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1
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Fan G, Liu Y, Tao L, Wang D, Huang Y, Yang X. Sodium butyrate alleviates colitis by inhibiting mitochondrial ROS mediated macrophage pyroptosis. Biochim Biophys Acta Mol Basis Dis 2025; 1871:167756. [PMID: 40044062 DOI: 10.1016/j.bbadis.2025.167756] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2024] [Revised: 02/06/2025] [Accepted: 02/26/2025] [Indexed: 04/15/2025]
Abstract
Inflammatory bowel disease (IBD) is a chronic inflammatory bowel disease with unclear causes and limited treatment options. Sodium butyrate (NaB), a byproduct of dietary fiber in the intestine, has demonstrated efficacy in treating inflammation. However, the precise anti-inflammatory mechanisms of NaB in colon inflammation remain largely unexplored. This study aims to investigate the effects of NaB on dextran sulfate sodium (DSS)-induced colitis in rats. The findings indicate that oral administration of NaB effectively prevent colitis and reduce levels of serum or colon inflammatory factors. Additionally, NaB demonstrated in vitro inhibition of RAW264.7 inflammation cytokines induced by LPS, along with suppression of the ERK and NF-κB signaling pathway activation. Moreover, NaB mitigated LPS and Nigericin-induced RAW264.7 pyroptosis by reducing indicators of mitochondrial damage, including increased mitochondrial membrane potential (JC-1) levels and decreased Mito-ROS production. NaB increases ZO-1 and Occludin expression in CaCo2 cells by inhibiting RAW264.7 pyroptosis. These results suggest that NaB could be utilized as a therapeutic agent or dietary supplement to alleviate colitis.
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Affiliation(s)
- Guoqiang Fan
- Key Laboratory of Animal Physiology & Biochemistry, Nanjing Agricultural University, Nanjing 210095, PR China
| | - Yaxin Liu
- Key Laboratory of Animal Physiology & Biochemistry, Nanjing Agricultural University, Nanjing 210095, PR China
| | - Limei Tao
- Key Laboratory of Animal Physiology & Biochemistry, Nanjing Agricultural University, Nanjing 210095, PR China
| | - Danping Wang
- Key Laboratory of Animal Physiology & Biochemistry, Nanjing Agricultural University, Nanjing 210095, PR China
| | - Yizhu Huang
- Singao Xiamen Company, Xiamen 361006, PR China
| | - Xiaojing Yang
- Key Laboratory of Animal Physiology & Biochemistry, Nanjing Agricultural University, Nanjing 210095, PR China; MOE Joint International Research Laboratory of Animal Health and Food Safety, Nanjing Agricultural University, Nanjing 210095, PR China.
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2
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Ogger PP, Murray PJ. Dissecting inflammation in the immunemetabolomic era. Cell Mol Life Sci 2025; 82:182. [PMID: 40293552 PMCID: PMC12037969 DOI: 10.1007/s00018-025-05715-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2025] [Revised: 04/11/2025] [Accepted: 04/12/2025] [Indexed: 04/30/2025]
Abstract
The role of immune metabolism, specific metabolites and cell-intrinsic and -extrinsic metabolic states across the time course of an inflammatory response are emerging knowledge. Targeted and untargeted metabolomic analysis is essential to understand how immune cells adapt their metabolic program throughout an immune response. In addition, metabolomic analysis can aid to identify pathophysiological patterns in inflammatory disease. Here, we discuss new metabolomic findings within the transition from inflammation to resolution, focusing on three key programs of immunity: Efferocytosis, IL-10 signaling and trained immunity. Particularly the tryptophan-derived metabolite kynurenine was identified as essential for efferocytosis and inflammation resolution as well as a potential biomarker in diverse inflammatory conditions. In summary, metabolomic analysis and integration with transcriptomic and proteomic data, high resolution imaging and spatial information is key to unravel metabolic drivers and dependencies during inflammation and progression to tissue-repair.
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Affiliation(s)
- Patricia P Ogger
- Immunoregulation Research Group, Max Planck Institute of Biochemistry, Martinsried, 82152, Germany
| | - Peter J Murray
- Immunoregulation Research Group, Max Planck Institute of Biochemistry, Martinsried, 82152, Germany.
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3
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Zhang Z, Liu Y, Yu T, Liu Z. Unraveling the Complex Nexus of Macrophage Metabolism, Periodontitis, and Associated Comorbidities. J Innate Immun 2025; 17:211-225. [PMID: 40058341 PMCID: PMC11968099 DOI: 10.1159/000542531] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2024] [Accepted: 11/07/2024] [Indexed: 04/05/2025] Open
Abstract
BACKGROUND Periodontitis is recognized as one of the most prevalent oral dysbiotic inflammatory diseases, ultimately leading to the irreversible destruction of periodontal tissues. Macrophages play a pivotal role in the development and progression of periodontitis, and the feasibility of targeting them therapeutically has been established. Since metabolic switching significantly contributes to macrophage regulation, conducting an in-depth review of macrophage metabolism in periodontitis may serve as the foundation for developing innovative treatments. SUMMARY This paper has been carefully reviewed to provide a comprehensive overview of the roles played by macrophages in periodontitis and associated comorbidities. Initially, detailed presentations on the metabolic reprogramming of macrophages, including glucose, lipid, and amino acid metabolism, were provided. Subsequently, dominating macrophage phenotype and metabolism under lipopolysaccharide (LPS) stimulation or during periodontitis were presented with emphasize on critical molecules involved. Furthermore, in recognition of the close association between periodontitis and several comorbidities, the interaction among macrophage metabolism, periodontitis, and related metabolic diseases, was thoroughly discussed. KEY MESSAGES Through the examination of current research on macrophage metabolic reprogramming induced by periodontitis, this review provides potential immunometabolic therapeutic targets for the future and raises many important, yet unstudied, subjects for follow-up. BACKGROUND Periodontitis is recognized as one of the most prevalent oral dysbiotic inflammatory diseases, ultimately leading to the irreversible destruction of periodontal tissues. Macrophages play a pivotal role in the development and progression of periodontitis, and the feasibility of targeting them therapeutically has been established. Since metabolic switching significantly contributes to macrophage regulation, conducting an in-depth review of macrophage metabolism in periodontitis may serve as the foundation for developing innovative treatments. SUMMARY This paper has been carefully reviewed to provide a comprehensive overview of the roles played by macrophages in periodontitis and associated comorbidities. Initially, detailed presentations on the metabolic reprogramming of macrophages, including glucose, lipid, and amino acid metabolism, were provided. Subsequently, dominating macrophage phenotype and metabolism under lipopolysaccharide (LPS) stimulation or during periodontitis were presented with emphasize on critical molecules involved. Furthermore, in recognition of the close association between periodontitis and several comorbidities, the interaction among macrophage metabolism, periodontitis, and related metabolic diseases, was thoroughly discussed. KEY MESSAGES Through the examination of current research on macrophage metabolic reprogramming induced by periodontitis, this review provides potential immunometabolic therapeutic targets for the future and raises many important, yet unstudied, subjects for follow-up.
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Affiliation(s)
- Zihan Zhang
- The State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Orthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Yi Liu
- The State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Orthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, China,
| | - Tian Yu
- Department of Stomatology, Nanbu Country People's Hospital, Nanchong, China
| | - Zhen Liu
- Department of Stomatology, Affiliated Hospital of North Sichuan Medical College, Nanchong, China
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Chang K, Luo P, Guo Z, Yang L, Pu J, Han F, Cai F, Tang J, Wang X. Lipid Metabolism: An Emerging Player in Sjögren's Syndrome. Clin Rev Allergy Immunol 2025; 68:15. [PMID: 39934534 PMCID: PMC11813826 DOI: 10.1007/s12016-025-09023-8] [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] [Accepted: 01/07/2025] [Indexed: 02/13/2025]
Abstract
Sjögren's syndrome (SS) is a chronic autoimmune disorder that primarily affects the exocrine glands. Due to the intricate nature of the disease progression, the exact mechanisms underlying SS are not completely understood. Recent research has highlighted the complex interplay between immune dysregulation and metabolic abnormalities in inflammatory diseases. Notably, lipid metabolism has emerged as a crucial factor in the modulation of immune function and the progression of autoimmune diseases, including SS. This review explores the prevalence of dyslipidemia in SS, emphasizing its role in the onset, progression, and prognosis of the disease. We specifically described the impact of altered lipid metabolism in exocrine glands and its association with disease-specific features, including inflammation and glandular dysfunction. Additionally, we discussed the potential clinical implications of lipid metabolism regulation, including the role of polyunsaturated fatty acids (PUFAs) and their deficits in SS pathogenesis. By identifying lipid metabolism as a promising therapeutic target, this review highlights the need for further research into lipid-based interventions for the management of SS.
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Affiliation(s)
- Keni Chang
- Department of Rheumatology and Immunology, School of Medicine, Tongji Hospital, Tongji University, No. 389 Xincun Road, Shanghai, 200065, China
| | - Peiming Luo
- Department of Rheumatology and Immunology, School of Medicine, Tongji Hospital, Tongji University, No. 389 Xincun Road, Shanghai, 200065, China
| | - Zizhen Guo
- Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Lufei Yang
- Department of Rheumatology and Immunology, School of Medicine, Tongji Hospital, Tongji University, No. 389 Xincun Road, Shanghai, 200065, China
| | - Jincheng Pu
- Department of Rheumatology and Immunology, School of Medicine, Tongji Hospital, Tongji University, No. 389 Xincun Road, Shanghai, 200065, China
| | - Fang Han
- Department of Rheumatology and Immunology, School of Medicine, Tongji Hospital, Tongji University, No. 389 Xincun Road, Shanghai, 200065, China
| | - Feiyang Cai
- Department of Experimental Medicine, Faculty of Medicine, McGill University, Montréal, Québec, Canada
- Gerald Bronfman Department of Oncology, Segal Cancer Centre, Lady Davis Institute and Jewish General Hospital, McGill University, Montreal, QC, Canada
| | - Jianping Tang
- Department of Rheumatology and Immunology, School of Medicine, Tongji Hospital, Tongji University, No. 389 Xincun Road, Shanghai, 200065, China.
| | - Xuan Wang
- Department of Rheumatology and Immunology, School of Medicine, Tongji Hospital, Tongji University, No. 389 Xincun Road, Shanghai, 200065, China.
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Li W, Liu H, Zheng J, Wang D, Wang Z, Hong M, Zhou Y. Kaempferol modulates ɑ2M secretion in bone marrow-derived macrophages by downregulating GR/PER1-mediated lipid metabolism to attenuate the emotional stress-aggravated metastasis of prostate cancer. JOURNAL OF ETHNOPHARMACOLOGY 2025; 339:119162. [PMID: 39603396 DOI: 10.1016/j.jep.2024.119162] [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: 09/10/2024] [Revised: 11/09/2024] [Accepted: 11/25/2024] [Indexed: 11/29/2024]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Prostate cancer patients often suffer from depression during androgen deprivation therapy. Chaihu-Shugan-San (CSS) can prevent prostate cancer metastasis caused by chronic unpredictable mild stress (CUMS), but its active ingredients and molecular mechanism remain unelucidated. AIM OF STUDY This study aims to explore the potential targets and molecular mechanisms of CSS in the treatment of emotional stress-aggravated metastasis of prostate cancer. RESULTS Stress induces nuclear translocation of GR, initiating the transcription of PER1, which leads to an enhanced lipid metabolism and decreased secretion of α2M in BMDMs. CSS, a classical Traditional Chinese Medicine (TCM) formula for alleviating depression, can improve prostate cancer metastasis caused by CUMS. Of the active ingredients in CSS, kaempferol demonstrated the highest potency for enhancing α2M secretion in BMDMs and inhibiting prostate cancer cell migration. Kaempferol also inhibited nuclear translocation of GR and the GR/PER1 pathway in Per1-overexpressed BMDMs. CONCLUSIONS These findings reveal that emotional stress-aggravated prostate cancer growth and metastasis rely on the GR/PER1 pathway and lipid metabolism, as the suppression of this pathway ultimately leads to an increase in α2M secretion in BMDMs and inhibition of PC-3 cell metastasis.
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Affiliation(s)
- Wei Li
- School of Integrated Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, 210023, China; Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Hao Liu
- School of Integrated Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Jie Zheng
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China; Department of Pharmacology, School of Medicine, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Dechao Wang
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, 210009, China
| | - Zhiying Wang
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, 210009, China
| | - Min Hong
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Yuxin Zhou
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, 210009, China.
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Griffin KV, Saunders MN, Lyssiotis CA, Shea LD. Engineering immunity using metabolically active polymeric nanoparticles. Trends Biotechnol 2024:S0167-7799(24)00345-7. [PMID: 39732608 DOI: 10.1016/j.tibtech.2024.11.016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2024] [Revised: 11/12/2024] [Accepted: 11/19/2024] [Indexed: 12/30/2024]
Abstract
Immune system functions play crucial roles in both health and disease, and these functions are regulated by their metabolic programming. The field of immune engineering has emerged to develop therapeutic strategies, including polymeric nanoparticles (NPs), that can direct immune cell phenotype and function by directing immunometabolic changes. Precise control of bioenergetic processes may offer the opportunity to prevent undesired immune activity and improve disease-specific outcomes. In this review we discuss the role that polymeric NPs can play in shaping immunometabolism and subsequent immune system activity through particle-mediated delivery of metabolically active agents as either structural components or cargo.
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Affiliation(s)
- Kate V Griffin
- Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, USA
| | - Michael N Saunders
- Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, USA
| | - Costas A Lyssiotis
- Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, USA; Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, MI, USA; Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA.
| | - Lonnie D Shea
- Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, USA; Department of Chemical Engineering, University of Michigan, Ann Arbor, MI, USA.
