic reprogramming to achieve metabolic homeostasis could be a viable therapy option for sepsis.
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Affiliation(s)
- Jingjing Liu
- Department of Critical Care Medicine, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, 1# Shuai Fu Yuan, Dong Cheng District, Beijing, 100730 China
| | - Gaosheng Zhou
- Department of Critical Care Medicine, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, 1# Shuai Fu Yuan, Dong Cheng District, Beijing, 100730 China
| | - Xiaoting Wang
- Department of Critical Care Medicine, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, 1# Shuai Fu Yuan, Dong Cheng District, Beijing, 100730 China
| | - Dawei Liu
- Department of Critical Care Medicine, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, 1# Shuai Fu Yuan, Dong Cheng District, Beijing, 100730 China
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21
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Goretzki A, Zimmermann J, Lin YJ, Schülke S. Immune Metabolism–An Opportunity to Better Understand Allergic Pathology and Improve Treatment of Allergic Diseases? FRONTIERS IN ALLERGY 2022; 3:825931. [PMID: 35386646 PMCID: PMC8974690 DOI: 10.3389/falgy.2022.825931] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Accepted: 01/25/2022] [Indexed: 01/16/2023] Open
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22
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Van Raemdonck K, Umar S, Palasiewicz K, Meyer A, Volin MV, Chang HJ, Al-Awqati M, Zomorrodi RK, Shahrara S. Metabolic reprogramming of macrophages instigates CCL21-induced arthritis. Immunol Cell Biol 2022; 100:127-135. [PMID: 34779007 PMCID: PMC8810694 DOI: 10.1111/imcb.12512] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2021] [Revised: 11/02/2021] [Accepted: 11/11/2021] [Indexed: 02/03/2023]
Abstract
This study was designed to delineate the functional significance of CCL21 in metabolic reprogramming in experimental arthritis and differentiated rheumatoid arthritis (RA) macrophages (MΦs). To characterize the influence of CCL21 on immunometabolism, its mechanism of action was elucidated by dysregulating glucose uptake in preclinical arthritis and RA MΦs. In CCL21 arthritic joints, the glycolytic intermediates hypoxia-inducible factor 1α (HIF1α), cMYC and GLUT1 were overexpressed compared with oxidative regulators estrogen-related receptor γ and peroxisome proliferator-activated receptor gamma coactivator 1 (PGC1)-α. Interestingly, 2-deoxy-D-glucose (2-DG) therapy mitigated CCL21-induced arthritis by restraining the number of joint F4/80+ iNOS+ MΦs without impacting F4/80+ Arginase+ MΦs. Similar to the preclinical findings, blockade of glycolysis negated CCL21-polarized CD14+ CD86+ GLUT+ MΦ frequency; however, CD14+ CD206+ GLUT+ MΦs were not implicated in this process. In CCL21-induced arthritis and differentiated RA MΦs, the inflammatory imprint was uniquely intercepted by 2-DG via interleukin-6 (IL-6) downregulation. Despite the more expansive inflammatory response of CCL21 in the arthritic joints relative to the differentiated RA MΦs, 2-DG was ineffective in joint tumor necrosis factor-α, IL-1β, CCL2 and CCL5 enrichment. By contrast, disruption of glycolysis markedly impaired CCL21-induced HIF1α and cMYC signaling in arthritic mice. Notably, in RA MΦs, glycolysis interception was directed toward dysregulating CCL21-enhanced HIF1α transcription. Nonetheless, in concurrence with the diminished IL-6 levels, CCL21 differentiation of CD14+ CD86+ GLUT1+ MΦs was reversed by glycolysis and HIIF1α inhibition. Moreover, in the CCL21 experimental arthritis or differentiated RA MΦs, the malfunctioning metabolic machinery was accompanied by impaired oxidative phosphorylation because of reduced PGC1α or peroxisome proliferator-activated receptor-γ expression. CCL21 reconfigures naïve myeloid cells into glycolytic RA CD14+ CD86+ GLUT+ IL-6high HIF1αhigh MΦs. Therefore, inhibiting the CCL21/CCR7 pathway may provide a promising therapeutic strategy.
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Affiliation(s)
- Katrien Van Raemdonck
- Jesse Brown VA Medical Center, Chicago, IL 60612, USA
- Department of Medicine, Division of Rheumatology, The University of Illinois at Chicago, IL 60612, USA
| | - Sadiq Umar
- Jesse Brown VA Medical Center, Chicago, IL 60612, USA
- Department of Medicine, Division of Rheumatology, The University of Illinois at Chicago, IL 60612, USA
| | - Karol Palasiewicz
- Jesse Brown VA Medical Center, Chicago, IL 60612, USA
- Department of Medicine, Division of Rheumatology, The University of Illinois at Chicago, IL 60612, USA
| | - Anja Meyer
- Jesse Brown VA Medical Center, Chicago, IL 60612, USA
- Department of Medicine, Division of Rheumatology, The University of Illinois at Chicago, IL 60612, USA
| | - Michael V Volin
- Department of Microbiology and Immunology, Midwestern University, Downers Grove, IL 60515, USA
| | - Huan J Chang
- Jesse Brown VA Medical Center, Chicago, IL 60612, USA
- Department of Medicine, Division of Rheumatology, The University of Illinois at Chicago, IL 60612, USA
| | - Mina Al-Awqati
- Jesse Brown VA Medical Center, Chicago, IL 60612, USA
- Department of Medicine, Division of Rheumatology, The University of Illinois at Chicago, IL 60612, USA
| | - Ryan K Zomorrodi
- Department of Medicine, Division of Rheumatology, The University of Illinois at Chicago, IL 60612, USA
| | - Shiva Shahrara
- Jesse Brown VA Medical Center, Chicago, IL 60612, USA
- Department of Medicine, Division of Rheumatology, The University of Illinois at Chicago, IL 60612, USA
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23
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Torrelles JB, Restrepo BI, Bai Y, Ross C, Schlesinger LS, Turner J. The Impact of Aging on the Lung Alveolar Environment, Predetermining Susceptibility to Respiratory Infections. FRONTIERS IN AGING 2022; 3:818700. [PMID: 35821836 PMCID: PMC9261427 DOI: 10.3389/fragi.2022.818700] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/19/2021] [Accepted: 01/03/2022] [Indexed: 12/15/2022]
Abstract
Respiratory infections are one of the top causes of death in the elderly population, displaying susceptibility factors with increasing age that are potentially amenable to interventions. We posit that with increasing age there are predictable tissue-specific changes that prevent the immune system from working effectively in the lung. This mini-review highlights recent evidence for altered local tissue environment factors as we age focusing on increased tissue oxidative stress with associated immune cell changes, likely driven by the byproducts of age-associated inflammatory disease. Potential intervention points are presented.
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Affiliation(s)
- Jordi B. Torrelles
- Population Health and Host-Pathogen Interactions Programs, Texas Biomedical Research Institute, San Antonio, TX, United States
| | - Blanca I. Restrepo
- School of Public Health in Brownsville, University of Texas Health Houston, Brownsville, TX, United States
- South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley, Edinburg, TX, United States
| | - Yidong Bai
- Department of Cell Systems and Anatomy, UT-Health San Antonio, San Antonio, TX, United States
| | - Corinna Ross
- Population Health and Host-Pathogen Interactions Programs, Texas Biomedical Research Institute, San Antonio, TX, United States
- Soutwest National Primate Research Center, Texas Biomedical Research Institute, San Antonio, TX, United States
| | - Larry S. Schlesinger
- Population Health and Host-Pathogen Interactions Programs, Texas Biomedical Research Institute, San Antonio, TX, United States
| | - Joanne Turner
- Population Health and Host-Pathogen Interactions Programs, Texas Biomedical Research Institute, San Antonio, TX, United States
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24
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Apoptotic cell-derived metabolites in efferocytosis-mediated resolution of inflammation. Cytokine Growth Factor Rev 2021; 62:42-53. [PMID: 34742632 DOI: 10.1016/j.cytogfr.2021.10.002] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2021] [Accepted: 10/13/2021] [Indexed: 12/21/2022]
Abstract
The resolution of inflammation, as part of standard host defense mechanism, is the process to guarantee timely termination of inflammatory responses and eventual restoration of tissue homeostasis . It is mainly achieved via efferocytosis, during which pro-resolving macrophages clear apoptotic neutrophils at the inflammatory site. Unfortunately, impaired resolution can be the leading cause of chronic inflammatory disorders and some autoimmune diseases. Existing studies have provided relatively comprehensive understandings about the recognition and uptake of apoptotic neutrophils by macrophages during early phases of efferocytosis. However, lack of information concerns macrophage metabolism of apoptotic cell-derived metabolites after being released from phagolysosomes or the relationship between such metabolism and efferocytosis. Notwithstanding, three recent studies have revealed macrophage metabolism of cholesterol, fatty acids and arginine, as well as their respective functions in the context of inflammation-resolution. This review provides an overview of the resolution of inflammation, efferocytosis and the key players involved, followed by a focus on the metabolism of apoptotic cell-derived metabolites within efferocytes. Hypotheses of more potential apoptotic cell-derived metabolites and their possible roles in the resolution are also formulated. Understanding the effect of these metabolites further advances the concept that apoptotic cells act as active players to regulate resolution, and also suggests novel therapeutic strategies for diseases driven by defective resolution and even cancer that may be treated through enhanced efferocytosis.
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25
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Alarcon PC, Damen MSMA, Madan R, Deepe GS, Spearman P, Way SS, Divanovic S. Adipocyte inflammation and pathogenesis of viral pneumonias: an overlooked contribution. Mucosal Immunol 2021; 14:1224-1234. [PMID: 33958704 PMCID: PMC8100369 DOI: 10.1038/s41385-021-00404-8] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2020] [Revised: 02/18/2021] [Accepted: 03/27/2021] [Indexed: 02/06/2023]
Abstract
Epidemiological evidence establishes obesity as an independent risk factor for increased susceptibility and severity to viral respiratory pneumonias associated with H1N1 influenza and SARS-CoV-2 pandemics. Given the global obesity prevalence, a better understanding of the mechanisms behind obese susceptibility to infection is imperative. Altered immune cell metabolism and function are often perceived as a key causative factor of dysregulated inflammation. However, the contribution of adipocytes, the dominantly altered cell type in obesity with broad inflammatory properties, to infectious disease pathogenesis remains largely ignored. Thus, skewing of adipocyte-intrinsic cellular metabolism may lead to the development of pathogenic inflammatory adipocytes, which shape the overall immune responses by contributing to either premature immunosenescence, delayed hyperinflammation, or cytokine storm in infections. In this review, we discuss the underappreciated contribution of adipocyte cellular metabolism and adipocyte-produced mediators on immune system modulation and how such interplay may modify disease susceptibility and pathogenesis of influenza and SARS-CoV-2 infections in obese individuals.
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Affiliation(s)
- Pablo C Alarcon
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA
- Divisions of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
- Medical Scientist Training Program, Cincinnati, OH, USA
- Immunology Graduate Program Cincinnati Children's Hospital Medical Center and the University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Michelle S M A Damen
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA
- Divisions of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
| | - Rajat Madan
- Division of Infectious Diseases, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, USA
- Veterans Affairs Medical Center, Cincinnati, OH, USA
| | - George S Deepe
- Division of Infectious Diseases, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Paul Spearman
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA
- Divisions of Infectious Diseases, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
| | - Sing Sing Way
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA
- Divisions of Infectious Diseases, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
- Center for Inflammation and Tolerance, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
| | - Senad Divanovic
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
- Divisions of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
- Medical Scientist Training Program, Cincinnati, OH, USA.
- Immunology Graduate Program Cincinnati Children's Hospital Medical Center and the University of Cincinnati College of Medicine, Cincinnati, OH, USA.
- Center for Inflammation and Tolerance, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
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26
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Herrera-Van Oostdam AS, Castañeda-Delgado JE, Oropeza-Valdez JJ, Borrego JC, Monárrez-Espino J, Zheng J, Mandal R, Zhang L, Soto-Guzmán E, Fernández-Ruiz JC, Ochoa-González F, Trejo Medinilla FM, López JA, Wishart DS, Enciso-Moreno JA, López-Hernández Y. Immunometabolic signatures predict risk of progression to sepsis in COVID-19. PLoS One 2021; 16:e0256784. [PMID: 34460840 PMCID: PMC8405033 DOI: 10.1371/journal.pone.0256784] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2021] [Accepted: 08/15/2021] [Indexed: 01/12/2023] Open
Abstract
Viral sepsis has been proposed as an accurate term to describe all multisystemic dysregulations and clinical findings in severe and critically ill COVID-19 patients. The adoption of this term may help the implementation of more accurate strategies of early diagnosis, prognosis, and in-hospital treatment. We accurately quantified 110 metabolites using targeted metabolomics, and 13 cytokines/chemokines in plasma samples of 121 COVID-19 patients with different levels of severity, and 37 non-COVID-19 individuals. Analyses revealed an integrated host-dependent dysregulation of inflammatory cytokines, neutrophil activation chemokines, glycolysis, mitochondrial metabolism, amino acid metabolism, polyamine synthesis, and lipid metabolism typical of sepsis processes distinctive of a mild disease. Dysregulated metabolites and cytokines/chemokines showed differential correlation patterns in mild and critically ill patients, indicating a crosstalk between metabolism and hyperinflammation. Using multivariate analysis, powerful models for diagnosis and prognosis of COVID-19 induced sepsis were generated, as well as for mortality prediction among septic patients. A metabolite panel made of kynurenine/tryptophan ratio, IL-6, LysoPC a C18:2, and phenylalanine discriminated non-COVID-19 from sepsis patients with an area under the curve (AUC (95%CI)) of 0.991 (0.986-0.995), with sensitivity of 0.978 (0.963-0.992) and specificity of 0.920 (0.890-0.949). The panel that included C10:2, IL-6, NLR, and C5 discriminated mild patients from sepsis patients with an AUC (95%CI) of 0.965 (0.952-0.977), with sensitivity of 0.993(0.984-1.000) and specificity of 0.851 (0.815-0.887). The panel with citric acid, LysoPC a C28:1, neutrophil-lymphocyte ratio (NLR) and kynurenine/tryptophan ratio discriminated severe patients from sepsis patients with an AUC (95%CI) of 0.829 (0.800-0.858), with sensitivity of 0.738 (0.695-0.781) and specificity of 0.781 (0.735-0.827). Septic patients who survived were different from those that did not survive with a model consisting of hippuric acid, along with the presence of Type II diabetes, with an AUC (95%CI) of 0.831 (0.788-0.874), with sensitivity of 0.765 (0.697-0.832) and specificity of 0.817 (0.770-0.865).