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7
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Song G, Li M, Zhou B, Qi H, Guo J. Streptococcus mutans outer membrane vesicles affect inflammasome activation and the glycolysis of macrophages. Microb Pathog 2024; 196:106994. [PMID: 39366588 DOI: 10.1016/j.micpath.2024.106994] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2024] [Revised: 09/21/2024] [Accepted: 10/01/2024] [Indexed: 10/06/2024]
Abstract
Recent studies indicate that bacterial outer membrane vesicles (OMVs) play a significant role in bacterial virulence and pathogenicity. Streptococcus mutans (S. mutans), a principal pathogen in dental caries, secretes a substantial number of OMVs. However, the impact of S. mutans OMVs on oral health and their underlying pathogenic mechanisms remain poorly understood. Macrophages were the initial innate immune cells to respond to bacterial invaders and their products. Therefore, we purified S. mutans OMVs, which stimulated macrophages. Compared to controls, RT-PCR and ELISA analyses revealed that S. mutans OMVs significantly increased the production of IL-1β, IL-6, TNF-α and IL-8, with IL-1β being notably elevated. IL-1β production and secretion are tightly regulated by the inflammasome. Western blot analyses demonstrated that S. mutans OMVs upregulated the expression of inflammasome components, including NLRP3, NLRC4, ASC and AIM2, with a marked increase in NLRP3 expression. Silencing different inflammasome components with siRNA revealed a reduction in IL-1β secretion induced by S. mutans OMVs, particularly through NLRP3. Additionally, ATP production and K+ efflux were found to be crucial for NLRP3 activation. Prolonged stimulation with S. mutans OMVs resulted in increased lactate production and elevated expression of glycolysis-related genes Glut-1, PFKFB3, and HK I, indicating that S. mutans OMVs significantly induce macrophage glycolysis. Furthermore, S. mutans OMVs were shown to enhance biofilm formation, increase S. mutans colonisation on epithelial cells, and inhibit macrophage phagocytosis, thereby improving the survival of S. mutans in the oral cavity. In summary, S. mutans OMVs promote the survival of S. mutans in the mouth through multiple mechanisms, potentially influencing the development of dental caries.
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Affiliation(s)
- Gongyuan Song
- The Second Hospital of Shijiazhuang, Shijiazhuang, 050000, China
| | - Min Li
- Handan Stomatology Hospital, Handan, 056000, China
| | - Bing Zhou
- Cangzhou People's Hospital, Cangzhou, 061000, China
| | - Hongguang Qi
- Gucheng County Hospital of Hebei Provence, Gucheng, 253800, China
| | - Jie Guo
- Department of Stomatology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, 050000, China.
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Bezze A, Mattioda C, Ciardelli G, Mattu C. Harnessing cells to improve transport of nanomedicines. Eur J Pharm Biopharm 2024; 203:114446. [PMID: 39122052 DOI: 10.1016/j.ejpb.2024.114446] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2024] [Revised: 07/18/2024] [Accepted: 08/05/2024] [Indexed: 08/12/2024]
Abstract
Efficient tumour treatment is hampered by the poor selectivity of anticancer drugs, resulting in scarce tumour accumulation and undesired off-target effects. Nano-sized drug-delivery systems in the form of nanoparticles (NPs) have been proposed to improve drug distribution to solid tumours, by virtue of their ability of passive and active tumour targeting. Despite these advantages, literature studies indicated that less than 1% of the administered NPs can successfully reach the tumour mass, highlighting the necessity for more efficient drug transporters in cancer treatment. Living cells, such as blood cells, circulating immune cells, platelets, and stem cells, are often found as an infiltrating component in most solid tumours, because of their ability to naturally circumvent immune recognition, bypass biological barriers, and reach inaccessible tissues through innate tropism and active motility. Therefore, the tumour-homing ability of these cells can be harnessed to design living cell carriers able to improve the transport of drugs and NPs to tumours. Albeit promising, this approach is still in its beginnings and suffers from difficult scalability, high cost, and poor reproducibility. In this review, we present an overview of the most common cell transporters of drugs and NPs, and we discuss how different cell types interact with biological barriers to deliver cargoes of various natures to tumours. Finally, we analyse the different techniques used to load drugs or NPs in living cells and discuss their advantages and disadvantages.
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Affiliation(s)
- Andrea Bezze
- Politecnico di Torino - DIMEAS, C.so Duca degli Abruzzi 24, 10129 Torino, Italy
| | - Carlotta Mattioda
- Politecnico di Torino - DIMEAS, C.so Duca degli Abruzzi 24, 10129 Torino, Italy
| | - Gianluca Ciardelli
- Politecnico di Torino - DIMEAS, C.so Duca degli Abruzzi 24, 10129 Torino, Italy
| | - Clara Mattu
- Politecnico di Torino - DIMEAS, C.so Duca degli Abruzzi 24, 10129 Torino, Italy.
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Li J, Guo T, Li Y, Wang Q, Du Y, Li R, Lin J, Fu J, Chen X, Luo S. Adipose stem cells regulate lipid metabolism by upregulating mitochondrial fatty acid β-oxidation in macrophages to improve the retention rate of transplanted fat. Stem Cell Res Ther 2024; 15:328. [PMID: 39334483 PMCID: PMC11438425 DOI: 10.1186/s13287-024-03953-4] [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: 06/12/2024] [Accepted: 09/19/2024] [Indexed: 09/30/2024] Open
Abstract
BACKGROUND At present, fat transplantation is widely used in the plastic surgery industry, but the long-term preservation rate of transplanted fat decreases because of complications such as oil cysts due to the inability in macrophages to metabolize absorption. In cell-assisted lipotransfer technology, adipose-derived stem cells (ASCs) can influence the inflammatory response of grafts through the immunoregulation in macrophages, and the lipid metabolism in macrophages plays an important role in this process. Therefore, we hypothesized ASCs could improve the retention rate of fat grafts by regulating the progress of lipid metabolism in macrophages. METHODS We established fat transplantation and ASC-assisted fat transplantation model in C57BL/6 mice in vivo, and bone marrow-derived macrophages cocultured with apoptotic adipocytes were treated with or without ASCs in vitro. Graft retention, tissue structure, fibrosis, macrophage phenotype transformation, lipid deposition, mitochondrial morphology, oxygen consumption rate (OCR), fatty acid β-oxidation (FAO) level, and ATP production were assessed. Additionally, fat transplantation and ASC-assisted fat transplantation model was treated with etomoxir which inhibits mitochondrial FAO. Macrophages pretreated with etomoxir were co-cultured with apoptotic adipocytes and treated with or without ASCs. The method aboved was used for detection and verification. RESULTS In vivo, ASC-assisted fat transplantation improved macrophage mitochondrial expression and FAO level, promoted the early transformation of M2 macrophages, reduced the long-term lipid deposition of macrophages, and improved the retention rate of fat grafts. In vitro, ASCs up-regulated the level of mitochondrial FAO, OCR and ATP production in macrophages, reduced lipid deposition of macrophages and promoted M2 macrophages polarization by paracine function. The ability of ASCs in group pretreated with etomoxir to reduce the foaming of macrophages, promote the transformation to M2 macrophages, and improve the retention rate of fat transplantation was weakened. CONCLUSIONS ASCs increased the retention rate of transplanted fat by upregulating mitochondrial FAO to promote M2 polaration in macrophages. In addition, ASCs up-regulate mitochondrial FAO by paracrine effect to reduce foam cells formation and promote M2 transformation in macrophages in vitro.
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Affiliation(s)
- Jiapeng Li
- The Plastic and Aesthetic Center, The First Affiliated Hospital of Harbin Medical University, No. 23 Youzheng Street, Nangang District, Harbin, 150000, Heilongjiang, People's Republic of China
- NHC Key Laboratory of Cell Transplantation, Harbin Medical University, Heilongjiang, 150000, China
| | - Tingting Guo
- The Plastic and Aesthetic Center, The First Affiliated Hospital of Harbin Medical University, No. 23 Youzheng Street, Nangang District, Harbin, 150000, Heilongjiang, People's Republic of China
- NHC Key Laboratory of Cell Transplantation, Harbin Medical University, Heilongjiang, 150000, China
| | - Ye Li
- Department of Plastic and Cosmetic Surgery, Nanfang Hospital, Southern Medical University, Guangdong, 510515, China
| | - Qing Wang
- The Plastic and Aesthetic Center, The First Affiliated Hospital of Harbin Medical University, No. 23 Youzheng Street, Nangang District, Harbin, 150000, Heilongjiang, People's Republic of China
- NHC Key Laboratory of Cell Transplantation, Harbin Medical University, Heilongjiang, 150000, China
| | - Yuyang Du
- The Plastic and Aesthetic Center, The First Affiliated Hospital of Harbin Medical University, No. 23 Youzheng Street, Nangang District, Harbin, 150000, Heilongjiang, People's Republic of China
- NHC Key Laboratory of Cell Transplantation, Harbin Medical University, Heilongjiang, 150000, China
| | - Rou Li
- China-Japan Friendship Hospital (Institute of Clinical Medical Sciences), Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100029, China
| | - Jiani Lin
- The Plastic and Aesthetic Center, The First Affiliated Hospital of Harbin Medical University, No. 23 Youzheng Street, Nangang District, Harbin, 150000, Heilongjiang, People's Republic of China
- NHC Key Laboratory of Cell Transplantation, Harbin Medical University, Heilongjiang, 150000, China
| | - Jiayue Fu
- The Plastic and Aesthetic Center, The First Affiliated Hospital of Harbin Medical University, No. 23 Youzheng Street, Nangang District, Harbin, 150000, Heilongjiang, People's Republic of China
- NHC Key Laboratory of Cell Transplantation, Harbin Medical University, Heilongjiang, 150000, China
| | - Xinyao Chen
- The Plastic and Aesthetic Center, The First Affiliated Hospital of Harbin Medical University, No. 23 Youzheng Street, Nangang District, Harbin, 150000, Heilongjiang, People's Republic of China.
- NHC Key Laboratory of Cell Transplantation, Harbin Medical University, Heilongjiang, 150000, China.
| | - Sai Luo
- The Plastic and Aesthetic Center, The First Affiliated Hospital of Harbin Medical University, No. 23 Youzheng Street, Nangang District, Harbin, 150000, Heilongjiang, People's Republic of China.
- NHC Key Laboratory of Cell Transplantation, Harbin Medical University, Heilongjiang, 150000, China.
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10
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Chapman NM, Chi H. Metabolic rewiring and communication in cancer immunity. Cell Chem Biol 2024; 31:862-883. [PMID: 38428418 PMCID: PMC11177544 DOI: 10.1016/j.chembiol.2024.02.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2023] [Revised: 01/29/2024] [Accepted: 02/08/2024] [Indexed: 03/03/2024]
Abstract
The immune system shapes tumor development and progression. Although immunotherapy has transformed cancer treatment, its overall efficacy remains limited, underscoring the need to uncover mechanisms to improve therapeutic effects. Metabolism-associated processes, including intracellular metabolic reprogramming and intercellular metabolic crosstalk, are emerging as instructive signals for anti-tumor immunity. Here, we first summarize the roles of intracellular metabolic pathways in controlling immune cell function in the tumor microenvironment. How intercellular metabolic communication regulates anti-tumor immunity, and the impact of metabolites or nutrients on signaling events, are also discussed. We then describe how targeting metabolic pathways in tumor cells or intratumoral immune cells or via nutrient-based interventions may boost cancer immunotherapies. Finally, we conclude with discussions on profiling and functional perturbation methods of metabolic activity in intratumoral immune cells, and perspectives on future directions. Uncovering the mechanisms for metabolic rewiring and communication in the tumor microenvironment may enable development of novel cancer immunotherapies.
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Affiliation(s)
- Nicole M Chapman
- Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, USA
| | - Hongbo Chi
- Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, USA.
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11
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Miyauchi H, Geisberger S, Luft FC, Wilck N, Stegbauer J, Wiig H, Dechend R, Jantsch J, Kleinewietfeld M, Kempa S, Müller DN. Sodium as an Important Regulator of Immunometabolism. Hypertension 2024; 81:426-435. [PMID: 37675565 PMCID: PMC10863658 DOI: 10.1161/hypertensionaha.123.19489] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/08/2023]
Abstract
Salt sensitivity concerns blood pressure alterations after a change in salt intake (sodium chloride). The heart is a pump, and vessels are tubes; sodium can affect both. A high salt intake increases cardiac output, promotes vascular dysfunction and capillary rarefaction, and chronically leads to increased systemic vascular resistance. More recent findings suggest that sodium also acts as an important second messenger regulating energy metabolism and cellular functions. Besides endothelial cells and fibroblasts, sodium also affects innate and adaptive immunometabolism, immune cell function, and influences certain microbes and microbiota-derived metabolites. We propose the idea that the definition of salt sensitivity should be expanded beyond high blood pressure to cellular and molecular salt sensitivity.
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Affiliation(s)
- Hidetaka Miyauchi
- Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany (H.M., S.G., F.C.L., N.W., R.D., S.K., D.N.M.)
- Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Experimental and Clinical Research Center, Germany (H.M., F.C.L., N.W., R.D., D.N.M.)
- Experimental and Clinical Research Center, a joint cooperation of Max Delbrück Center for Molecular Medicine and Charité-Universitätsmedizin Berlin, Germany (H.M., F.C.L., N.W., R.D., D.N.M.)
- German Centre for Cardiovascular Research, Partner Site Berlin, Germany (H.M., N.W., R.D., D.N.M.)
| | - Sabrina Geisberger
- Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany (H.M., S.G., F.C.L., N.W., R.D., S.K., D.N.M.)
| | - Friedrich C. Luft
- Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany (H.M., S.G., F.C.L., N.W., R.D., S.K., D.N.M.)
- Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Experimental and Clinical Research Center, Germany (H.M., F.C.L., N.W., R.D., D.N.M.)
- Experimental and Clinical Research Center, a joint cooperation of Max Delbrück Center for Molecular Medicine and Charité-Universitätsmedizin Berlin, Germany (H.M., F.C.L., N.W., R.D., D.N.M.)
| | - Nicola Wilck
- Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany (H.M., S.G., F.C.L., N.W., R.D., S.K., D.N.M.)
- Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Experimental and Clinical Research Center, Germany (H.M., F.C.L., N.W., R.D., D.N.M.)
- Experimental and Clinical Research Center, a joint cooperation of Max Delbrück Center for Molecular Medicine and Charité-Universitätsmedizin Berlin, Germany (H.M., F.C.L., N.W., R.D., D.N.M.)
- German Centre for Cardiovascular Research, Partner Site Berlin, Germany (H.M., N.W., R.D., D.N.M.)
| | - Johannes Stegbauer
- Department of Nephrology, Faculty of Medicine, University Hospital, Heinrich-Heine-University, Düsseldorf, Germany (J.S.)
- CARID, Cardiovascular Research Institute Düsseldorf, Medical Faculty and University Hospital, Düsseldorf, Germany (J.S.)
| | - Helge Wiig
- Department of Biomedicine, University of Bergen, Norway (H.W.)
| | - Ralf Dechend
- Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany (H.M., S.G., F.C.L., N.W., R.D., S.K., D.N.M.)
- Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Experimental and Clinical Research Center, Germany (H.M., F.C.L., N.W., R.D., D.N.M.)
- Experimental and Clinical Research Center, a joint cooperation of Max Delbrück Center for Molecular Medicine and Charité-Universitätsmedizin Berlin, Germany (H.M., F.C.L., N.W., R.D., D.N.M.)
- German Centre for Cardiovascular Research, Partner Site Berlin, Germany (H.M., N.W., R.D., D.N.M.)
- HELIOS Clinic, Department of Cardiology and Nephrology, Berlin, Germany (R.D.)
| | - Jonathan Jantsch
- Institute of Clinical Microbiology and Hygiene, University Hospital Regensburg and University of Regensburg, Germany (J.J.)
- Institute for Medical Microbiology, Immunology, and Hygiene, and Center for Molecular Medicine Cologne, University Hospital Cologne and Faculty of Medicine, University of Cologne, Germany (J.J.)
| | - Markus Kleinewietfeld
- VIB Laboratory of Translational Immunomodulation, VIB Center for Inflammation Research, Hasselt University, Diepenbeek, Belgium (M.K.)
- Department of Immunology, Biomedical Research Institute, Hasselt University, Diepenbeek, Belgium (M.K.)
- University Multiple Sclerosis Center, Hasselt University/Campus Diepenbeek, Belgium (M.K.)
| | - Stefan Kempa
- Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany (H.M., S.G., F.C.L., N.W., R.D., S.K., D.N.M.)
| | - Dominik N. Müller
- Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany (H.M., S.G., F.C.L., N.W., R.D., S.K., D.N.M.)
- Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Experimental and Clinical Research Center, Germany (H.M., F.C.L., N.W., R.D., D.N.M.)
- Experimental and Clinical Research Center, a joint cooperation of Max Delbrück Center for Molecular Medicine and Charité-Universitätsmedizin Berlin, Germany (H.M., F.C.L., N.W., R.D., D.N.M.)
- German Centre for Cardiovascular Research, Partner Site Berlin, Germany (H.M., N.W., R.D., D.N.M.)
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12
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Shi W, Cassmann TJ, Bhagwate AV, Hitosugi T, Ip WKE. Lactic acid induces transcriptional repression of macrophage inflammatory response via histone acetylation. Cell Rep 2024; 43:113746. [PMID: 38329873 PMCID: PMC10957222 DOI: 10.1016/j.celrep.2024.113746] [Citation(s) in RCA: 30] [Impact Index Per Article: 30.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2023] [Revised: 12/09/2023] [Accepted: 01/22/2024] [Indexed: 02/10/2024] Open
Abstract
Lactic acid has emerged as an important modulator of immune cell function. It can be produced by both gut microbiota and the host metabolism at homeostasis and during disease states. The production of lactic acid in the gut microenvironment is vital for tissue homeostasis. In the present study, we examined how lactic acid integrates cellular metabolism to shape the epigenome of macrophages during pro-inflammatory response. We found that lactic acid serves as a primary fuel source to promote histone H3K27 acetylation, which allows the expression of immunosuppressive gene program including Nr4a1. Consequently, macrophage pro-inflammatory function was transcriptionally repressed. Furthermore, the histone acetylation induced by lactic acid promotes a form of long-term immunosuppression ("trained immunosuppression"). Pre-exposure to lactic acid induces lipopolysaccharide tolerance. These findings thus indicate that lactic acid sensing and its effect on chromatin remodeling in macrophages represent a key homeostatic mechanism that can provide a tolerogenic tissue microenvironment.
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Affiliation(s)
- Weiwei Shi
- Department of Immunology, Mayo Clinic, 200 1st Street SW, Rochester, MN 55905, USA
| | - Tiffany J Cassmann
- Department of Immunology, Mayo Clinic, 200 1st Street SW, Rochester, MN 55905, USA
| | - Aditya Vijay Bhagwate
- Departments of Health Science Research, Mayo Clinic, 200 1st Street SW, Rochester, MN 55905, USA
| | - Taro Hitosugi
- Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, 200 1st Street SW, Rochester, MN 55905, USA
| | - W K Eddie Ip
- Department of Immunology, Mayo Clinic, 200 1st Street SW, Rochester, MN 55905, USA; Division of Gastroenterology and Hepatology, Mayo Clinic, 200 1st Street SW, Rochester, MN 55905, USA.
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13
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Michalski C, Cheung C, Oh JH, Ackermann E, Popescu CR, Archambault AS, Prusinkiewicz MA, Da Silva R, Majdoubi A, Viñeta Paramo M, Xu RY, Reicherz F, Patterson AE, Golding L, Sharma AA, Lim CJ, Orban PC, Klein Geltink RI, Lavoie PM. DDIT4L regulates mitochondrial and innate immune activities in early life. JCI Insight 2024; 9:e172312. [PMID: 38319716 PMCID: PMC11143921 DOI: 10.1172/jci.insight.172312] [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: 05/15/2023] [Accepted: 01/31/2024] [Indexed: 02/07/2024] Open
Abstract
Pattern recognition receptor responses are profoundly attenuated before the third trimester of gestation in the relatively low-oxygen human fetal environment. However, the mechanisms regulating these responses are uncharacterized. Herein, genome-wide transcription and functional metabolic experiments in primary neonatal monocytes linked the negative mTOR regulator DDIT4L to metabolic stress, cellular bioenergetics, and innate immune activity. Using genetically engineered monocytic U937 cells, we confirmed that DDIT4L overexpression altered mitochondrial dynamics, suppressing their activity, and blunted LPS-induced cytokine responses. We also showed that monocyte mitochondrial function is more restrictive in earlier gestation, resembling the phenotype of DDIT4L-overexpressing U937 cells. Gene expression analyses in neonatal granulocytes and lung macrophages in preterm infants confirmed upregulation of the DDIT4L gene in the early postnatal period and also suggested a potential protective role against inflammation-associated chronic neonatal lung disease. Taken together, these data show that DDIT4L regulates mitochondrial activity and provide what we believe to be the first direct evidence for its potential role supressing innate immune activity in myeloid cells during development.
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Affiliation(s)
- Christina Michalski
- British Columbia Children’s Hospital Research Institute, Vancouver, British Columbia, Canada
- Department of Pediatrics and
| | - Claire Cheung
- British Columbia Children’s Hospital Research Institute, Vancouver, British Columbia, Canada
- Department of Pediatrics and
| | - Ju Hee Oh
- British Columbia Children’s Hospital Research Institute, Vancouver, British Columbia, Canada
- Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada
| | - Emma Ackermann
- British Columbia Children’s Hospital Research Institute, Vancouver, British Columbia, Canada
| | - Constantin R. Popescu
- British Columbia Children’s Hospital Research Institute, Vancouver, British Columbia, Canada
- Department of Pediatrics and
- Department of Pediatrics, Université Laval, Quebec, Quebec, Canada
| | - Anne-Sophie Archambault
- British Columbia Children’s Hospital Research Institute, Vancouver, British Columbia, Canada
- Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada
| | - Martin A. Prusinkiewicz
- British Columbia Children’s Hospital Research Institute, Vancouver, British Columbia, Canada
- Department of Pediatrics and
| | - Rachel Da Silva
- British Columbia Children’s Hospital Research Institute, Vancouver, British Columbia, Canada
| | - Abdelilah Majdoubi
- British Columbia Children’s Hospital Research Institute, Vancouver, British Columbia, Canada
- Department of Pediatrics and
| | - Marina Viñeta Paramo
- British Columbia Children’s Hospital Research Institute, Vancouver, British Columbia, Canada
- Women+ and Children′s Health, Department of Obstetrics and Gynecology, University of British Columbia, Vancouver, British Columbia, Canada
| | - Rui Yang Xu
- British Columbia Children’s Hospital Research Institute, Vancouver, British Columbia, Canada
- Women+ and Children′s Health, Department of Obstetrics and Gynecology, University of British Columbia, Vancouver, British Columbia, Canada
| | - Frederic Reicherz
- British Columbia Children’s Hospital Research Institute, Vancouver, British Columbia, Canada
- Department of Pediatrics and
| | - Annette E. Patterson
- British Columbia Children’s Hospital Research Institute, Vancouver, British Columbia, Canada
- Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada
| | - Liam Golding
- British Columbia Children’s Hospital Research Institute, Vancouver, British Columbia, Canada
- Department of Pediatrics and
- Women+ and Children′s Health, Department of Obstetrics and Gynecology, University of British Columbia, Vancouver, British Columbia, Canada
| | - Ashish A. Sharma
- Department of Pathology and Laboratory Medicine, Emory University, Atlanta, Georgia, USA
| | - Chinten J. Lim
- British Columbia Children’s Hospital Research Institute, Vancouver, British Columbia, Canada
- Department of Pediatrics and
| | - Paul C. Orban
- British Columbia Children’s Hospital Research Institute, Vancouver, British Columbia, Canada
- Department of Surgery, University of British Columbia, Vancouver, British Columbia, Canada
| | - Ramon I. Klein Geltink
- British Columbia Children’s Hospital Research Institute, Vancouver, British Columbia, Canada
- Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada
| | - Pascal M. Lavoie
- British Columbia Children’s Hospital Research Institute, Vancouver, British Columbia, Canada
- Department of Pediatrics and
- Women+ and Children′s Health, Department of Obstetrics and Gynecology, University of British Columbia, Vancouver, British Columbia, Canada
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14
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Tang X, Huang Z, Wang F, Chen J, Qin D, Peng D, Yu B. Macrophage-specific deletion of MIC26 (APOO) mitigates advanced atherosclerosis by increasing efferocytosis. Atherosclerosis 2023; 386:117374. [PMID: 37995600 DOI: 10.1016/j.atherosclerosis.2023.117374] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/16/2023] [Revised: 10/01/2023] [Accepted: 11/01/2023] [Indexed: 11/25/2023]
Abstract
BACKGROUND AND AIMS Recent studies have suggested that MIC26 (apolipoprotein O, APOO), a novel mitochondrial inner membrane protein, is involved in inflammation. Thus, the role of macrophage MIC26 in acute inflammation and chronic inflammatory disease atherosclerosis was investigated. METHODS Macrophage-specific MIC26 knockout mice (MIC26LysM) were generated by crossing Apooflox/flox and LysMcre+/- mice. An endotoxemia mouse model was generated to explore the effects of macrophage MIC26 deficiency on acute inflammation, while an atherosclerosis mouse model was constructed by crossing MIC26LysM mice with Apoe-/- mice and challenged with a Western diet. Atherosclerotic plaques, primary macrophage function, and mitochondrial structure and function were analyzed. RESULTS MIC26 knockout did not affect the median survival time and post-injection serum interleukin 1β concentrations in mice with endotoxemia. Mice with MIC26 deficiency in an Apoe-/- background had smaller atherosclerotic lesions and necrotic core than the control group. In vitro studies found that the loss of MIC26 did not affect macrophage polarization, apoptosis, or lipid handling capacity, but increased efferocytosis (the ability to clear apoptotic cells). An in situ efferocytosis assay of plaques also showed that the ratio of macrophage-associated apoptotic cells to free apoptotic cells was higher in the MIC26-deficient group than in the control group, indicating increased efferocytosis. In addition, an in vivo thymus efferocytosis assay indicated that MIC26 deletion promoted efferocytosis. Mechanistically, the loss of MIC26 resulted in an abnormal mitochondrial inner membrane structure, increased mitochondrial fission, and decreased mitochondrial membrane potential. Loss of MIC26 reduced mitochondria optic atrophy type 1 (OPA1) protein, and OPA1 silencing in macrophages promoted efferocytosis. Overexpression of OPA1 abolished the increase in efferocytosis produced by MIC26 deficiency. CONCLUSIONS Macrophage MIC26 deletion alleviated advanced atherosclerosis and necrotic core expansion by promoting efferocytosis. This mechanism may be related to the increased mitochondrial fission caused by reduced mitochondrial OPA1.