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Affiliation(s)
- Ana Sofía Herrera-Van Oostdam
- Doctorado en Ciencias Biomédicas Básicas, Centro de Investigación en Ciencias de la Salud y Biomedicina, Universidad Autónoma de San Luis Potosí, San Luis Potosí, San Luis Potosí, México
| | - Julio E. Castañeda-Delgado
- Cátedras-CONACyT, Consejo Nacional de Ciencia y Tecnología, Ciudad de México, México
- Unidad de Investigación Biomédica de Zacatecas, Instituto Mexicano del Seguro Social, Zacatecas, Zacatecas, México
| | - Juan José Oropeza-Valdez
- Doctorado en Ciencias Biomédicas Básicas, Centro de Investigación en Ciencias de la Salud y Biomedicina, Universidad Autónoma de San Luis Potosí, San Luis Potosí, San Luis Potosí, México
- Unidad de Investigación Biomédica de Zacatecas, Instituto Mexicano del Seguro Social, Zacatecas, Zacatecas, México
| | - Juan Carlos Borrego
- Departmento de Epidemiología, Hospital General de Zona #1 “Emilio Varela Luján”, Instituto Mexicano del Seguro Social, Zacatecas, Zacatecas, México
| | - Joel Monárrez-Espino
- Christus Muguerza Hospital Chihuahua - University of Monterrey, Chihuahua, Chihuahua, Mexico
| | - Jiamin Zheng
- The Metabolomics Innovation Center, University of Alberta, Edmonton, Alberta, Canada
| | - Rupasri Mandal
- The Metabolomics Innovation Center, University of Alberta, Edmonton, Alberta, Canada
| | - Lun Zhang
- The Metabolomics Innovation Center, University of Alberta, Edmonton, Alberta, Canada
| | - Elizabeth Soto-Guzmán
- Maestría en Ciencias Biomédicas, Universidad Autónoma de Zacatecas, Zacatecas, Zacatecas, México
| | - Julio César Fernández-Ruiz
- Doctorado en Ciencias Biomédicas Básicas, Centro de Investigación en Ciencias de la Salud y Biomedicina, Universidad Autónoma de San Luis Potosí, San Luis Potosí, San Luis Potosí, México
- Unidad de Investigación Biomédica de Zacatecas, Instituto Mexicano del Seguro Social, Zacatecas, Zacatecas, México
| | - Fátima Ochoa-González
- Unidad de Investigación Biomédica de Zacatecas, Instituto Mexicano del Seguro Social, Zacatecas, Zacatecas, México
- Doctorado en Ciencias Básicas, Universidad Autónoma de Zacatecas, Zacatecas, Zacatecas, México
| | - Flor M. Trejo Medinilla
- Doctorado en Ciencias Básicas, Universidad Autónoma de Zacatecas, Zacatecas, Zacatecas, México
| | - Jesús Adrián López
- MicroRNAs Laboratory, Academic Unit for Biological Sciences, Autonomous University of Zacatecas, Zacatecas, Zacatecas, Mexico
| | - David S. Wishart
- The Metabolomics Innovation Center, University of Alberta, Edmonton, Alberta, Canada
| | - José A. Enciso-Moreno
- Unidad de Investigación Biomédica de Zacatecas, Instituto Mexicano del Seguro Social, Zacatecas, Zacatecas, México
| | - Yamilé López-Hernández
- Cátedras-CONACyT, Consejo Nacional de Ciencia y Tecnología, Ciudad de México, México
- Metabolomics and Proteomics Laboratory, Autonomous University of Zacatecas, Zacatecas, Zacatecas, Mexico
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27
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Sangaletti S, Botti L, Gulino A, Lecis D, Bassani B, Portararo P, Milani M, Cancila V, De Cecco L, Dugo M, Tripodo C, Colombo MP. SPARC regulation of PMN clearance protects from pristane-induced lupus and rheumatoid arthritis. iScience 2021; 24:102510. [PMID: 34142027 PMCID: PMC8188360 DOI: 10.1016/j.isci.2021.102510] [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: 08/17/2020] [Revised: 12/15/2020] [Accepted: 04/30/2021] [Indexed: 11/22/2022] Open
Abstract
The secreted protein acidic and rich in cysteine (SPARC) is a matricellular protein with unexpected immunosuppressive function in myeloid cells. We investigated the role of SPARC in autoimmunity using the pristane-induced model of lupus that, in mice, mimics human systemic lupus erythematosus (SLE). Sparc -/- mice developed earlier and more severe renal disease, multi-organ parenchymal damage, and arthritis than the wild-type counterpart. Sparc +/- heterozygous mice showed an intermediate phenotype suggesting Sparc gene dosage in autoimmune-related events. Mechanistically, reduced Sparc expression in neutrophils blocks their clearance by macrophages, through defective delivery of don't-eat-me signals. Dying Sparc -/- neutrophils that escape macrophage scavenging become source of autoantigens for dendritic cell presentation and are a direct stimulation for γδT cells. Gene profile analysis of knee synovial biopsies from SLE-associated arthritis showed an inverse correlation between SPARC and key autoimmune genes. These results point to SPARC down-regulation as a leading event characterizing SLE and rheumatoid arthritis pathogenesis.
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Affiliation(s)
- Sabina Sangaletti
- Molecular Immunology Unit, Department of Research, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy
| | - Laura Botti
- Molecular Immunology Unit, Department of Research, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy
| | | | - Daniele Lecis
- Molecular Immunology Unit, Department of Research, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy
| | - Barbara Bassani
- Molecular Immunology Unit, Department of Research, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy
| | - Paola Portararo
- Molecular Immunology Unit, Department of Research, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy
| | - Matteo Milani
- Molecular Immunology Unit, Department of Research, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy
| | - Valeria Cancila
- Tumor Immunology Unit, University of Palermo, Palermo, Italy
| | - Loris De Cecco
- Platform of Integrated Biology, Department of Applied Research and Technology Development, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy
| | - Matteo Dugo
- Platform of Integrated Biology, Department of Applied Research and Technology Development, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy
| | - Claudio Tripodo
- Tumor Immunology Unit, University of Palermo, Palermo, Italy
| | - Mario P. Colombo
- Molecular Immunology Unit, Department of Research, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy
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28
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Nguyen LT, Hoang DM, Nguyen KT, Bui DM, Nguyen HT, Le HTA, Hoang VT, Bui HTH, Dam PTM, Hoang XTA, Ngo ATL, Le HM, Phung NY, Vu DM, Duong TT, Nguyen TD, Ha LT, Bui HTP, Nguyen HK, Heke M, Bui AV. Type 2 diabetes mellitus duration and obesity alter the efficacy of autologously transplanted bone marrow-derived mesenchymal stem/stromal cells. Stem Cells Transl Med 2021; 10:1266-1278. [PMID: 34080789 PMCID: PMC8380443 DOI: 10.1002/sctm.20-0506] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2020] [Revised: 03/11/2021] [Accepted: 04/08/2021] [Indexed: 12/17/2022] Open
Abstract
Human bone marrow-derived mesenchymal stem/stromal cells (BM-MSCs) represent promising stem cell therapy for the treatment of type 2 diabetes mellitus (T2DM), but the results of autologous BM-MSC administration in T2DM patients are contradictory. The purpose of this study was to test the hypothesis that autologous BM-MSC administration in T2DM patient is safe and that the efficacy of the treatment is dependant on the quality of the autologous BM-MSC population and administration routes. T2DM patients were enrolled, randomly assigned (1:1) by a computer-based system into the intravenous and dorsal pancreatic arterial groups. The safety was assessed in all the treated patients, and the efficacy was evaluated based on the absolute changes in the hemoglobin A1c, fasting blood glucose, and C-peptide levels throughout the 12-month follow-up. Our data indicated that autologous BM-MSC administration was well tolerated in 30 T2DM patients. Short-term therapeutic effects were observed in patients with T2DM duration of <10 years and a body mass index <23, which is in line with the phenotypic analysis of the autologous BM-MSC population. T2DM duration directly altered the proliferation rate of BM-MSCs, abrogated the glycolysis and mitochondria respiration of BM-MSCs, and induced the accumulation of mitochondria DNA mutation. Our data suggest that autologous administration of BM-MSCs in the treatment of T2DM should be performed in patients with T2DM duration <10 years and no obesity. Prior to further confirming the effects of T2DM on BM-MSC biology, future work with a larger cohort focusing on patients with different T2DM history is needed to understand the mechanism underlying our observation.
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Affiliation(s)
- Liem Thanh Nguyen
- Department of Research and Development (R&D), Vinmec Research Institute of Stem Cell and Gene Technology, Vinmec Healthcare System, Hanoi, Vietnam
| | - Duc M Hoang
- Department of Research and Development (R&D), Vinmec Research Institute of Stem Cell and Gene Technology, Vinmec Healthcare System, Hanoi, Vietnam
| | - Kien T Nguyen
- Department of Research and Development (R&D), Vinmec Research Institute of Stem Cell and Gene Technology, Vinmec Healthcare System, Hanoi, Vietnam
| | - Duc M Bui
- Department of Internal Medicine, Vinmec Times City International Hospital, Hanoi, Vietnam
| | - Hieu T Nguyen
- Department of Research and Development (R&D), Vinmec Research Institute of Stem Cell and Gene Technology, Vinmec Healthcare System, Hanoi, Vietnam
| | - Hong T A Le
- Department of Research and Development (R&D), Vinmec Research Institute of Stem Cell and Gene Technology, Vinmec Healthcare System, Hanoi, Vietnam
| | - Van T Hoang
- Department of Research and Development (R&D), Vinmec Research Institute of Stem Cell and Gene Technology, Vinmec Healthcare System, Hanoi, Vietnam
| | - Hue T H Bui
- Department of Cellular Therapy, Vinmec High-Tech Center, Hanoi, Vietnam
| | - Phuong T M Dam
- Department of Cellular Therapy, Vinmec High-Tech Center, Hanoi, Vietnam
| | - Xuan T A Hoang
- Department of Research and Development (R&D), Vinmec Research Institute of Stem Cell and Gene Technology, Vinmec Healthcare System, Hanoi, Vietnam
| | - Anh T L Ngo
- Department of Research and Development (R&D), Vinmec Research Institute of Stem Cell and Gene Technology, Vinmec Healthcare System, Hanoi, Vietnam
| | - Hang M Le
- Department of Cellular Therapy, Vinmec High-Tech Center, Hanoi, Vietnam
| | - Nhi Y Phung
- Department of Cellular Therapy, Vinmec High-Tech Center, Hanoi, Vietnam
| | - Duc M Vu
- Department of Research and Development (R&D), Vinmec Research Institute of Stem Cell and Gene Technology, Vinmec Healthcare System, Hanoi, Vietnam
| | - Trung T Duong
- Department of Research and Development (R&D), Vinmec Research Institute of Stem Cell and Gene Technology, Vinmec Healthcare System, Hanoi, Vietnam
| | - Tu D Nguyen
- Department of Cellular Therapy, Vinmec High-Tech Center, Hanoi, Vietnam
| | - Lien T Ha
- Department of Medical Genetics, Vinmec High-Tech Center, Hanoi, Vietnam
| | - Hoa T P Bui
- Department of Medical Genetics, Vinmec High-Tech Center, Hanoi, Vietnam
| | - Hoa K Nguyen
- Department of Research and Development (R&D), Vinmec Research Institute of Stem Cell and Gene Technology, Vinmec Healthcare System, Hanoi, Vietnam
| | - Michael Heke
- Department of Biology, Stanford University, Stanford, California, USA
| | - Anh V Bui
- Department of Cellular Therapy, Vinmec High-Tech Center, Hanoi, Vietnam
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29
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Bahadoran A, Bezavada L, Smallwood HS. Fueling influenza and the immune response: Implications for metabolic reprogramming during influenza infection and immunometabolism. Immunol Rev 2021; 295:140-166. [PMID: 32320072 DOI: 10.1111/imr.12851] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2019] [Revised: 02/19/2020] [Accepted: 02/24/2020] [Indexed: 12/11/2022]
Abstract
Recent studies support the notion that glycolysis and oxidative phosphorylation are rheostats in immune cells whose bioenergetics have functional outputs in terms of their biology. Specific intrinsic and extrinsic molecular factors function as molecular potentiometers to adjust and control glycolytic to respiratory power output. In many cases, these potentiometers are used by influenza viruses and immune cells to support pathogenesis and the host immune response, respectively. Influenza virus infects the respiratory tract, providing a specific environmental niche, while immune cells encounter variable nutrient concentrations as they migrate in response to infection. Immune cell subsets have distinct metabolic programs that adjust to meet energetic and biosynthetic requirements to support effector functions, differentiation, and longevity in their ever-changing microenvironments. This review details how influenza coopts the host cell for metabolic reprogramming and describes the overlap of these regulatory controls in immune cells whose function and fate are dictated by metabolism. These details are contextualized with emerging evidence of the consequences of influenza-induced changes in metabolic homeostasis on disease progression.