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Affiliation(s)
- Xiaoyu Tang
- Department of Cardiovascular Medicine, The Second Xiangya Hospital of Central South University, No. 139 Middle Renmin Road, Changsha, 410011, Hunan, China; Department of Rheumatology and Immunology, The Second Xiangya Hospital of Central South University, No. 139 Middle Renmin Road, Changsha, 410011, Hunan, China; Clinical Medical Research Center for Systemic Autoimmune Diseases in Hunan Province, No. 139 Middle Renmin Road, Changsha, 410011, Hunan, China
| | - Zhijie Huang
- Department of Cardiovascular Medicine, The Second Xiangya Hospital of Central South University, No. 139 Middle Renmin Road, Changsha, 410011, Hunan, China; Research Institute of Blood Lipid and Atherosclerosis, Central South University, No. 139 Middle Renmin Road, Changsha, 410011, Hunan, China; Hunan Key Laboratory of Cardiometabolic Medicine, No. 139 Middle Renmin Road, Changsha, 410011, Hunan, China
| | - Fengjiao Wang
- Department of Cardiovascular Medicine, The Second Xiangya Hospital of Central South University, No. 139 Middle Renmin Road, Changsha, 410011, Hunan, China; Research Institute of Blood Lipid and Atherosclerosis, Central South University, No. 139 Middle Renmin Road, Changsha, 410011, Hunan, China; Hunan Key Laboratory of Cardiometabolic Medicine, No. 139 Middle Renmin Road, Changsha, 410011, Hunan, China
| | - Jin Chen
- Department of Cardiovascular Medicine, The Second Xiangya Hospital of Central South University, No. 139 Middle Renmin Road, Changsha, 410011, Hunan, China; Research Institute of Blood Lipid and Atherosclerosis, Central South University, No. 139 Middle Renmin Road, Changsha, 410011, Hunan, China; Hunan Key Laboratory of Cardiometabolic Medicine, No. 139 Middle Renmin Road, Changsha, 410011, Hunan, China
| | - Donglu Qin
- Department of Cardiovascular Medicine, The Second Xiangya Hospital of Central South University, No. 139 Middle Renmin Road, Changsha, 410011, Hunan, China; Research Institute of Blood Lipid and Atherosclerosis, Central South University, No. 139 Middle Renmin Road, Changsha, 410011, Hunan, China; Hunan Key Laboratory of Cardiometabolic Medicine, No. 139 Middle Renmin Road, Changsha, 410011, Hunan, China
| | - Daoquan Peng
- Department of Cardiovascular Medicine, The Second Xiangya Hospital of Central South University, No. 139 Middle Renmin Road, Changsha, 410011, Hunan, China; Research Institute of Blood Lipid and Atherosclerosis, Central South University, No. 139 Middle Renmin Road, Changsha, 410011, Hunan, China; Hunan Key Laboratory of Cardiometabolic Medicine, No. 139 Middle Renmin Road, Changsha, 410011, Hunan, China.
| | - Bilian Yu
- Department of Cardiovascular Medicine, The Second Xiangya Hospital of Central South University, No. 139 Middle Renmin Road, Changsha, 410011, Hunan, China; Research Institute of Blood Lipid and Atherosclerosis, Central South University, No. 139 Middle Renmin Road, Changsha, 410011, Hunan, China; Hunan Key Laboratory of Cardiometabolic Medicine, No. 139 Middle Renmin Road, Changsha, 410011, Hunan, China; FuRong Laboratory, Changsha, 410078, Hunan, China.
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15
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Henneberg LT, Singh J, Duda DM, Baek K, Yanishevski D, Murray PJ, Mann M, Sidhu SS, Schulman BA. Activity-based profiling of cullin-RING E3 networks by conformation-specific probes. Nat Chem Biol 2023; 19:1513-1523. [PMID: 37653169 PMCID: PMC10667097 DOI: 10.1038/s41589-023-01392-5] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2023] [Accepted: 06/29/2023] [Indexed: 09/02/2023]
Abstract
The cullin-RING ubiquitin ligase (CRL) network comprises over 300 unique complexes that switch from inactive to activated conformations upon site-specific cullin modification by the ubiquitin-like protein NEDD8. Assessing cellular repertoires of activated CRL complexes is critical for understanding eukaryotic regulation. However, probes surveying networks controlled by site-specific ubiquitin-like protein modifications are lacking. We developed a synthetic antibody recognizing the active conformation of NEDD8-linked cullins. Implementing the probe to profile cellular networks of activated CUL1-, CUL2-, CUL3- and CUL4-containing E3s revealed the complexes responding to stimuli. Profiling several cell types showed their baseline neddylated CRL repertoires vary, and prime efficiency of targeted protein degradation. Our probe also unveiled differential rewiring of CRL networks across distinct primary cell activation pathways. Thus, conformation-specific probes can permit nonenzymatic activity-based profiling across a system of numerous multiprotein complexes, which in the case of neddylated CRLs reveals widespread regulation and could facilitate the development of degrader drugs.
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Affiliation(s)
- Lukas T Henneberg
- Department of Molecular Machines and Signaling, Max Planck Institute of Biochemistry, Martinsried, Germany
| | - Jaspal Singh
- School of Pharmacy, University of Waterloo, Waterloo, Ontario, Canada
| | - David M Duda
- Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, TN, USA
- Siduma Therapeutics, New Haven, CT, USA
| | - Kheewoong Baek
- Department of Molecular Machines and Signaling, Max Planck Institute of Biochemistry, Martinsried, Germany
| | - David Yanishevski
- Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, TN, USA
| | - Peter J Murray
- Immunoregulation, Max Planck Institute of Biochemistry, Martinsried, Germany
| | - Matthias Mann
- Department of Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Martinsried, Germany
- NNF Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Sachdev S Sidhu
- School of Pharmacy, University of Waterloo, Waterloo, Ontario, Canada.
| | - Brenda A Schulman
- Department of Molecular Machines and Signaling, Max Planck Institute of Biochemistry, Martinsried, Germany.
- Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, TN, USA.
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16
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Lu Y, Chen Y, Li Y, Xu S, Lian D, Liang J, Jiang D, Chen S, Hou S. Monotropein inhibits colitis associated cancer through VDR/JAK1/STAT1 regulation of macrophage polarization. Int Immunopharmacol 2023; 124:110838. [PMID: 37633235 DOI: 10.1016/j.intimp.2023.110838] [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: 07/03/2023] [Revised: 08/02/2023] [Accepted: 08/18/2023] [Indexed: 08/28/2023]
Abstract
Colorectal cancer (CRC) is a growing concern due to its high morbidity and mortality, and the search for effective and less toxic active substances against inflammatory bowel diseases has been a hot topic in the research and development of drugs against CRC. It is reported that monotropein isolated from the roots of Morinda officinalis, can improve Dextran Sodium Sulfate (DSS)-induced ulcerative colitis in mice, but its therapeutic effects and mechanisms for CRC treatment are still to be investigated. In the present study, we first used molecular docking, BLI, CESTA, and DARTS methods to detest whether monotropein targets VDR proteins. In addition, we used tumor cell conditioned co-culture and four models of macrophage polarisation to investigate the regulation of four macrophage polarisations by monotropein using RT-PCR, IF and western blot. Furthermore, we further validated the target of action of monotropein for the treatment of Azoxymethane (AOM)/DSS induced colitis associated cancer (CAC) using knockout animals. Meanwhile, we further explored the mechanism of action of monotropein in regulating polarisation by detecting JAK/STAT1-related genes and proteins. Molecular docking and biofilm interference techniques showed that monotropein bound to the VDR, and additional results from CESTA and DARTS suggested that VDR proteins are targets of monotropein. Furthermore, in tumor cell conditioned co-cultures or LPS + IFN-γ induced RAW264.7 cells, VDR translocation to the nucleus was reduced, JAK1/STAT1 signaling pathway proteins were up-regulated, and macrophages were polarised towards the M1-type after monotropein intervention. Animal models in which normal VDR or myeloid VDR was knocked out confirmed that JAK1 levels in intestinal tissues were increased after monotropein intervention, macrophages were polarised towards the M1 type, and CAC paracarcinomas were ameliorated. Taken together, the present study concluded that monotropein inhibited colitis-associated cancers through macrophage polarisation regulated by VDR/JAK1/STAT1.
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Affiliation(s)
- Yingyu Lu
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510006, PR China
| | - Yonger Chen
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510006, PR China
| | - Yuhua Li
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510006, PR China
| | - Shuoxi Xu
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510006, PR China
| | - Dawei Lian
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510006, PR China
| | - Jian Liang
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510006, PR China
| | - Dongxu Jiang
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510006, PR China
| | - Shuxian Chen
- Department of Hepatobiliary Surgery, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong 510000, PR China.
| | - Shaozhen Hou
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510006, PR China.
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17
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Forde AJ, Kolter J, Zwicky P, Baasch S, Lohrmann F, Eckert M, Gres V, Lagies S, Gorka O, Rambold AS, Buescher JM, Kammerer B, Lachmann N, Prinz M, Groß O, Pearce EJ, Becher B, Henneke P. Metabolic rewiring tunes dermal macrophages in staphylococcal skin infection. Sci Immunol 2023; 8:eadg3517. [PMID: 37566679 DOI: 10.1126/sciimmunol.adg3517] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2022] [Accepted: 07/19/2023] [Indexed: 08/13/2023]
Abstract
The skin needs to balance tolerance of colonizing microflora with rapid detection of potential pathogens. Flexible response mechanisms would seem most suitable to accommodate the dynamic challenges of effective antimicrobial defense and restoration of tissue homeostasis. Here, we dissected macrophage-intrinsic mechanisms and microenvironmental cues that tune macrophage signaling in localized skin infection with the colonizing and opportunistic pathogen Staphylococcus aureus. Early in skin infection, the cytokine granulocyte-macrophage colony-stimulating factor (GM-CSF) produced by γδ T cells and hypoxic conditions within the dermal microenvironment diverted macrophages away from a homeostatic M-CSF- and hypoxia-inducible factor 1α (HIF-1α)-dependent program. This allowed macrophages to be metabolically rewired for maximal inflammatory activity, which requires expression of Irg1 and generation of itaconate, but not HIF-1α. This multifactorial macrophage rewiring program was required for both the timely clearance of bacteria and for the provision of local immune memory. These findings indicate that immunometabolic conditioning allows dermal macrophages to cycle between antimicrobial activity and protection against secondary infections.
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Affiliation(s)
- Aaron James Forde
- Institute for Immunodeficiency, Center for Chronic Immunodeficiency, Medical Center and Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
- Faculty of Biology, University of Freiburg, 79104 Freiburg, Germany
| | - Julia Kolter
- Institute for Immunodeficiency, Center for Chronic Immunodeficiency, Medical Center and Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
| | - Pascale Zwicky
- Institute of Experimental Immunology, University of Zurich, CH-8057 Zurich, Switzerland
| | - Sebastian Baasch
- Institute for Immunodeficiency, Center for Chronic Immunodeficiency, Medical Center and Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
| | - Florens Lohrmann
- Institute for Immunodeficiency, Center for Chronic Immunodeficiency, Medical Center and Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
- Spemann Graduate School of Biology and Medicine, University of Freiburg, 79104 Freiburg, Germany
- Center for Pediatrics and Adolescent Medicine, University Medical Center, 79106 Freiburg, Germany
| | - Marleen Eckert
- Institute for Immunodeficiency, Center for Chronic Immunodeficiency, Medical Center and Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
- Faculty of Biology, University of Freiburg, 79104 Freiburg, Germany
| | - Vitka Gres
- Institute for Immunodeficiency, Center for Chronic Immunodeficiency, Medical Center and Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
- Faculty of Biology, University of Freiburg, 79104 Freiburg, Germany
| | - Simon Lagies
- Spemann Graduate School of Biology and Medicine, University of Freiburg, 79104 Freiburg, Germany
- 1 Core Competence Metabolomics, Institute of Organic Chemistry, University of Freiburg, 79104 Freiburg, Germany
| | - Oliver Gorka
- Institute of Neuropathology, Medical Center and Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Angelika S Rambold
- Department of Developmental Immunology, Max-Planck-Institute of Immunobiology and Epigenetics, Freiburg, Germany
| | - Joerg M Buescher
- Department of Immunometabolism, Max-Planck-Institute of Immunobiology and Epigenetics, Freiburg, Germany
| | - Bernd Kammerer
- Spemann Graduate School of Biology and Medicine, University of Freiburg, 79104 Freiburg, Germany
- 1 Core Competence Metabolomics, Institute of Organic Chemistry, University of Freiburg, 79104 Freiburg, Germany
- Signalling Research Centre's BIOSS and CIBSS, University of Freiburg, 79104 Freiburg, Germany
| | - Nico Lachmann
- Department of Pediatric Pneumology, Allergology and Neonatology and Cluster of Excellence RESIST (EXC 2155), Hannover Medical School, 30625 Hannover, Germany
| | - Marco Prinz
- Institute of Neuropathology, Medical Center and Faculty of Medicine, University of Freiburg, Freiburg, Germany
- Signalling Research Centre's BIOSS and CIBSS, University of Freiburg, 79104 Freiburg, Germany
- Center for Basics in NeuroModulation (NeuroModulBasics), Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
- CIBSS-Center for Integrative Biological Signaling Studies, University of Freiburg, 79104 Freiburg, Germany
| | - Olaf Groß
- Institute of Neuropathology, Medical Center and Faculty of Medicine, University of Freiburg, Freiburg, Germany
- Signalling Research Centre's BIOSS and CIBSS, University of Freiburg, 79104 Freiburg, Germany
- Center for Basics in NeuroModulation (NeuroModulBasics), Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
- CIBSS-Center for Integrative Biological Signaling Studies, University of Freiburg, 79104 Freiburg, Germany
| | - Edward J Pearce
- Department of Immunometabolism, Max-Planck-Institute of Immunobiology and Epigenetics, Freiburg, Germany
| | - Burkhard Becher
- Institute of Experimental Immunology, University of Zurich, CH-8057 Zurich, Switzerland
| | - Philipp Henneke
- Institute for Immunodeficiency, Center for Chronic Immunodeficiency, Medical Center and Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
- Center for Pediatrics and Adolescent Medicine, University Medical Center, 79106 Freiburg, Germany
- CIBSS-Center for Integrative Biological Signaling Studies, University of Freiburg, 79104 Freiburg, Germany
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18
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Almeida FS, Vanderley SER, Comberlang FC, Andrade AGD, Cavalcante-Silva LHA, Silva EDS, Palmeira PHDS, Amaral IPGD, Keesen TSL. Leishmaniasis: Immune Cells Crosstalk in Macrophage Polarization. Trop Med Infect Dis 2023; 8:tropicalmed8050276. [PMID: 37235324 DOI: 10.3390/tropicalmed8050276] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2023] [Revised: 05/09/2023] [Accepted: 05/11/2023] [Indexed: 05/28/2023] Open
Abstract
Leishmaniasis is a complex infectious parasitic disease caused by protozoa of the genus Leishmania, belonging to a group of neglected tropical diseases. It establishes significant global health challenges, particularly in socio-economically disadvantaged regions. Macrophages, as innate immune cells, play a crucial role in initiating the inflammatory response against the pathogens responsible for this disease. Macrophage polarization, the process of differentiating macrophages into pro-inflammatory (M1) or anti-inflammatory (M2) phenotypes, is essential for the immune response in leishmaniasis. The M1 phenotype is associated with resistance to Leishmania infection, while the M2 phenotype is predominant in susceptible environments. Notably, various immune cells, including T cells, play a significant role in modulating macrophage polarization by releasing cytokines that influence macrophage maturation and function. Furthermore, other immune cells can also impact macrophage polarization in a T-cell-independent manner. Therefore, this review comprehensively examines macrophage polarization's role in leishmaniasis and other immune cells' potential involvement in this intricate process.