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Affiliation(s)
- Azadeh Bahadoran
- Department of Pediatrics, University of Tennessee Health Science Center, Memphis, TN, USA
| | - Lavanya Bezavada
- Department of Pediatrics, University of Tennessee Health Science Center, Memphis, TN, USA
| | - Heather S Smallwood
- Department of Pediatrics, University of Tennessee Health Science Center, Memphis, TN, USA
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30
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Zago G, Saavedra PHV, Keshari KR, Perry JSA. Immunometabolism of Tissue-Resident Macrophages - An Appraisal of the Current Knowledge and Cutting-Edge Methods and Technologies. Front Immunol 2021; 12:665782. [PMID: 34025667 PMCID: PMC8138590 DOI: 10.3389/fimmu.2021.665782] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2021] [Accepted: 04/07/2021] [Indexed: 12/23/2022] Open
Abstract
Tissue-resident macrophages exist in unique environments, or niches, that inform their identity and function. There is an emerging body of literature suggesting that the qualities of this environment, such as the types of cells and debris they eat, the intercellular interactions they form, and the length of time spent in residence, collectively what we call habitare, directly inform their metabolic state. In turn, a tissue-resident macrophage’s metabolic state can inform their function, including whether they resolve inflammation and protect the host from excessive perturbations of homeostasis. In this review, we summarize recent work that seeks to understand the metabolic requirements for tissue-resident macrophage identity and maintenance, for how they respond to inflammatory challenges, and for how they perform homeostatic functions or resolve inflammatory insults. We end with a discussion of the emerging technologies that are enabling, or will enable, in situ study of tissue-resident macrophage metabolism.
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Affiliation(s)
- Giulia Zago
- Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY, United States
| | - Pedro H V Saavedra
- Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY, United States
| | - Kayvan R Keshari
- Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY, United States.,Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY, United States
| | - Justin S A Perry
- Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY, United States.,Louis V. Gerstner Jr. Graduate School of Biomedical Sciences, Memorial Sloan Kettering Cancer Center, New York, NY, United States.,Department of Immunology and Microbial Pathogenesis, Weill Cornell Medical College, New York, NY, United States
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31
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Xiao N, Nie M, Pang H, Wang B, Hu J, Meng X, Li K, Ran X, Long Q, Deng H, Chen N, Li S, Tang N, Huang A, Hu Z. Integrated cytokine and metabolite analysis reveals immunometabolic reprogramming in COVID-19 patients with therapeutic implications. Nat Commun 2021; 12:1618. [PMID: 33712622 PMCID: PMC7955129 DOI: 10.1038/s41467-021-21907-9] [Citation(s) in RCA: 182] [Impact Index Per Article: 45.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2020] [Accepted: 02/19/2021] [Indexed: 01/08/2023] Open
Abstract
Cytokine release syndrome (CRS) is a major cause of the multi-organ injury and fatal outcome induced by SARS-CoV-2 infection in severe COVID-19 patients. Metabolism can modulate the immune responses against infectious diseases, yet our understanding remains limited on how host metabolism correlates with inflammatory responses and affects cytokine release in COVID-19 patients. Here we perform both metabolomics and cytokine/chemokine profiling on serum samples from healthy controls, mild and severe COVID-19 patients, and delineate their global metabolic and immune response landscape. Correlation analyses show tight associations between metabolites and proinflammatory cytokines/chemokines, such as IL-6, M-CSF, IL-1α, IL-1β, and imply a potential regulatory crosstalk between arginine, tryptophan, purine metabolism and hyperinflammation. Importantly, we also demonstrate that targeting metabolism markedly modulates the proinflammatory cytokines release by peripheral blood mononuclear cells isolated from SARS-CoV-2-infected rhesus macaques ex vivo, hinting that exploiting metabolic alterations may be a potential strategy for treating fatal CRS in COVID-19. Metabolism changes can modulate immune responses in many contexts, and vice versa. Here the authors associate metabolomic, as well as cytokine and chemokine, data from stratified COVID-19 patients to find that arginine, tryptophan and purine metabolic pathways correlate with hyperproliferation, thus hinting at potential therapeutic targets for severe COVID-19 patients.
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Affiliation(s)
- Nan Xiao
- School of Pharmaceutical Sciences, Tsinghua University, Beijing, 100084, China
| | - Meng Nie
- School of Pharmaceutical Sciences, Tsinghua University, Beijing, 100084, China.,Tsinghua-Peking Joint Center for Life Sciences, Tsinghua University, Beijing, 100084, China
| | - Huanhuan Pang
- School of Pharmaceutical Sciences, Tsinghua University, Beijing, 100084, China.,Tsinghua-Peking Joint Center for Life Sciences, Tsinghua University, Beijing, 100084, China
| | - Bohong Wang
- School of Pharmaceutical Sciences, Tsinghua University, Beijing, 100084, China.,Tsinghua-Peking Joint Center for Life Sciences, Tsinghua University, Beijing, 100084, China
| | - Jieli Hu
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Chongqing Medical University, Chongqing, China
| | - Xiangjun Meng
- School of Pharmaceutical Sciences, Tsinghua University, Beijing, 100084, China
| | - Ke Li
- NHC Key Laboratory of Biotechnology of Antibiotics, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100050, China
| | - Xiaorong Ran
- Agilent Technologies (China), Chaoyang District, Beijing, 100102, China
| | - Quanxin Long
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Chongqing Medical University, Chongqing, China
| | - Haijun Deng
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Chongqing Medical University, Chongqing, China
| | - Na Chen
- School of Pharmaceutical Sciences, Tsinghua University, Beijing, 100084, China
| | - Shao Li
- Institute for TCM-X, MOE Key Laboratory of Bioinformatics, Bioinformatics Division, BNRIST, Department of Automation, Tsinghua University, Beijing, 100084, China
| | - Ni Tang
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Chongqing Medical University, Chongqing, China.
| | - Ailong Huang
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Chongqing Medical University, Chongqing, China.
| | - Zeping Hu
- School of Pharmaceutical Sciences, Tsinghua University, Beijing, 100084, China. .,Tsinghua-Peking Joint Center for Life Sciences, Tsinghua University, Beijing, 100084, China. .,Beijing Frontier Research Center for Biological Structure, Tsinghua University, Beijing, 100084, China.
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32
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Kang S, Kumanogoh A. The spectrum of macrophage activation by immunometabolism. Int Immunol 2020; 32:467-473. [PMID: 32179900 DOI: 10.1093/intimm/dxaa017] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2020] [Accepted: 03/12/2020] [Indexed: 12/28/2022] Open
Abstract
Macrophages are heterogeneous and plastic, and play several diverse functions in immune responses. Emerging data provide evidence of multiple roles for metabolic pathways in the control of macrophage effector functions. The diverse functions of macrophages are categorized into two main subsets: classical activated macrophages (M1) and alternative activated macrophages (M2). M1 macrophages secrete pro-inflammatory cytokines and reactive oxygen species and migrate into inflamed sites as a part of host defenses. On the other hand, M2 macrophages are involved in immune homeostasis by producing anti-inflammatory cytokines and phagocytosing apoptotic cells. Metabolic reprogramming of environmental or cellular nutrients such as glucose, lipids and amino acids supports this diversity. Mechanistically, the mammalian target of rapamycin (mTOR) network plays important roles in the effector functions of macrophages by modulating cellular metabolism and regulating gene expression at the transcriptional and translational levels. In this review, we outline immunometabolism and provide insights into metabolic regulation by mTOR in macrophages.
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Affiliation(s)
- Sujin Kang
- Department of Immune Regulation, Immunology Frontier Research Center, Osaka University, Suita City, Osaka, Japan
| | - Atsushi Kumanogoh
- Department of Immunopathology, Immunology Frontier Research Center, Osaka University, Suita City, Osaka, Japan.,Department of Respiratory Medicine and Clinical Immunology, Graduate School of Medicine, Osaka University, Suita City, Osaka, Japan
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33
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Amiel E, Perona‐Wright G. Metabolic mediators: How immunometabolism directs the immune response to infection. Immunology 2020; 161:163-164. [PMID: 33085098 PMCID: PMC7576874 DOI: 10.1111/imm.13275] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Here we announce the first part of an exciting new series of reviews exploring the impact of immunometabolism in the interaction between host and pathogen, and in the outcome of infection. This collection discusses the links between metabolism and epigenetic control of cell function, post-translation modifications of host proteins that determine protein fate and host cell function, the metabolic determinants of cell migration and immune cell activity, and the tussle for iron as a metabolic mediator of host-pathogen domination. Together these reviews provide engaging new insight into the metabolic signals that guide the dynamic conversation between microbial pathogens and the mammalian hosts they aim to occupy.
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Affiliation(s)
- Eyal Amiel
- Department of Biomedical and Health SciencesUniversity of VermontBurlingtonVTUSA
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34
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Shippy DC, Ulland TK. Microglial Immunometabolism in Alzheimer's Disease. Front Cell Neurosci 2020; 14:563446. [PMID: 33192310 PMCID: PMC7531234 DOI: 10.3389/fncel.2020.563446] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2020] [Accepted: 08/28/2020] [Indexed: 12/11/2022] Open
Abstract
Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by amyloid-β (Aβ) plaques and the formation of neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau. In response to Aβ and tau aggregates, microglia, the primary innate immune cells of the central nervous system (CNS), facilitate Aβ and tau clearance and contribute to neuroinflammation that damages neurons. Microglia also perform a wide range of other functions, e.g., synaptic pruning, within the CNS that require a large amount of energy. Glucose appears to be the primary energy source, but microglia can utilize several other substrates for energy production including other sugars and ketone bodies. Recent studies have demonstrated that changes in the metabolic profiles of immune cells, including macrophages, are important in controlling their activation and effector functions. Additional studies have focused on the role of metabolism in neuron and astrocyte function while until recently microglia metabolism has been considerably less well understood. Considering many neurological disorders, such as neurodegeneration associated with AD, are associated with chronic inflammation and alterations in brain energy metabolism, it is hypothesized that microglial metabolism plays a significant role in the inflammatory responses of microglia during neurodegeneration. Here, we review the role of microglial immunometabolism in AD.
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Affiliation(s)
- Daniel C Shippy
- Department of Pathology and Laboratory Medicine, University of Wisconsin, Madison, WI, United States
| | - Tyler K Ulland
- Department of Pathology and Laboratory Medicine, University of Wisconsin, Madison, WI, United States
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35
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Cumming BM, Pacl HT, Steyn AJC. Relevance of the Warburg Effect in Tuberculosis for Host-Directed Therapy. Front Cell Infect Microbiol 2020; 10:576596. [PMID: 33072629 PMCID: PMC7531540 DOI: 10.3389/fcimb.2020.576596] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2020] [Accepted: 08/13/2020] [Indexed: 12/12/2022] Open
Abstract
Tuberculosis (TB) was responsible for more deaths in 2019 than any other infectious agent. This epidemic is exacerbated by the ongoing development of multi-drug resistance and HIV co-infection. Recent studies have therefore focused on identifying host-directed therapies (HDTs) that can be used in combination with anti-mycobacterial drugs to shorten the duration of TB treatment and improve TB outcomes. In searching for effective HDTs for TB, studies have looked toward immunometabolism, the study of the role of metabolism in host immunity and, in particular, the Warburg effect. Across a variety of experimental paradigms ranging from in vitro systems to the clinic, studies on the role of the Warburg effect in TB have produced seemingly conflicting results and contradictory conclusions. To reconcile this literature, we take a historical approach to revisit the definition of the Warburg effect, re-examine the foundational papers on the Warburg effect in the cancer field and explore its application to immunometabolism. With a firm context established, we assess the literature investigating metabolism and immunometabolism in TB for sufficient evidence to support the role of the Warburg effect in TB immunity. The effects of the differences between animal models, species of origin of the macrophages, duration of infection and Mycobacterium tuberculosis strains used for these studies are highlighted. In addition, the shortcomings of using 2-deoxyglucose as an inhibitor of glycolysis are discussed. We conclude by proposing experimental criteria that are essential for future studies on the Warburg effect in TB to assist with the research for HDTs to combat TB.
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Affiliation(s)
| | - Hayden T Pacl
- Department of Microbiology, University of Alabama, Birmingham, AL, United States
| | - Adrie J C Steyn
- Africa Health Research Institute, Durban, South Africa.,Department of Microbiology, University of Alabama, Birmingham, AL, United States.,Centers for Free Radical Biology (CFRB) and AIDS Research (CFAR), University of Alabama, Birmingham, AL, United States
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36
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Sun L, Guo M, Lv Z, Shao Y, Li C. Hypoxia-inducible factor-1α shifts metabolism from oxidative phosphorylation to glycolysis in response to pathogen challenge in Apostichopus japonicus. AQUACULTURE 2020; 526:735393. [DOI: 10.1016/j.aquaculture.2020.735393] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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37
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Ludwig K, Husain RA, Rubio I. mTORC1 Is Not Principally Involved in the Induction of Human Endotoxin Tolerance. Front Immunol 2020; 11:1515. [PMID: 32849516 PMCID: PMC7426365 DOI: 10.3389/fimmu.2020.01515] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2020] [Accepted: 06/09/2020] [Indexed: 11/13/2022] Open
Abstract
Endotoxin tolerance represents a safeguard mechanism for preventing detrimental prolonged inflammation and exaggerated immune/inflammatory responses from innate immune cells to recurrent harmless pathogens. On the other hand, excessive immune tolerance can contribute to pathological immunosuppression, e.g., as present in sepsis. Monocyte activation is accompanied by intracellular metabolic rearrangements that are reportedly orchestrated by the metabolic signaling node mTORC1. mTORC1-dependent metabolic re-wiring plays a major role in monocyte/macrophage polarization, but whether mTORC1 participates in the induction of endotoxin tolerance and other immune adaptive programs, such as immune training, is not clear. This connection has been difficult to test in the past due to the lack of appropriate models of human endotoxin tolerance allowing for the genetic manipulation of mTORC1. We have addressed this shortcoming by investigating monocytes from tuberous sclerosis (TSC) patients that feature a functional loss of the tumor suppressor TSC1/2 and a concomitant hyperactivation of mTORC1. Subjecting these cells to various protocols of immune priming and adaptation showed that the TSC monocytes are not compromised in the induction of tolerance. Analogously, we find that pharmacological mTORC1 inhibition does not prevent endotoxin tolerance induction in human monocytes. Interestingly, neither manipulation affected the capacity of activated monocytes to switch to increased lactic fermentation. In sum, our findings document that mTORC1 is unlikely to be involved in the induction of endotoxin tolerance in human monocytes and argue against a causal link between an mTORC1-dependent metabolic switch and the induction of immune tolerance.