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Affiliation(s)
- Fernanda Silva Almeida
- Immunology of Infectious Diseases Laboratory, Department of Cellular and Molecular Biology, Federal University of Paraiba, João Pessoa 58051-900, PB, Brazil
| | - Shayenne Eduarda Ramos Vanderley
- Immunology of Infectious Diseases Laboratory, Department of Cellular and Molecular Biology, Federal University of Paraiba, João Pessoa 58051-900, PB, Brazil
| | - Fernando Cézar Comberlang
- Immunology of Infectious Diseases Laboratory, Department of Cellular and Molecular Biology, Federal University of Paraiba, João Pessoa 58051-900, PB, Brazil
| | - Arthur Gomes de Andrade
- Immunology of Infectious Diseases Laboratory, Department of Cellular and Molecular Biology, Federal University of Paraiba, João Pessoa 58051-900, PB, Brazil
| | - Luiz Henrique Agra Cavalcante-Silva
- Immunology of Infectious Diseases Laboratory, Department of Cellular and Molecular Biology, Federal University of Paraiba, João Pessoa 58051-900, PB, Brazil
| | - Edson Dos Santos Silva
- Immunology of Infectious Diseases Laboratory, Department of Cellular and Molecular Biology, Federal University of Paraiba, João Pessoa 58051-900, PB, Brazil
| | - Pedro Henrique de Sousa Palmeira
- Immunology of Infectious Diseases Laboratory, Department of Cellular and Molecular Biology, Federal University of Paraiba, João Pessoa 58051-900, PB, Brazil
| | - Ian P G do Amaral
- Laboratory of Biochemistry, Department of Cellular and Molecular Biology, Federal University of Paraiba, João Pessoa 58051-900, PB, Brazil
| | - Tatjana S L Keesen
- Immunology of Infectious Diseases Laboratory, Department of Cellular and Molecular Biology, Federal University of Paraiba, João Pessoa 58051-900, PB, Brazil
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19
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Zhang HY, Xiao HL, Wang GX, Lu ZQ, Xie MR, Li CS. Predictive value of presepsin and acylcarnitines for severity and biliary drainage in acute cholangitis. World J Gastroenterol 2023; 29:2502-2514. [PMID: 37179587 PMCID: PMC10167903 DOI: 10.3748/wjg.v29.i16.2502] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/09/2023] [Revised: 02/21/2023] [Accepted: 03/31/2023] [Indexed: 04/24/2023] Open
Abstract
BACKGROUND Bacteremia, which is a major cause of mortality in patients with acute cholangitis, induces hyperactive immune response and mitochondrial dysfunction. Presepsin is responsible for pathogen recognition by innate immunity. Acylcarnitines are established mitochondrial biomarkers. AIM To clarify the early predictive value of presepsin and acylcarnitines as biomarkers of severity of acute cholangitis and the need for biliary drainage. METHODS Of 280 patients with acute cholangitis were included and the severity was stratified according to the Tokyo Guidelines 2018. Blood presepsin and plasma acylcarnitines were tested at enrollment by chemiluminescent enzyme immunoassay and ultra-high-performance liquid chromatography-mass spectrometry, respectively. RESULTS The concentrations of presepsin, procalcitonin, short- and medium-chain acylcarnitines increased, while long-chain acylcarnitines decreased with the severity of acute cholangitis. The areas under the receiver operating characteristic curves (AUC) of presepsin for diagnosing moderate/severe and severe cholangitis (0.823 and 0.801, respectively) were greater than those of conventional markers. The combination of presepsin, direct bilirubin, alanine aminotransferase, temperature, and butyryl-L-carnitine showed good predictive ability for biliary drainage (AUC: 0.723). Presepsin, procalcitonin, acetyl-L-carnitine, hydroxydodecenoyl-L-carnitine, and temperature were independent predictors of bloodstream infection. After adjusting for severity classification, acetyl-L-carnitine was the only acylcarnitine independently associated with 28-d mortality (hazard ratio 14.396; P < 0.001) (AUC: 0.880). Presepsin concentration showed positive correlation with direct bilirubin or acetyl-L-carnitine. CONCLUSION Presepsin could serve as a specific biomarker to predict the severity of acute cholangitis and need for biliary drainage. Acetyl-L-carnitine is a potential prognostic factor for patients with acute cholangitis. Innate immune response was associated with mitochondrial metabolic dysfunction in acute cholangitis.
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Affiliation(s)
- Han-Yu Zhang
- Department of Emergency Medicine, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China
| | - Hong-Li Xiao
- Department of Emergency Medicine, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China
| | - Guo-Xing Wang
- Department of Emergency Medicine, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China
| | - Zhao-Qing Lu
- Department of Emergency Medicine, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China
| | - Miao-Rong Xie
- Department of Emergency Medicine, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China
| | - Chun-Sheng Li
- Department of Emergency Medicine, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China
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20
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Thai LM, O’Reilly L, Reibe-Pal S, Sue N, Holliday H, Small L, Schmitz-Peiffer C, Dhenni R, Wang-Wei Tsai V, Norris N, Yau B, Zhang X, Lee K, Yan C, Shi YC, Kebede MA, Brink R, Cooney GJ, Irvine KM, Breit SN, Phan TG, Swarbrick A, Biden TJ. β-cell function is regulated by metabolic and epigenetic programming of islet-associated macrophages, involving Axl, Mertk, and TGFβ receptor signaling. iScience 2023; 26:106477. [PMID: 37091234 PMCID: PMC10113792 DOI: 10.1016/j.isci.2023.106477] [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: 09/27/2022] [Revised: 01/13/2023] [Accepted: 03/19/2023] [Indexed: 04/25/2023] Open
Abstract
We have exploited islet-associated macrophages (IAMs) as a model of resident macrophage function, focusing on more physiological conditions than the commonly used extremes of M1 (inflammation) versus M2 (tissue remodeling) polarization. Under steady state, murine IAMs are metabolically poised between aerobic glycolysis and oxidative phosphorylation, and thereby exert a brake on glucose-stimulated insulin secretion (GSIS). This is underpinned by epigenetic remodeling via the metabolically regulated histone demethylase Kdm5a. Conversely, GSIS is enhanced by engaging Axl receptors on IAMs, or by augmenting their oxidation of glucose. Following high-fat feeding, efferocytosis is stimulated in IAMs in conjunction with Mertk and TGFβ receptor signaling. This impairs GSIS and potentially contributes to β-cell failure in pre-diabetes. Thus, IAMs serve as relays in many more settings than currently appreciated, fine-tuning insulin secretion in response to dynamic changes in the external environment. Intervening in this nexus might represent a means of preserving β-cell function during metabolic disease.
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Affiliation(s)
- Le May Thai
- Garvan Institute of Medical Research, Sydney, NSW, Australia
| | - Liam O’Reilly
- Garvan Institute of Medical Research, Sydney, NSW, Australia
| | | | - Nancy Sue
- Garvan Institute of Medical Research, Sydney, NSW, Australia
| | - Holly Holliday
- Garvan Institute of Medical Research, Sydney, NSW, Australia
| | - Lewin Small
- Garvan Institute of Medical Research, Sydney, NSW, Australia
| | - Carsten Schmitz-Peiffer
- Garvan Institute of Medical Research, Sydney, NSW, Australia
- St Vincent’s Clinical School, Faculty of Medicine, UNSW Sydney, Sydney, NSW, Australia
- School of Medical Sciences, Charles Perkins Centre, University of Sydney, Sydney, NSW, Australia
| | - Rama Dhenni
- Garvan Institute of Medical Research, Sydney, NSW, Australia
| | | | - Nicholas Norris
- School of Medical Sciences, Charles Perkins Centre, University of Sydney, Sydney, NSW, Australia
| | - Belinda Yau
- Centre for Applied Medical Research, Sydney, NSW, Australia
| | - Xuan Zhang
- Garvan Institute of Medical Research, Sydney, NSW, Australia
| | - Kailun Lee
- Garvan Institute of Medical Research, Sydney, NSW, Australia
| | - Chenxu Yan
- Garvan Institute of Medical Research, Sydney, NSW, Australia
| | - Yan-Chuan Shi
- Garvan Institute of Medical Research, Sydney, NSW, Australia
- St Vincent’s Clinical School, Faculty of Medicine, UNSW Sydney, Sydney, NSW, Australia
| | - Melkam A. Kebede
- School of Medical Sciences, Charles Perkins Centre, University of Sydney, Sydney, NSW, Australia
| | - Robert Brink
- Garvan Institute of Medical Research, Sydney, NSW, Australia
- St Vincent’s Clinical School, Faculty of Medicine, UNSW Sydney, Sydney, NSW, Australia
| | - Gregory J. Cooney
- Garvan Institute of Medical Research, Sydney, NSW, Australia
- St Vincent’s Clinical School, Faculty of Medicine, UNSW Sydney, Sydney, NSW, Australia
- School of Medical Sciences, Charles Perkins Centre, University of Sydney, Sydney, NSW, Australia
| | | | - Samuel N. Breit
- St Vincent’s Clinical School, Faculty of Medicine, UNSW Sydney, Sydney, NSW, Australia
- Centre for Applied Medical Research, Sydney, NSW, Australia
| | - Tri G. Phan
- Garvan Institute of Medical Research, Sydney, NSW, Australia
- St Vincent’s Clinical School, Faculty of Medicine, UNSW Sydney, Sydney, NSW, Australia
| | - Alexander Swarbrick
- Garvan Institute of Medical Research, Sydney, NSW, Australia
- St Vincent’s Clinical School, Faculty of Medicine, UNSW Sydney, Sydney, NSW, Australia
| | - Trevor J. Biden
- Garvan Institute of Medical Research, Sydney, NSW, Australia
- St Vincent’s Clinical School, Faculty of Medicine, UNSW Sydney, Sydney, NSW, Australia
- Corresponding author
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21
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Kabat AM, Pearce EL, Pearce EJ. Metabolism in type 2 immune responses. Immunity 2023; 56:723-741. [PMID: 37044062 PMCID: PMC10938369 DOI: 10.1016/j.immuni.2023.03.007] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2023] [Revised: 03/11/2023] [Accepted: 03/15/2023] [Indexed: 04/14/2023]
Abstract
The immune response is tailored to the environment in which it takes place. Immune cells sense and adapt to changes in their surroundings, and it is now appreciated that in addition to cytokines made by stromal and epithelial cells, metabolic cues provide key adaptation signals. Changes in immune cell activation states are linked to changes in cellular metabolism that support function. Furthermore, metabolites themselves can signal between as well as within cells. Here, we discuss recent progress in our understanding of how metabolic regulation relates to type 2 immunity firstly by considering specifics of metabolism within type 2 immune cells and secondly by stressing how type 2 immune cells are integrated more broadly into the metabolism of the organism as a whole.
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Affiliation(s)
- Agnieszka M Kabat
- Bloomberg Kimmel Institute, and Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - Erika L Pearce
- Bloomberg Kimmel Institute, and Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA; Department of Biochemistry and Molecular Biology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD 21287, USA
| | - Edward J Pearce
- Bloomberg Kimmel Institute, and Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA; Department of Molecular Microbiology and Immunology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD 21287, USA.
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22
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Henneberg LT, Singh J, Duda DM, Baek K, Yanishevski D, Murray PJ, Mann M, Sidhu SS, Schulman B. Activity-based profiling of cullin-RING ligase networks by conformation-specific probes. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.01.14.524048. [PMID: 36711970 PMCID: PMC9882101 DOI: 10.1101/2023.01.14.524048] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
The cullin-RING E3 ligase (CRL) network comprises over 300 unique complexes that switch from inactive to activated conformations upon site-specific cullin modification by the ubiquitin-like protein NEDD8. Assessing cellular repertoires of activated CRL complexes is critical for understanding eukaryotic regulation. However, probes surveying networks controlled by site-specific ubiquitin-like protein modifications are lacking. We report development of a synthetic antibody recognizing the active conformation of a NEDD8-linked cullin. We established a pipeline probing cellular networks of activated CUL1-, CUL2-, CUL3- and CUL4-containing CRLs, revealing the CRL complexes responding to stimuli. Profiling several cell types showed their baseline neddylated CRL repertoires vary, prime efficiency of targeted protein degradation, and are differentially rewired across distinct primary cell activation pathways. Thus, conformation-specific probes can permit nonenzymatic activity-based profiling across a system of numerous multiprotein complexes, which in the case of neddylated CRLs reveals widespread regulation and could facilitate development of degrader drugs.
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Affiliation(s)
- Lukas T Henneberg
- Department of Molecular Machines and Signaling, Max Planck Institute of Biochemistry, Martinsried, Germany
| | - Jaspal Singh
- Donnelly Centre, University of Toronto, Toronto, ON, Canada
| | - David M Duda
- Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, TN, USA
- Present address: The Janssen Pharmaceutical Companies of Johnson & Johnson, Spring House, Pennsylvania, USA
| | - Kheewoong Baek
- Department of Molecular Machines and Signaling, Max Planck Institute of Biochemistry, Martinsried, Germany
| | - David Yanishevski
- Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, TN, USA
| | - Peter J Murray
- Immunoregulation, Max Planck Institute of Biochemistry, Martinsried, Germany
| | - Matthias Mann
- Department of Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Martinsried, Germany
- NNF Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Sachdev S Sidhu
- Donnelly Centre, University of Toronto, Toronto, ON, Canada
- The Anvil Institute, Kitchener, Ontario, Canada, School of Pharmacy, University of Waterloo, Waterloo, Ontario, Canada
| | - Brenda Schulman
- Department of Molecular Machines and Signaling, Max Planck Institute of Biochemistry, Martinsried, Germany
- Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, TN, USA
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23
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Namgaladze D, Brüne B. Rapid glycolytic activation accompanying innate immune responses: mechanisms and function. Front Immunol 2023; 14:1180488. [PMID: 37153593 PMCID: PMC10158531 DOI: 10.3389/fimmu.2023.1180488] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2023] [Accepted: 04/03/2023] [Indexed: 05/09/2023] Open
Abstract
Innate immune responses to pathogens, mediated by activation of pattern recognition receptors and downstream signal transduction cascades, trigger rapid transcriptional and epigenetic changes to support increased expression of pro-inflammatory cytokines and other effector molecules. Innate immune cells also rapidly rewire their metabolism. The most prominent metabolic alteration following innate immune activation is rapid up-regulation of glycolysis. In this mini-review, we summarize recent advances regarding the mechanisms of rapid glycolytic activation in innate immune cells, highlighting the relevant signaling components. We also discuss the impact of glycolytic activation on inflammatory responses, including the recently elucidated links of metabolism and epigenetics. Finally, we highlight unresolved mechanistic details of glycolytic activation and possible avenues of future research in this area.