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Affiliation(s)
- Kristin Ludwig
- Institute of Molecular Cell Biology, Center for Molecular Biomedicine, University Hospital Jena, Jena, Germany
| | - Ralf A Husain
- Department of Neuropediatrics, University Hospital Jena, Jena, Germany
| | - Ignacio Rubio
- Institute of Molecular Cell Biology, Center for Molecular Biomedicine, University Hospital Jena, Jena, Germany.,Clinic of Anaesthesiology and Intensive Care and Center for Sepsis Control and Care (CSCC), University Hospital Jena, Jena, Germany
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38
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Abstract
Antiretroviral therapies efficiently block HIV-1 replication but need to be maintained for life. Moreover, chronic inflammation is a hallmark of HIV-1 infection that persists despite treatment. There is, therefore, an urgent need to better understand the mechanisms driving HIV-1 pathogenesis and to identify new targets for therapeutic intervention. In the past few years, the decisive role of cellular metabolism in the fate and activity of immune cells has been uncovered, as well as its impact on the outcome of infectious diseases. Emerging evidence suggests that immunometabolism has a key role in HIV-1 pathogenesis. The metabolic pathways of CD4+ T cells and macrophages determine their susceptibility to infection, the persistence of infected cells and the establishment of latency. Immunometabolism also shapes immune responses against HIV-1, and cell metabolic products are key drivers of inflammation during infection. In this Review, we summarize current knowledge of the links between HIV-1 infection and immunometabolism, and we discuss the potential opportunities and challenges for therapeutic interventions.
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39
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Lactate released by inflammatory bone marrow neutrophils induces their mobilization via endothelial GPR81 signaling. Nat Commun 2020; 11:3547. [PMID: 32669546 PMCID: PMC7363928 DOI: 10.1038/s41467-020-17402-2] [Citation(s) in RCA: 113] [Impact Index Per Article: 22.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2020] [Accepted: 06/22/2020] [Indexed: 12/12/2022] Open
Abstract
Neutrophils provide first line of host defense against bacterial infections utilizing glycolysis for their effector functions. How glycolysis and its major byproduct lactate are triggered in bone marrow (BM) neutrophils and their contribution to neutrophil mobilization in acute inflammation is not clear. Here we report that bacterial lipopolysaccharides (LPS) or Salmonella Typhimurium triggers lactate release by increasing glycolysis, NADPH-oxidase-mediated reactive oxygen species and HIF-1α levels in BM neutrophils. Increased release of BM lactate preferentially promotes neutrophil mobilization by reducing endothelial VE-Cadherin expression, increasing BM vascular permeability via endothelial lactate-receptor GPR81 signaling. GPR81-/- mice mobilize reduced levels of neutrophils in response to LPS, unless rescued by VE-Cadherin disrupting antibodies. Lactate administration also induces release of the BM neutrophil mobilizers G-CSF, CXCL1 and CXCL2, indicating that this metabolite drives neutrophil mobilization via multiple pathways. Our study reveals a metabolic crosstalk between lactate-producing neutrophils and BM endothelium, which controls neutrophil mobilization under bacterial infection.
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40
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Dramé M, Buchrieser C, Escoll P. Danger-associated metabolic modifications during bacterial infection of macrophages. Int Immunol 2020; 32:475-483. [DOI: 10.1093/intimm/dxaa035] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2020] [Accepted: 05/15/2020] [Indexed: 02/06/2023] Open
Abstract
Abstract
In this review, we propose that certain modifications in cellular metabolism might function as danger signals triggering inflammasome-mediated immune responses. We propose to call them danger-associated metabolic modifications (DAMMs). As intracellular bacteria can actively modulate macrophage metabolism for their benefit, infected host cells might sense bacteria-induced metabolic alterations and activate immune reactions. Here we report the known metabolic interactions that occur during infection of macrophages by intracellular bacteria and discuss the possible emergence of DAMMs upon bacteria-induced alterations of cellular metabolism.
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Affiliation(s)
- Mariatou Dramé
- Institut Pasteur, Unité de Biologie des Bactéries Intracellulaires, Paris, France
- CNRS-UMR 3525, Paris, France
- Sorbonne Université, Paris, France
| | - Carmen Buchrieser
- Institut Pasteur, Unité de Biologie des Bactéries Intracellulaires, Paris, France
- CNRS-UMR 3525, Paris, France
| | - Pedro Escoll
- Institut Pasteur, Unité de Biologie des Bactéries Intracellulaires, Paris, France
- CNRS-UMR 3525, Paris, France
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41
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Chen S, Fuller KK, Dunlap JC, Loros JJ. A Pro- and Anti-inflammatory Axis Modulates the Macrophage Circadian Clock. Front Immunol 2020; 11:867. [PMID: 32477351 PMCID: PMC7240016 DOI: 10.3389/fimmu.2020.00867] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2020] [Accepted: 04/15/2020] [Indexed: 12/17/2022] Open
Abstract
The circadian clock broadly governs immune cell function, leading to time-of-day differences in inflammatory responses and subsequently, pathogen clearance. However, the effect of inflammatory signals on circadian machinery is poorly understood. We found that in bone marrow-derived macrophages, some host-derived pro-inflammatory cytokines, e.g., IFN-γ or TNF-α, and pathogen-associated molecular patterns, e.g., LPS or Pam3Csk4, suppress the amplitude in oscillations of circadian negative feedback arm clock components such as PER2, and when examined, specific combinations of these immune-related signals suppressed the amplitude of these oscillations to a greater degree in both bone marrow-derived and peritoneal macrophages. At the transcript level, multiple components of the circadian clock were affected in different ways by pro-inflammatory stimulus, including Per2 and Nr1d1. This suppressive effect on PER2 did not arise from nor correlate with cell death or clock resetting. Suppression of the clock by IFN-γ was dependent on its cognate receptor; however, pharmacological inhibition of the canonical JAK/STAT and MEK pathways did not hinder suppression, suggesting a mechanism involving a non-canonical pathway. In contrast, anti-inflammatory signals such as IL-4 and dexamethasone enhanced the expression of PER2 protein and Per2 mRNA. Our results suggest that the circadian system in macrophages can differentially respond to pro- and anti-inflammatory signals in their microenvironments.
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Affiliation(s)
- Shan Chen
- Department of Molecular and Systems Biology, Geisel School of Medicine at Dartmouth, Hanover, NH, United States
| | - Kevin K Fuller
- Department of Molecular and Systems Biology, Geisel School of Medicine at Dartmouth, Hanover, NH, United States
| | - Jay C Dunlap
- Department of Molecular and Systems Biology, Geisel School of Medicine at Dartmouth, Hanover, NH, United States
| | - Jennifer J Loros
- Department of Molecular and Systems Biology, Geisel School of Medicine at Dartmouth, Hanover, NH, United States.,Department of Biochemistry and Cell Biology, Geisel School of Medicine at Dartmouth, Hanover, NH, United States
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42
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Khaing P, Summer R. Maxed Out on Glycolysis: Alveolar Macrophages Rely on Oxidative Phosphorylation for Cytokine Production. Am J Respir Cell Mol Biol 2020; 62:139-140. [PMID: 31560565 PMCID: PMC6993550 DOI: 10.1165/rcmb.2019-0329ed] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Affiliation(s)
- Phue Khaing
- Jane and Leonard Korman Respiratory InstituteSidney Kimmel Medical College at Thomas Jefferson UniversityPhiladelphia, Pennsylvania
| | - Ross Summer
- Jane and Leonard Korman Respiratory InstituteSidney Kimmel Medical College at Thomas Jefferson UniversityPhiladelphia, Pennsylvania
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43
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Glutamine Metabolism and Its Role in Immunity, a Comprehensive Review. Animals (Basel) 2020; 10:ani10020326. [PMID: 32092847 PMCID: PMC7070879 DOI: 10.3390/ani10020326] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2020] [Revised: 02/13/2020] [Accepted: 02/17/2020] [Indexed: 02/07/2023] Open
Abstract
In the body of an animal, glutamine is a plentiful and very useful amino acid. Glutamine consumption in the body of animals in normal or disease conditions is the same or higher than the glucose. Many in vivo as well as in vitro experiments have been conducted to evaluate the importance of glutamine. Glutamine is a valuable nutrient for the proliferation of the lymphocytes. It also plays a crucial role in the production of cytokines, macrophages, phagocytic, and neutrophil to kill the bacteria. Most of the metabolic organs like the liver, gut, and skeletal muscles control the circulation and availability secretion of glutamine. In catabolic and hypercatabolic conditions, glutamine can turn out to be essential and plays a vital role in metabolism; however, availability may be compromised due to the impairment of homeostasis in the inter-tissue metabolism of amino acids. This is why the supplementation of glutamine is commonly used in clinical nutrition and is especially recommended to immune-suppressed persons. Despite this, in catabolic and hyper-catabolic conditions, it is challenging due to the amino acid concentration in plasma/bloodstream and glutamine should be provided via either the oral, enteral or parenteral route. However, the effect of glutamine as an immune-based supplement has been previously recognized as many research studies conducted in vivo and in-vitro evaluated the beneficial effects of glutamine. Hence, the present study delivers a combined review of glutamine metabolism in essential organs of the cell immune system. In this review, we have also reviewed the metabolism and action of glutamine and crucial problems due to glutamine supplementation in catabolic conditions.