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Affiliation(s)
- Dmitry Namgaladze
- Institute of Biochemistry I, Faculty of Medicine, Goethe-University Frankfurt, Frankfurt, Germany
- *Correspondence: Dmitry Namgaladze,
| | - Bernhard Brüne
- Institute of Biochemistry I, Faculty of Medicine, Goethe-University Frankfurt, Frankfurt, Germany
- Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Frankfurt, Germany
- German Cancer Consortium (DKTK), Partner Site Frankfurt, Frankfurt, Germany
- Frankfurt Cancer Institute, Goethe-University Frankfurt, Frankfurt, Germany
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24
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Macrophage Mitochondrial Biogenesis and Metabolic Reprogramming Induced by Leishmania donovani Require Lipophosphoglycan and Type I Interferon Signaling. mBio 2022; 13:e0257822. [PMID: 36222510 PMCID: PMC9764995 DOI: 10.1128/mbio.02578-22] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Pathogen-specific rewiring of host cell metabolism creates the metabolically adapted microenvironment required for pathogen replication. Here, we investigated the mechanisms governing the modulation of macrophage mitochondrial properties by the vacuolar pathogen Leishmania. We report that induction of oxidative phosphorylation and mitochondrial biogenesis by Leishmania donovani requires the virulence glycolipid lipophosphoglycan, which stimulates the expression of key transcriptional regulators and structural genes associated with the electron transport chain. Leishmania-induced mitochondriogenesis also requires a lipophosphoglycan-independent pathway involving type I interferon (IFN) receptor signaling. The observation that pharmacological induction of mitochondrial biogenesis enables an avirulent lipophosphoglycan-defective L. donovani mutant to survive in macrophages supports the notion that mitochondrial biogenesis contributes to the creation of a metabolically adapted environment propitious to the colonization of host cells by the parasite. This study provides novel insight into the complex mechanism by which Leishmania metacyclic promastigotes alter host cell mitochondrial biogenesis and metabolism during the colonization process. IMPORTANCE To colonize host phagocytes, Leishmania metacyclic promastigotes subvert host defense mechanisms and create a specialized intracellular niche adapted to their replication. This is accomplished through the action of virulence factors, including the surface coat glycoconjugate lipophosphoglycan. In addition, Leishmania induces proliferation of host cell mitochondria as well as metabolic reprogramming of macrophages. These metabolic alterations are crucial to the colonization process of macrophages, as they may provide metabolites required for parasite growth. In this study, we describe a new key role for lipophosphoglycan in the stimulation of oxidative phosphorylation and mitochondrial biogenesis. We also demonstrate that host cell pattern recognition receptors Toll-like receptor 4 (TLR4) and endosomal TLRs mediate these Leishmania-induced alterations of host cell mitochondrial biology, which also require type I IFN signaling. These findings provide new insight into how Leishmania creates a metabolically adapted environment favorable to their replication.
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25
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Sun Y, Jiang W, Horng T. Circadian metabolism regulates the macrophage inflammatory response. LIFE METABOLISM 2022; 1:224-233. [PMID: 39872076 PMCID: PMC11749265 DOI: 10.1093/lifemeta/loac037] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 09/13/2022] [Revised: 11/24/2022] [Accepted: 12/05/2022] [Indexed: 01/29/2025]
Abstract
Macrophages are an integral part of the innate immune system and coordinate host defense to microbial infections, as well as shaping the remodeling response after tissue injury. Metabolism is now appreciated to be a powerful and pervasive regulator of the identity and function of macrophages. Upon exposure to microbial ligands, macrophage inflammatory activation and the associated induction of phagocytosis, inflammatory responses, and other host defense activities are supported by dynamic changes to cellular metabolism. Of note, metabolic activity is robustly regulated in a circadian fashion, with many metabolic processes displaying peak activity in one phase of the circadian cycle and trough activity in an antiphase manner. Here, we review recent findings suggesting that circadian metabolism influences macrophage activities and particularly the inflammatory response. First, we summarize macrophage activities known to display time-of-day-dependent variation and their mechanistic basis. Second, we review metabolic processes that have been shown to be rhythmically regulated in macrophages and discuss how such circadian metabolism affects or is likely to affect macrophage activities. Third, we discuss the concept of entrainment of the macrophage clock, and consider how loss of rhythmic regulation of macrophage activities may contribute to pathophysiological conditions like shift work, obesity, and aging. Finally, we propose that circadian metabolism can be used to understand the rationale and mechanistic basis of dynamic regulation of inflammatory responses during infection.
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Affiliation(s)
- Yulong Sun
- School of Life Sciences and Technology, ShanghaiTech University, Shanghai 201210, China
| | - Wenjiao Jiang
- School of Life Sciences and Technology, ShanghaiTech University, Shanghai 201210, China
| | - Tiffany Horng
- School of Life Sciences and Technology, ShanghaiTech University, Shanghai 201210, China
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26
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Andrews JT, Voth DE, Huang SCC, Huang L. Breathe In, Breathe Out: Metabolic Regulation of Lung Macrophages in Host Defense Against Bacterial Infection. Front Cell Infect Microbiol 2022; 12:934460. [PMID: 35899042 PMCID: PMC9309258 DOI: 10.3389/fcimb.2022.934460] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2022] [Accepted: 06/15/2022] [Indexed: 12/03/2022] Open
Abstract
Lung macrophages are substantially distinct from other tissue-resident macrophages. They act as frontier sentinels of the alveolar-blood interface and are constantly exposed to various pathogens. Additionally, they precisely regulate immune responses under homeostatic and pathological conditions to curtail tissue damage while containing respiratory infections. As a highly heterogeneous population, the phenotypes and functions of lung macrophages with differing developmental ontogenies are linked to both intrinsic and extrinsic metabolic processes. Importantly, targeting these metabolic pathways greatly impacts macrophage functions, which in turn leads to different disease outcomes in the lung. In this review, we will discuss underlying metabolic regulation of lung macrophage subsets and how metabolic circuits, together with epigenetic modifications, dictate lung macrophage function during bacterial infection.
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Affiliation(s)
- J. Tucker Andrews
- Department of Microbiology and Immunology, University of Arkansas for Medical Sciences, Little Rock, AR, United States
| | - Daniel E. Voth
- Department of Microbiology and Immunology, University of Arkansas for Medical Sciences, Little Rock, AR, United States
| | - Stanley Ching-Cheng Huang
- Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH, United States
- Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, OH, United States
- *Correspondence: Lu Huang, ; Stanley Ching-Cheng Huang,
| | - Lu Huang
- Department of Microbiology and Immunology, University of Arkansas for Medical Sciences, Little Rock, AR, United States
- *Correspondence: Lu Huang, ; Stanley Ching-Cheng Huang,
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27
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Seim GL, Fan J. A matter of time: temporal structure and functional relevance of macrophage metabolic rewiring. Trends Endocrinol Metab 2022; 33:345-358. [PMID: 35331615 PMCID: PMC9010376 DOI: 10.1016/j.tem.2022.02.005] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 02/21/2022] [Accepted: 02/22/2022] [Indexed: 12/24/2022]
Abstract
The response of macrophages to stimulation is a dynamic process which coordinates the orderly adoption and resolution of various immune functions. Accumulating work over the past decade has demonstrated that during the immune response macrophage metabolism is substantially rewired to support important cellular processes, including the production of bioactive molecules, intercellular communication, and the regulation of intracellular signaling and transcriptional programming. In particular, we discuss an important concept emerging from recent studies - metabolic rewiring during the immune response is temporally structured. We review the regulatory mechanisms that drive the dynamic remodeling of metabolism, and examine the functional implications of these metabolic dynamics.
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Affiliation(s)
- Gretchen L Seim
- Morgridge Institute for Research, Madison, WI, USA; Department of Nutritional Sciences, University of Wisconsin-Madison, Madison, WI, USA
| | - Jing Fan
- Morgridge Institute for Research, Madison, WI, USA; Department of Nutritional Sciences, University of Wisconsin-Madison, Madison, WI, USA.
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28
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Abstract
Coronary atherosclerosis is a chronic inflammatory disease that can lead to varying degrees of blood flow obstruction and a common pathophysiological basis of cardiovascular disease. Inflammatory factors run through the whole process of atherosclerotic lesions. Macrophages, T cells, and neutrophils play important roles in the process of atherosclerotic inflammation. Considering the evolutionary characteristics, atherosclerosis can be divided into different stages as early atherosclerotic plaque, plaque formation stage, and plaque rupture stage. In this paper, the changes in inflammatory cells at different stages of lesions and their related mechanisms are discussed, which can provide new insights from a clinical to bench perspective for atherosclerosis me chanism.
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29
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Wenjie L, Fazhi Q. Hypothesis of immune homeostasis regulator: the nervous system regulates glucose immunometabolism to control immunity. Med Hypotheses 2022. [DOI: 10.1016/j.mehy.2022.110841] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
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30
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Schiattarella GG, Alcaide P, Condorelli G, Gillette TG, Heymans S, Jones EAV, Kallikourdis M, Lichtman A, Marelli-Berg F, Shah S, Thorp EB, Hill JA. Immunometabolic Mechanisms of Heart Failure with Preserved Ejection Fraction. NATURE CARDIOVASCULAR RESEARCH 2022; 1:211-222. [PMID: 35755006 PMCID: PMC9229992 DOI: 10.1038/s44161-022-00032-w] [Citation(s) in RCA: 32] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Heart failure with preserved ejection fraction (HFpEF) is increasing in prevalence worldwide, already accounting for at least half of all heart failure (HF). As most patients with HFpEF are obese with metabolic syndrome, metabolic stress has been implicated in syndrome pathogenesis. Recently, compelling evidence for bidirectional crosstalk between metabolic stress and chronic inflammation has emerged, and alterations in systemic and cardiac immune responses are held to participate in HFpEF pathophysiology. Indeed, based on both preclinical and clinical evidence, comorbidity-driven systemic inflammation, coupled with metabolic stress, have been implicated together in HFpEF pathogenesis. As metabolic alterations impact immune function(s) in HFpEF, major changes in immune cell metabolism are also recognized in HFpEF and in HFpEF-predisposing conditions. Both arms of immunity - innate and adaptive - are implicated in the cardiomyocyte response in HFpEF. Indeed, we submit that crosstalk among adipose tissue, the immune system, and the heart represents a critical component of HFpEF pathobiology. Here, we review recent evidence in support of immunometabolic mechanisms as drivers of HFpEF pathogenesis, discuss pivotal biological mechanisms underlying the syndrome, and highlight questions requiring additional inquiry.
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Affiliation(s)
- Gabriele G. Schiattarella
- Center for Cardiovascular Research (CCR), Department of Cardiology, Charité - Universitätsmedizin Berlin, Berlin, Germany.,DZHK (German Centre for Cardiovascular Research), Partner Site Berlin, Berlin, Germany.,Translational Approaches in Heart Failure and Cardiometabolic Disease, Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany.,Division of Cardiology, Department of Advanced Biomedical Sciences, Federico II University, Naples, Italy.,Department of Internal Medicine (Cardiology), University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Pilar Alcaide
- Department of Immunology, Tufts University School of Medicine, Boston, Massachusetts, USA
| | - Gianluigi Condorelli
- Humanitas University, Via Rita Levi Montalcini 4, Pieve Emanuele, Italy,Cardio Center, Humanitas Research Hospital IRCCS, Rozzano, Italy
| | - Thomas G. Gillette
- Department of Internal Medicine (Cardiology), University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Stephane Heymans
- Department of Cardiology, Maastricht University, CARIM School for Cardiovascular Diseases, Maastricht, Netherlands,Centre for Molecular and Vascular Biology, Department of Cardiovascular Sciences, KU Leuven, Leuven, Belgium
| | - Elizabeth A. V. Jones
- Department of Cardiology, Maastricht University, CARIM School for Cardiovascular Diseases, Maastricht, Netherlands,Centre for Molecular and Vascular Biology, Department of Cardiovascular Sciences, KU Leuven, Leuven, Belgium
| | - Marinos Kallikourdis
- Humanitas University, Via Rita Levi Montalcini 4, Pieve Emanuele, Italy,Adaptive Immunity Lab, Humanitas Research Hospital IRCCS, Rozzano, Italy
| | - Andrew Lichtman
- Department of Pathology, Brigham and Women’s Hospital, Boston, MA, USA
| | - Federica Marelli-Berg
- William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Sanjiv Shah
- Division of Cardiology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Edward B. Thorp
- Feinberg School of Medicine, Northwestern University, Chicago, IL
| | - Joseph A. Hill
- Department of Internal Medicine (Cardiology), University of Texas Southwestern Medical Center, Dallas, TX, USA.,Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas, USA
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31
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Dichtl S, Sanin DE, Koss CK, Willenborg S, Petzold A, Tanzer MC, Dahl A, Kabat AM, Lindenthal L, Zeitler L, Satzinger S, Strasser A, Mann M, Roers A, Eming SA, El Kasmi KC, Pearce EJ, Murray PJ. Gene-selective transcription promotes the inhibition of tissue reparative macrophages by TNF. Life Sci Alliance 2022; 5:5/4/e202101315. [PMID: 35027468 PMCID: PMC8761491 DOI: 10.26508/lsa.202101315] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2021] [Revised: 01/03/2022] [Accepted: 01/04/2022] [Indexed: 12/24/2022] Open
Abstract
Pro-inflammatory TNF is a highly gene-selective inhibitor of the gene expression program of tissue repair and wound healing macrophages. Anti-TNF therapies are a core anti-inflammatory approach for chronic diseases such as rheumatoid arthritis and Crohn’s Disease. Previously, we and others found that TNF blocks the emergence and function of alternative-activated or M2 macrophages involved in wound healing and tissue-reparative functions. Conceivably, anti-TNF drugs could mediate their protective effects in part by an altered balance of macrophage activity. To understand the mechanistic basis of how TNF regulates tissue-reparative macrophages, we used RNAseq, scRNAseq, ATACseq, time-resolved phospho-proteomics, gene-specific approaches, metabolic analysis, and signaling pathway deconvolution. We found that TNF controls tissue-reparative macrophage gene expression in a highly gene-specific way, dependent on JNK signaling via the type 1 TNF receptor on specific populations of alternative-activated macrophages. We further determined that JNK signaling has a profound and broad effect on activated macrophage gene expression. Our findings suggest that TNF’s anti-M2 effects evolved to specifically modulate components of tissue and reparative M2 macrophages and TNF is therefore a context-specific modulator of M2 macrophages rather than a pan-M2 inhibitor.