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44
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Orliaguet L, Dalmas E, Drareni K, Venteclef N, Alzaid F. Mechanisms of Macrophage Polarization in Insulin Signaling and Sensitivity. Front Endocrinol (Lausanne) 2020; 11:62. [PMID: 32140136 PMCID: PMC7042402 DOI: 10.3389/fendo.2020.00062] [Citation(s) in RCA: 72] [Impact Index Per Article: 14.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/03/2019] [Accepted: 01/30/2020] [Indexed: 12/11/2022] Open
Abstract
Type-2 diabetes (T2D) is a disease of two etiologies: metabolic and inflammatory. At the cross-section of these etiologies lays the phenomenon of metabolic inflammation. Whilst metabolic inflammation is characterized as systemic, a common starting point is the tissue-resident macrophage, who's successful physiological or aberrant pathological adaptation to its microenvironment determines disease course and severity. This review will highlight the key mechanisms in macrophage polarization, inflammatory and non-inflammatory signaling that dictates the development and progression of insulin resistance and T2D. We first describe the known homeostatic functions of tissue macrophages in insulin secreting and major insulin sensitive tissues. Importantly we highlight the known mechanisms of aberrant macrophage activation in these tissues and the ways in which this leads to impairment of insulin sensitivity/secretion and the development of T2D. We next describe the cellular mechanisms that are known to dictate macrophage polarization. We review recent progress in macrophage bio-energetics, an emerging field of research that places cellular metabolism at the center of immune-effector function. Importantly, following the advent of the metabolically-activated macrophage, we cover the known transcriptional and epigenetic factors that canonically and non-canonically dictate macrophage differentiation and inflammatory polarization. In closing perspectives, we discuss emerging research themes and highlight novel non-inflammatory or non-immune roles that tissue macrophages have in maintaining microenvironmental and systemic homeostasis.
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Affiliation(s)
- Lucie Orliaguet
- Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, USPC, Université Paris Descartes, Université Paris Diderot, Paris, France
| | - Elise Dalmas
- Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, USPC, Université Paris Descartes, Université Paris Diderot, Paris, France
| | - Karima Drareni
- Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, USPC, Université Paris Descartes, Université Paris Diderot, Paris, France
- Institute for Diabetes, Obesity and Metabolism, University of Pennsylvania, Philadelphia, PA, United States
| | - Nicolas Venteclef
- Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, USPC, Université Paris Descartes, Université Paris Diderot, Paris, France
| | - Fawaz Alzaid
- Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, USPC, Université Paris Descartes, Université Paris Diderot, Paris, France
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45
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Bouchery T, Coakley G, Harris N. Tissue Location Drives the Metabolic Re-Profiling of Macrophages. IMMUNOMETABOLISM 2020; 2. [DOI: 10.20900/immunometab20200007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
Abstract
Abstract
That metabolic phenotype can dictate the function of macrophages has been widely demonstrated in vitro, however in vivo relevance of these findings has been lacking. Sverdberg et al., observe that the in vivo microenvironment shapes the ability of macrophages to utilize glucose and thus affects their responsiveness to stimuli.
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46
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Zuo H, Wan Y. Metabolic Reprogramming in Mitochondria of Myeloid Cells. Cells 2019; 9:cells9010005. [PMID: 31861356 PMCID: PMC7017304 DOI: 10.3390/cells9010005] [Citation(s) in RCA: 43] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2019] [Revised: 12/15/2019] [Accepted: 12/16/2019] [Indexed: 12/17/2022] Open
Abstract
The myeloid lineage consists of multiple immune cell types, such as macrophages, monocytes, and dendritic cells. It actively participates in both innate and adaptive immunity. In response to pro- or anti-inflammatory signals, these cells undergo distinct programmed metabolic changes especially in mitochondria. Pro-inflammatory signals induce not only a simple shift from oxidative phosphorylation to glycolysis, but also complicated metabolic alterations during the early and tolerant stages in myeloid cells. In mitochondria, a broken Krebs cycle leads to the accumulation of two metabolites, citrate and succinate, both of which trigger pro-inflammatory responses of myeloid cells. A deficient electron transport chain induces pro-inflammatory responses in the resting myeloid cells while it suppresses these responses in the polarized cells during inflammation. The metabolic reprogramming in mitochondria is also associated with altered mitochondrial morphology. On the other hand, intact oxidative phosphorylation is required for the anti-inflammatory functions of myeloid cells. Fatty acid synthesis is essential for the pro-inflammatory effect and glutamine metabolism in mitochondria exhibits the anti-inflammatory effect. A few aspects of metabolic reprogramming remain uncertain, for example, glycolysis and fatty acid oxidation in anti-inflammation. Overall, metabolic reprogramming is an important element of immune responses in myeloid cells.
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Affiliation(s)
- Hao Zuo
- Department of Pharmacology, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Yihong Wan
- Department of Pharmacology, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
- Harold C. Simmons Comprehensive Cancer Center, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
- Hamon Center for Regenerative Science and Medicine, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
- Correspondence: ; Tel.: +1-214-645-6062
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Martano G, Borroni EM, Lopci E, Cattaneo MG, Mattioli M, Bachi A, Decimo I, Bifari F. Metabolism of Stem and Progenitor Cells: Proper Methods to Answer Specific Questions. Front Mol Neurosci 2019; 12:151. [PMID: 31249511 PMCID: PMC6584756 DOI: 10.3389/fnmol.2019.00151] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2019] [Accepted: 05/28/2019] [Indexed: 01/01/2023] Open
Abstract
Stem cells can stay quiescent for a long period of time or proliferate and differentiate into multiple lineages. The activity of stage-specific metabolic programs allows stem cells to best adapt their functions in different microenvironments. Specific cellular phenotypes can be, therefore, defined by precise metabolic signatures. Notably, not only cellular metabolism describes a defined cellular phenotype, but experimental evidence now clearly indicate that also rewiring cells towards a particular cellular metabolism can drive their cellular phenotype and function accordingly. Cellular metabolism can be studied by both targeted and untargeted approaches. Targeted analyses focus on a subset of identified metabolites and on their metabolic fluxes. In addition, the overall assessment of the oxygen consumption rate (OCR) gives a measure of the overall cellular oxidative metabolism and mitochondrial function. Untargeted approach provides a large-scale identification and quantification of the whole metabolome with the aim to describe a metabolic fingerprinting. In this review article, we overview the methodologies currently available for the study of invitro stem cell metabolism, including metabolic fluxes, fingerprint analyses, and single-cell metabolomics. Moreover, we summarize available approaches for the study of in vivo stem cell metabolism. For all of the described methods, we highlight their specificities and limitations. In addition, we discuss practical concerns about the most threatening steps, including metabolic quenching, sample preparation and extraction. A better knowledge of the precise metabolic signature defining specific cell population is instrumental to the design of novel therapeutic strategies able to drive undifferentiated stem cells towards a selective and valuable cellular phenotype.
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Affiliation(s)
| | - Elena Monica Borroni
- Humanitas Clinical and Research Center, Rozzano, Italy.,Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan, Italy
| | - Egesta Lopci
- Nuclear Medicine Unit, Humanitas Clinical and Research Hospital-IRCCS, Rozzano, Italy
| | - Maria Grazia Cattaneo
- Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan, Italy
| | - Milena Mattioli
- Laboratory of Cell Metabolism and Regenerative Medicine, Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan, Italy
| | - Angela Bachi
- IFOM-FIRC Institute of Molecular Oncology, Milan, Italy
| | - Ilaria Decimo
- Laboratory of Pharmacology, Department of Diagnostics and Public Health, University of Verona, Verona, Italy
| | - Francesco Bifari
- Laboratory of Cell Metabolism and Regenerative Medicine, Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan, Italy
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Zhang S, Bories G, Lantz C, Emmons R, Becker A, Liu E, Abecassis MM, Yvan-Charvet L, Thorp EB. Immunometabolism of Phagocytes and Relationships to Cardiac Repair. Front Cardiovasc Med 2019; 6:42. [PMID: 31032261 PMCID: PMC6470271 DOI: 10.3389/fcvm.2019.00042] [Citation(s) in RCA: 39] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2018] [Accepted: 03/22/2019] [Indexed: 12/21/2022] Open
Abstract
Cardiovascular disease remains the leading cause of death worldwide. Myocardial ischemia is a major contributor to cardiovascular morbidity and mortality. In the case of acute myocardial infarction, subsequent cardiac repair relies upon the acute, and coordinated response to injury by innate myeloid phagocytes. This includes neutrophils, monocytes, macrophage subsets, and immature dendritic cells. Phagocytes function to remove necrotic cardiomyocytes, apoptotic inflammatory cells, and to remodel extracellular matrix. These innate immune cells also secrete cytokines and growth factors that promote tissue replacement through fibrosis and angiogenesis. Within the injured myocardium, macrophages polarize from pro-inflammatory to inflammation-resolving phenotypes. At the core of this functional plasticity is cellular metabolism, which has gained an appreciation for its integration with phagocyte function and remodeling of the transcriptional and epigenetic landscape. Immunometabolic rewiring is particularly relevant after ischemia and clinical reperfusion given the rapidly changing oxygen and metabolic milieu. Hypoxia reduces mitochondrial oxidative phosphorylation and leads to increased reliance on glycolysis, which can support biosynthesis of pro-inflammatory cytokines. Reoxygenation is permissive for shifts back to mitochondrial metabolism and fatty acid oxidation and this is ultimately linked to pro-reparative macrophage polarization. Improved understanding of mechanisms that regulate metabolic adaptations holds the potential to identify new metabolite targets and strategies to reduce cardiac damage through nutrient signaling.