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Affiliation(s)
| | - David E Sanin
- Department of Immunometabolism, Max Planck Institute for Immunobiology and Epigenetics, Freiburg, Germany.,The Bloomberg∼Kimmel Institute for Cancer Immunotherapy at Johns Hopkins, Johns Hopkins University, Baltimore, MD, USA
| | - Carolin K Koss
- Boehringer Ingelheim Pharma GmbH and Co KG, Biberach, Germany
| | | | - Andreas Petzold
- Deep Sequencing Group, Biotechnology Center, Technische Universität Dresden, Dresden, Germany
| | - Maria C Tanzer
- Max Planck Institute of Biochemistry, Martinsried, Germany
| | - Andreas Dahl
- Deep Sequencing Group, Biotechnology Center, Technische Universität Dresden, Dresden, Germany
| | - Agnieszka M Kabat
- Department of Immunometabolism, Max Planck Institute for Immunobiology and Epigenetics, Freiburg, Germany.,The Bloomberg∼Kimmel Institute for Cancer Immunotherapy at Johns Hopkins, Johns Hopkins University, Baltimore, MD, USA
| | | | - Leonie Zeitler
- Max Planck Institute of Biochemistry, Martinsried, Germany
| | | | | | - Matthias Mann
- Max Planck Institute of Biochemistry, Martinsried, Germany
| | - Axel Roers
- Institute for Immunology, Medical Faculty Carl Gustav Carus, TU Dresden, Dresden, Germany
| | - Sabine A Eming
- Department of Dermatology, University of Cologne, Cologne, Germany.,Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany.,Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, Cologne, Germany.,Institute of Zoology, Developmental Biology Unit, University of Cologne, Cologne, Germany
| | | | - Edward J Pearce
- Department of Immunometabolism, Max Planck Institute for Immunobiology and Epigenetics, Freiburg, Germany.,The Bloomberg∼Kimmel Institute for Cancer Immunotherapy at Johns Hopkins, Johns Hopkins University, Baltimore, MD, USA
| | - Peter J Murray
- Max Planck Institute of Biochemistry, Martinsried, Germany
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32
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Cannabinoids induce functional Tregs by promoting tolerogenic DCs via autophagy and metabolic reprograming. Mucosal Immunol 2022; 15:96-108. [PMID: 34548620 PMCID: PMC8732281 DOI: 10.1038/s41385-021-00455-x] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2021] [Revised: 08/04/2021] [Accepted: 09/07/2021] [Indexed: 02/04/2023]
Abstract
The generation of functional regulatory T cells (Tregs) is essential to keep tissue homeostasis and restore healthy immune responses in many biological and inflammatory contexts. Cannabinoids have been pointed out as potential therapeutic tools for several diseases. Dendritic cells (DCs) express the endocannabinoid system, including the cannabinoid receptors CB1 and CB2. However, how cannabinoids might regulate functional properties of DCs is not completely understood. We uncover that the triggering of cannabinoid receptors promote human tolerogenic DCs that are able to prime functional FOXP3+ Tregs in the context of different inflammatory diseases. Mechanistically, cannabinoids imprint tolerogenicity in human DCs by inhibiting NF-κB, MAPK and mTOR signalling pathways while inducing AMPK and functional autophagy flux via CB1- and PPARα-mediated activation, which drives metabolic rewiring towards increased mitochondrial activity and oxidative phosphorylation. Cannabinoids exhibit in vivo protective and anti-inflammatory effects in LPS-induced sepsis and also promote the generation of FOXP3+ Tregs. In addition, immediate anaphylactic reactions are decreased in peanut allergic mice and the generation of allergen-specific FOXP3+ Tregs are promoted, demonstrating that these immunomodulatory effects take place in both type 1- and type 2-mediated inflammatory diseases. Our findings might open new avenues for novel cannabinoid-based interventions in different inflammatory and immune-mediated diseases.
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33
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Snyder JP, Gullickson SK, del Rio-Guerra R, Sweezy A, Vagher B, Hogan TC, Lahue KG, Reisz JA, D’Alessandro A, Krementsov DN, Amiel E. Divergent Genetic Regulation of Nitric Oxide Production between C57BL/6J and Wild-Derived PWD/PhJ Mice Controls Postactivation Mitochondrial Metabolism, Cell Survival, and Bacterial Resistance in Dendritic Cells. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2022; 208:97-109. [PMID: 34872978 PMCID: PMC8702458 DOI: 10.4049/jimmunol.2100375] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/20/2021] [Accepted: 10/04/2021] [Indexed: 01/03/2023]
Abstract
Dendritic cell (DC) activation is characterized by sustained commitment to glycolysis that is a requirement for survival in DC subsets that express inducible NO synthase (Nos2) due to NO-mediated inhibition of mitochondrial respiration. This phenomenon primarily has been studied in DCs from the classic laboratory inbred mouse strain C57BL/6J (B6) mice, where DCs experience a loss of mitochondrial function due to NO accumulation. To assess the conservation of NO-driven metabolic regulation in DCs, we compared B6 mice to the wild-derived genetically divergent PWD/PhJ (PWD) strain. We show preserved mitochondrial respiration and enhanced postactivation survival due to attenuated NO production in LPS-stimulated PWD DCs phenocopying human monocyte-derived DCs. To genetically map this phenotype, we used a congenic mouse strain (B6.PWD-Chr11.2) that carries a PWD-derived portion of chromosome 11, including Nos2, on a B6 background. B6.PWD-Chr11.2 DCs show preserved mitochondrial function and produce lower NO levels than B6 DCs. We demonstrate that activated B6.PWD-Chr11.2 DCs maintain mitochondrial respiration and TCA cycle carbon flux, compared with B6 DCs. However, reduced NO production by the PWD Nos2 allele results in impaired cellular control of Listeria monocytogenes replication. These studies establish a natural genetic model for restrained endogenous NO production to investigate the contribution of NO in regulating the interplay between DC metabolism and immune function. These findings suggest that reported differences between human and murine DCs may be an artifact of the limited genetic diversity of the mouse models used, underscoring the need for mouse genetic diversity in immunology research.
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Affiliation(s)
- Julia P. Snyder
- Cell, Molecular, and Biomedical Sciences Program, University of Vermont, Burlington, VT 05405, USA,Department of Biomedical and Health Sciences, College of Nursing and Health Sciences, University of Vermont, Burlington, VT, 05405, USA
| | - Soyeon K. Gullickson
- Cell, Molecular, and Biomedical Sciences Program, University of Vermont, Burlington, VT 05405, USA
| | - Roxana del Rio-Guerra
- Flow Cytometry and Cell Sorting Facility, Larner College of Medicine, University of Vermont, Burlington, Vermont
| | - Andrea Sweezy
- Undergraduate Student Researcher, University of Vermont
| | - Bay Vagher
- Cell, Molecular, and Biomedical Sciences Program, University of Vermont, Burlington, VT 05405, USA,Department of Biomedical and Health Sciences, College of Nursing and Health Sciences, University of Vermont, Burlington, VT, 05405, USA
| | - Tyler C. Hogan
- Department of Biomedical and Health Sciences, College of Nursing and Health Sciences, University of Vermont, Burlington, VT, 05405, USA
| | - Karolyn G. Lahue
- Department of Biomedical and Health Sciences, College of Nursing and Health Sciences, University of Vermont, Burlington, VT, 05405, USA
| | - Julie A. Reisz
- Department of Biochemistry and Molecular Genetics, University of Colorado – Anschutz Medical Campus, Aurora, CO, 80045, USA
| | - Angelo D’Alessandro
- Department of Biochemistry and Molecular Genetics, University of Colorado – Anschutz Medical Campus, Aurora, CO, 80045, USA
| | - Dimitry N. Krementsov
- Cell, Molecular, and Biomedical Sciences Program, University of Vermont, Burlington, VT 05405, USA,Department of Biomedical and Health Sciences, College of Nursing and Health Sciences, University of Vermont, Burlington, VT, 05405, USA
| | - Eyal Amiel
- Cell, Molecular, and Biomedical Sciences Program, University of Vermont, Burlington, VT 05405, USA,Department of Biomedical and Health Sciences, College of Nursing and Health Sciences, University of Vermont, Burlington, VT, 05405, USA,Corresponding author: please direct all correspondence to
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34
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Vogel A, Brunner JS, Hajto A, Sharif O, Schabbauer G. Lipid scavenging macrophages and inflammation. Biochim Biophys Acta Mol Cell Biol Lipids 2022; 1867:159066. [PMID: 34626791 DOI: 10.1016/j.bbalip.2021.159066] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2021] [Accepted: 08/18/2021] [Indexed: 12/11/2022]
Abstract
Macrophages are professional phagocytes, indispensable for maintenance of tissue homeostasis and integrity. Depending on their resident tissue, macrophages are exposed to highly diverse metabolic environments. Adapted to their niche, they can contribute to local metabolic turnover through metabolite uptake, conversion, storage and release. Disturbances in tissue homeostasis caused by infection, inflammation or damage dramatically alter the local milieu, impacting macrophage activation status and metabolism. In the case of persisting stimuli, defective macrophage responses ensue, which can promote tissue damage and disease. Especially relevant herein are disbalances in lipid rich environments, where macrophages are crucially involved in lipid uptake and turnover, preventing lipotoxicity. Lipid uptake is to a large extent facilitated by macrophage expressed scavenger receptors that are dynamically regulated and important in many metabolic diseases. Here, we review the receptors mediating lipid uptake and summarize recent findings on their role in health and disease. We further highlight the underlying pathways driving macrophage lipid acquisition and their impact on myeloid metabolic remodelling.
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Affiliation(s)
- Andrea Vogel
- Institute for Vascular Biology, Centre for Physiology and Pharmacology, Medical University Vienna, Vienna, Austria; Christian Doppler Laboratory for Arginine Metabolism in Rheumatoid Arthritis and Multiple Sclerosis, Vienna, Austria
| | - Julia Stefanie Brunner
- Institute for Vascular Biology, Centre for Physiology and Pharmacology, Medical University Vienna, Vienna, Austria; Christian Doppler Laboratory for Arginine Metabolism in Rheumatoid Arthritis and Multiple Sclerosis, Vienna, Austria
| | - Alexander Hajto
- Institute for Vascular Biology, Centre for Physiology and Pharmacology, Medical University Vienna, Vienna, Austria; Christian Doppler Laboratory for Arginine Metabolism in Rheumatoid Arthritis and Multiple Sclerosis, Vienna, Austria
| | - Omar Sharif
- Institute for Vascular Biology, Centre for Physiology and Pharmacology, Medical University Vienna, Vienna, Austria; Christian Doppler Laboratory for Arginine Metabolism in Rheumatoid Arthritis and Multiple Sclerosis, Vienna, Austria.
| | - Gernot Schabbauer
- Institute for Vascular Biology, Centre for Physiology and Pharmacology, Medical University Vienna, Vienna, Austria; Christian Doppler Laboratory for Arginine Metabolism in Rheumatoid Arthritis and Multiple Sclerosis, Vienna, Austria.
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35
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Morgan PK, Huynh K, Pernes G, Miotto PM, Mellett NA, Giles C, Meikle PJ, Murphy AJ, Lancaster GI. Macrophage polarization state affects lipid composition and the channeling of exogenous fatty acids into endogenous lipid pools. J Biol Chem 2021; 297:101341. [PMID: 34695418 PMCID: PMC8604758 DOI: 10.1016/j.jbc.2021.101341] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2021] [Revised: 10/14/2021] [Accepted: 10/20/2021] [Indexed: 12/23/2022] Open
Abstract
Adipose-tissue-resident macrophages (ATMs) maintain metabolic homeostasis but also contribute to obesity-induced adipose tissue inflammation and metabolic dysfunction. Central to these contrasting effects of ATMs on metabolic homeostasis is the interaction of macrophages with fatty acids. Fatty acid levels are increased within adipose tissue in various pathological and physiological conditions, but appear to initiate inflammatory responses only upon interaction with particular macrophage subsets within obese adipose tissue. The molecular basis underlying these divergent outcomes is likely due to phenotypic differences between ATM subsets, although how macrophage polarization state influences the metabolism of exogenous fatty acids is relatively unknown. Herein, using stable isotope-labeled and nonlabeled fatty acids in combination with mass spectrometry lipidomics, we show marked differences in the utilization of exogenous fatty acids within inflammatory macrophages (M1 macrophages) and macrophages involved in tissue homeostasis (M2 macrophages). Specifically, the accumulation of exogenous fatty acids within triacylglycerols and cholesterol esters is significantly higher in M1 macrophages, while there is an increased enrichment of exogenous fatty acids within glycerophospholipids, ether lipids, and sphingolipids in M2 macrophages. Finally, we show that functionally distinct ATM populations in vivo have distinct lipid compositions. Collectively, this study identifies new aspects of the metabolic reprogramming that occur in distinct macrophage polarization states. The channeling of exogenous fatty acids into particular lipid synthetic pathways may contribute to the sensitivity/resistance of macrophage subsets to the inflammatory effects of increased environmental fatty acid levels.