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Affiliation(s)
- Shuang Zhang
- Departments of Pathology and Pediatrics, Feinberg Cardiovascular and Renal Research Institute, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
| | - Gael Bories
- UMR INSERM U1065/UNS, C3M, Bâtiment Universitaire ARCHIMED, Nice, France
| | - Connor Lantz
- Departments of Pathology and Pediatrics, Feinberg Cardiovascular and Renal Research Institute, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
| | - Russel Emmons
- Departments of Pathology and Pediatrics, Feinberg Cardiovascular and Renal Research Institute, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
| | - Amanda Becker
- Department of Pediatrics, Ann & Robert H. Lurie Children's Hospital of Chicago, Northwestern University, Chicago, IL, United States
| | - Esther Liu
- Departments of Pathology and Pediatrics, Feinberg Cardiovascular and Renal Research Institute, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
| | - Michael M. Abecassis
- Comprehensive Transplant Center, Northwestern Feinberg School of Medicine, Chicago, IL, United States
| | | | - Edward B. Thorp
- Departments of Pathology and Pediatrics, Feinberg Cardiovascular and Renal Research Institute, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
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49
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Zhang S, Weinberg S, DeBerge M, Gainullina A, Schipma M, Kinchen JM, Ben-Sahra I, Gius DR, Yvan-Charvet L, Chandel NS, Schumacker PT, Thorp EB. Efferocytosis Fuels Requirements of Fatty Acid Oxidation and the Electron Transport Chain to Polarize Macrophages for Tissue Repair. Cell Metab 2019; 29:443-456.e5. [PMID: 30595481 PMCID: PMC6471613 DOI: 10.1016/j.cmet.2018.12.004] [Citation(s) in RCA: 289] [Impact Index Per Article: 48.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/15/2018] [Revised: 09/22/2018] [Accepted: 11/30/2018] [Indexed: 10/27/2022]
Abstract
During wound injury, efferocytosis fills the macrophage with a metabolite load nearly equal to the phagocyte itself. A timely question pertains to how metabolic phagocytic signaling regulates the signature anti-inflammatory macrophage response. Here we report the metabolome of activated macrophages during efferocytosis to reveal an interleukin-10 (IL-10) cytokine escalation that was independent of glycolysis yet bolstered by apoptotic cell fatty acids and mitochondrial β-oxidation, the electron transport chain, and heightened coenzyme NAD+. Loss of IL-10 due to mitochondrial complex III defects was remarkably rescued by adding NAD+ precursors. This activated a SIRTUIN1 signaling cascade, largely independent of ATP, that culminated in activation of IL-10 transcription factor PBX1. Il-10 activation by the respiratory chain was also important in vivo, as efferocyte mitochondrial dysfunction led to cardiac rupture after myocardial injury. These findings highlight a new paradigm whereby macrophages leverage efferocytic metabolites and electron transport for anti-inflammatory reprogramming that culminates in organ repair.
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Affiliation(s)
- Shuang Zhang
- Department of Pathology, Feinberg School of Medicine, Chicago, IL, USA; Feinberg Cardiovascular & Renal Research Institute, Feinberg School of Medicine, Chicago, IL, USA
| | - Samuel Weinberg
- Department of Medicine, Feinberg School of Medicine, Chicago, IL, USA
| | - Matthew DeBerge
- Department of Pathology, Feinberg School of Medicine, Chicago, IL, USA; Feinberg Cardiovascular & Renal Research Institute, Feinberg School of Medicine, Chicago, IL, USA
| | - Anastasiia Gainullina
- ITMO University, Saint Petersburg, Russia; Washington University in St. Louis, St. Louis, MO, USA
| | - Matthew Schipma
- Feinberg Cardiovascular & Renal Research Institute, Feinberg School of Medicine, Chicago, IL, USA
| | | | - Issam Ben-Sahra
- Department of Pharmacology, Feinberg School of Medicine, Chicago, IL, USA
| | - David R Gius
- Department of Radiation Oncology, Feinberg School of Medicine, Chicago, IL, USA
| | - Laurent Yvan-Charvet
- Institut National de la Sante et de la Recherche Medicale (INSERM) U1065, Centre Mediterraneen de Medecine Moleculaire (C3M), Atip-Avenir, Nice, France
| | - Navdeep S Chandel
- Department of Medicine, Feinberg School of Medicine, Chicago, IL, USA
| | - Paul T Schumacker
- Department of Pediatrics, Feinberg School of Medicine, Chicago, IL, USA
| | - Edward B Thorp
- Department of Pathology, Feinberg School of Medicine, Chicago, IL, USA; Feinberg Cardiovascular & Renal Research Institute, Feinberg School of Medicine, Chicago, IL, USA.
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50
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Cruzat V, Macedo Rogero M, Noel Keane K, Curi R, Newsholme P. Glutamine: Metabolism and Immune Function, Supplementation and Clinical Translation. Nutrients 2018; 10:nu10111564. [PMID: 30360490 PMCID: PMC6266414 DOI: 10.3390/nu10111564] [Citation(s) in RCA: 642] [Impact Index Per Article: 91.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2018] [Revised: 10/13/2018] [Accepted: 10/16/2018] [Indexed: 02/07/2023] Open
Abstract
Glutamine is the most abundant and versatile amino acid in the body. In health and disease, the rate of glutamine consumption by immune cells is similar or greater than glucose. For instance, in vitro and in vivo studies have determined that glutamine is an essential nutrient for lymphocyte proliferation and cytokine production, macrophage phagocytic plus secretory activities, and neutrophil bacterial killing. Glutamine release to the circulation and availability is mainly controlled by key metabolic organs, such as the gut, liver, and skeletal muscles. During catabolic/hypercatabolic situations glutamine can become essential for metabolic function, but its availability may be compromised due to the impairment of homeostasis in the inter-tissue metabolism of amino acids. For this reason, glutamine is currently part of clinical nutrition supplementation protocols and/or recommended for immune suppressed individuals. However, in a wide range of catabolic/hypercatabolic situations (e.g., ill/critically ill, post-trauma, sepsis, exhausted athletes), it is currently difficult to determine whether glutamine supplementation (oral/enteral or parenteral) should be recommended based on the amino acid plasma/bloodstream concentration (also known as glutaminemia). Although the beneficial immune-based effects of glutamine supplementation are already established, many questions and evidence for positive in vivo outcomes still remain to be presented. Therefore, this paper provides an integrated review of how glutamine metabolism in key organs is important to cells of the immune system. We also discuss glutamine metabolism and action, and important issues related to the effects of glutamine supplementation in catabolic situations.
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Affiliation(s)
- Vinicius Cruzat
- School of Pharmacy and Biomedical Sciences, Curtin Health Innovation Research Institute, Biosciences, Curtin University, Perth 6102, Australia.
- Faculty of Health, Torrens University, Melbourne 3065, Australia.
| | - Marcelo Macedo Rogero
- Department of Nutrition, Faculty of Public Health, University of São Paulo, Avenida Doutor Arnaldo 715, São Paulo 01246-904, Brazil.
| | - Kevin Noel Keane
- School of Pharmacy and Biomedical Sciences, Curtin Health Innovation Research Institute, Biosciences, Curtin University, Perth 6102, Australia.
| | - Rui Curi
- Interdisciplinary Post-Graduate Program in Health Sciences, Cruzeiro do Sul University, São Paulo 01506-000, Brazil.
| | - Philip Newsholme
- School of Pharmacy and Biomedical Sciences, Curtin Health Innovation Research Institute, Biosciences, Curtin University, Perth 6102, Australia.
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