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Affiliation(s)
- Pooranee K Morgan
- Baker Heart and Diabetes Institute, Melbourne, Australia; School of Life Sciences, La Trobe University, Melbourne, Australia
| | - Kevin Huynh
- Baker Heart and Diabetes Institute, Melbourne, Australia
| | - Gerard Pernes
- Baker Heart and Diabetes Institute, Melbourne, Australia
| | - Paula M Miotto
- Department of Anatomy and Physiology, School of Biomedical Sciences, University of Melboure, Melbourne, Australia
| | | | - Corey Giles
- Baker Heart and Diabetes Institute, Melbourne, Australia
| | - Peter J Meikle
- Baker Heart and Diabetes Institute, Melbourne, Australia
| | - Andrew J Murphy
- Baker Heart and Diabetes Institute, Melbourne, Australia; Department of Immunology, Monash University, Melbourne, Australia.
| | - Graeme I Lancaster
- Baker Heart and Diabetes Institute, Melbourne, Australia; Department of Immunology, Monash University, Melbourne, Australia.
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36
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Abstract
Cell membrane fusion and multinucleation in macrophages are associated with physiologic homeostasis as well as disease. Osteoclasts are multinucleated macrophages that resorb bone through increased metabolic activity resulting from cell fusion. Fusion of macrophages also generates multinucleated giant cells (MGCs) in white adipose tissue (WAT) of obese individuals. For years, our knowledge of MGCs in WAT has been limited to their description as part of crown-like structures (CLS) surrounding damaged adipocytes. However, recent evidence indicates that these cells can phagocytose oversized lipid remnants, suggesting that, as in osteoclasts, cell fusion and multinucleation are required for specialized catabolic functions. We thus reason that WAT MGCs can be viewed as functionally analogous to osteoclasts and refer to them in this article as adipoclasts. We first review current knowledge on adipoclasts and their described functions. In view of recent advances in single cell genomics, we describe WAT macrophages from a ‘fusion perspective’ and speculate on the ontogeny of adipoclasts. Specifically, we highlight the role of CD9 and TREM2, two plasma membrane markers of lipid-associated macrophages in WAT, which have been previously described as regulators of fusion and multinucleation in osteoclasts and MGCs. Finally, we consider whether strategies aiming to target WAT macrophages can be more selectively directed against adipoclasts.
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37
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Metabolic orchestration of the wound healing response. Cell Metab 2021; 33:1726-1743. [PMID: 34384520 DOI: 10.1016/j.cmet.2021.07.017] [Citation(s) in RCA: 138] [Impact Index Per Article: 34.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/23/2021] [Revised: 06/16/2021] [Accepted: 07/26/2021] [Indexed: 12/12/2022]
Abstract
Wound healing requires cooperation between different cell types, among which macrophages play a central role. In particular, inflammatory macrophages are engaged in the initial response to wounding, and alternatively activated macrophages are essential for wound closure and the resolution of tissue repair. The links between temporal activation-induced changes in the metabolism of such macrophages and the influence this has on their functional states, along with the realization that metabolites play both intrinsic and extrinsic roles in the cells that produce them, has focused attention on the metabolism of wound healing. Here, we discuss macrophage metabolism during distinct stages of normal healing and its related pathologic processes, such as during cancer and fibrosis. Further, we frame these insights in a broader context of the current understanding of macrophage metabolic reprogramming linked to cellular activation and function. Finally, we discuss parallels between the metabolism of macrophages and fibroblasts, the latter being a key stromal cell type in wound healing, and consider the importance of the metabolic interplay between different cell types in the wound microenvironment.
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38
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The gate to metabolic crossroads. Sci Bull (Beijing) 2021; 66:1488-1490. [PMID: 36654273 DOI: 10.1016/j.scib.2021.03.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
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39
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De Melo P, Pineros Alvarez AR, Ye X, Blackman A, Alves-Filho JC, Medeiros AI, Rathmell J, Pua H, Serezani CH. Macrophage-Derived MicroRNA-21 Drives Overwhelming Glycolytic and Inflammatory Response during Sepsis via Repression of the PGE 2/IL-10 Axis. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2021; 207:902-912. [PMID: 34301845 PMCID: PMC8323968 DOI: 10.4049/jimmunol.2001251] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/10/2020] [Accepted: 05/24/2021] [Indexed: 12/20/2022]
Abstract
Myeloid cells are critical for systemic inflammation, microbial control, and organ damage during sepsis. MicroRNAs are small noncoding RNAs that can dictate the outcome of sepsis. The role of myeloid-based expression of microRNA-21 (miR-21) in sepsis is inconclusive. In this study, we show that sepsis enhanced miR-21 expression in both peritoneal macrophages and neutrophils from septic C57BL/6J mice, and the deletion of miR-21 locus in myeloid cells (miR-21Δmyel mice) enhanced animal survival, decreased bacterial growth, decreased systemic inflammation, and decreased organ damage. Resistance to sepsis was associated with a reduction of aerobic glycolysis and increased levels of the anti-inflammatory mediators PGE2 and IL-10 in miR-21Δmyel in vivo and in vitro. Using blocking Abs and pharmacological tools, we discovered that increased survival and decreased systemic inflammation in septic miR-21Δmyel mice is dependent on PGE2/IL-10-mediated inhibition of glycolysis. Together, these findings demonstrate that expression of miR-21 in myeloid cells orchestrates the balance between anti-inflammatory mediators and metabolic reprogramming that drives cytokine storm during sepsis.
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Affiliation(s)
- Paulo De Melo
- Division of Infectious Diseases, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN
| | | | - Xiang Ye
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN
| | - Amondrea Blackman
- Division of Infectious Diseases, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN
| | - Jose Carlos Alves-Filho
- Department of Pharmacology, School of Medicine of Ribeirão Preto, University of São Paulo, São Paulo, Brazil
| | - Alexandra I Medeiros
- Department of Biological Sciences, School of Pharmaceutical Sciences, São Paulo State University, Araraquara, São Paulo, Brazil
- Department of Biochemistry and Immunology, Faculty of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, Brazil
| | - Jeffrey Rathmell
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN
- Vanderbilt Center for Immunobiology, Vanderbilt University Medical Center, Nashville, TN; and
- Vanderbilt Institute for Infection, Inflammation, and Immunity, Vanderbilt University Medical Center, Nashville, TN
| | - Heather Pua
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN
- Department of Pharmacology, School of Medicine of Ribeirão Preto, University of São Paulo, São Paulo, Brazil
- Vanderbilt Center for Immunobiology, Vanderbilt University Medical Center, Nashville, TN; and
- Vanderbilt Institute for Infection, Inflammation, and Immunity, Vanderbilt University Medical Center, Nashville, TN
| | - C Henrique Serezani
- Division of Infectious Diseases, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN;
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN
- Vanderbilt Center for Immunobiology, Vanderbilt University Medical Center, Nashville, TN; and
- Vanderbilt Institute for Infection, Inflammation, and Immunity, Vanderbilt University Medical Center, Nashville, TN
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40
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Natoli G, Pileri F, Gualdrini F, Ghisletti S. Integration of transcriptional and metabolic control in macrophage activation. EMBO Rep 2021; 22:e53251. [PMID: 34328708 DOI: 10.15252/embr.202153251] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2021] [Revised: 07/07/2021] [Accepted: 07/08/2021] [Indexed: 11/09/2022] Open
Abstract
Macrophages react to microbial and endogenous danger signals by activating a broad panel of effector and homeostatic responses. Such responses entail rapid and stimulus-specific changes in gene expression programs accompanied by extensive rewiring of metabolism, with alterations in chromatin modifications providing one layer of integration of transcriptional and metabolic regulation. A systematic and mechanistic understanding of the mutual influences between signal-induced metabolic changes and gene expression is still lacking. Here, we discuss current evidence, controversies, knowledge gaps, and future areas of investigation on how metabolic and transcriptional changes are dynamically integrated during macrophage activation. The cross-talk between metabolism and inflammatory gene expression is in part accounted for by alterations in the production, usage, and availability of metabolic intermediates that impact the macrophage epigenome. In addition, stimulus-inducible gene expression changes alter the production of inflammatory mediators, such as nitric oxide, that in turn modulate the activity of metabolic enzymes thus determining complex regulatory loops. Critical issues remain to be understood, notably whether and how metabolic rewiring can bring about gene-specific (as opposed to global) expression changes.
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Affiliation(s)
- Gioacchino Natoli
- Department of Experimental Oncology, European Institute of Oncology (IEO) IRCCS, Milan, Italy.,Humanitas University, Milan, Italy
| | - Francesco Pileri
- Department of Experimental Oncology, European Institute of Oncology (IEO) IRCCS, Milan, Italy
| | - Francesco Gualdrini
- Department of Experimental Oncology, European Institute of Oncology (IEO) IRCCS, Milan, Italy
| | - Serena Ghisletti
- Department of Experimental Oncology, European Institute of Oncology (IEO) IRCCS, Milan, Italy
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41
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Sullivan KD, Galbraith MD, Kinning KT, Bartsch KW, Levinsky NC, Araya P, Smith KP, Granrath RE, Shaw JR, Baxter RM, Jordan KR, Russell SA, Dzieciatkowska ME, Reisz JA, Gamboni F, Cendali FI, Ghosh T, Monte AA, Bennett TD, Miller MG, Hsieh EWY, D'Alessandro A, Hansen KC, Espinosa JM. The COVIDome Explorer researcher portal. Cell Rep 2021; 36:109527. [PMID: 34348131 PMCID: PMC8316015 DOI: 10.1016/j.celrep.2021.109527] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2021] [Revised: 06/30/2021] [Accepted: 07/22/2021] [Indexed: 01/08/2023] Open
Abstract
COVID-19 pathology involves dysregulation of diverse molecular, cellular, and physiological processes. To expedite integrated and collaborative COVID-19 research, we completed multi-omics analysis of hospitalized COVID-19 patients, including matched analysis of the whole-blood transcriptome, plasma proteomics with two complementary platforms, cytokine profiling, plasma and red blood cell metabolomics, deep immune cell phenotyping by mass cytometry, and clinical data annotation. We refer to this multidimensional dataset as the COVIDome. We then created the COVIDome Explorer, an online researcher portal where the data can be analyzed and visualized in real time. We illustrate herein the use of the COVIDome dataset through a multi-omics analysis of biosignatures associated with C-reactive protein (CRP), an established marker of poor prognosis in COVID-19, revealing associations between CRP levels and damage-associated molecular patterns, depletion of protective serpins, and mitochondrial metabolism dysregulation. We expect that the COVIDome Explorer will rapidly accelerate data sharing, hypothesis testing, and discoveries worldwide.
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Affiliation(s)
- Kelly Daniel Sullivan
- Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA; Department of Pediatrics, Section of Developmental Biology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
| | - Matthew Dominic Galbraith
- Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA; Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
| | - Kohl Thomas Kinning
- Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
| | - Kyle William Bartsch
- Information Services, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
| | - Nik Caldwell Levinsky
- Information Services, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
| | - Paula Araya
- Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
| | - Keith Patrick Smith
- Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
| | - Ross Erich Granrath
- Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
| | - Jessica Rose Shaw
- Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
| | - Ryan Michael Baxter
- Department of Immunology and Microbiology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
| | - Kimberly Rae Jordan
- Department of Immunology and Microbiology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
| | - Seth Aaron Russell
- Data Science to Patient Value, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
| | - Monika Ewa Dzieciatkowska
- Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
| | - Julie Ann Reisz
- Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
| | - Fabia Gamboni
- Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
| | - Francesca Isabelle Cendali
- Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
| | - Tusharkanti Ghosh
- Department of Biostatistics and Informatics, Colorado School of Public Health, Aurora, CO 80045, USA
| | - Andrew Albert Monte
- Department of Emergency Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
| | - Tellen Demeke Bennett
- Department of Pediatrics, Sections of Informatics and Data Science and Critical Care Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
| | - Michael George Miller
- Information Services, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
| | - Elena Wen-Yuan Hsieh
- Department of Immunology and Microbiology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA; Department of Pediatrics, Division of Allergy/Immunology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
| | - Angelo D'Alessandro
- Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
| | - Kirk Charles Hansen
- Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
| | - Joaquin Maximiliano Espinosa
- Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA; Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
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42
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Falcão-Holanda RB, Brunialti MKC, Jasiulionis MG, Salomão R. Epigenetic Regulation in Sepsis, Role in Pathophysiology and Therapeutic Perspective. Front Med (Lausanne) 2021; 8:685333. [PMID: 34322502 PMCID: PMC8312749 DOI: 10.3389/fmed.2021.685333] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2021] [Accepted: 06/09/2021] [Indexed: 12/12/2022] Open
Abstract
Sepsis is characterized by an initial hyperinflammatory response, with intense cell activation and cytokine storm. In parallel, a prolonged compensatory anti-inflammatory response, known as immunological tolerance, can lead to immunosuppression. Clinically, this condition is associated with multiple organ failure, resulting in the patient's death. The mechanisms underlying the pathophysiology of sepsis are not yet fully understood, but evidence is strong showing that epigenetic changes, including DNA methylation and post-translational modifications of histones, modulate the inflammatory response of sepsis. During the onset of infection, host cells undergo epigenetic changes that favor pathogen survival. Besides, epigenetic changes in essential genes also orchestrate the patient's inflammatory response. In this review, we gathered studies on sepsis and epigenetics to show the central role of epigenetic mechanisms in various aspects of the pathogenesis of sepsis and the potential of epigenetic interventions for its treatment.
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Affiliation(s)
- Renata Brito Falcão-Holanda
- Division of Infectious Diseases, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil
| | - Milena Karina Colo Brunialti
- Division of Infectious Diseases, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil
| | - Miriam Galvonas Jasiulionis
- Department of Pharmacology, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil
| | - Reinaldo Salomão
- Division of Infectious Diseases, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil
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43
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Gautier EL, Askia H, Murcy F, Yvan-Charvet L. Macrophage ontogeny and functional diversity in cardiometabolic diseases. Semin Cell Dev Biol 2021; 119:119-129. [PMID: 34229949 DOI: 10.1016/j.semcdb.2021.06.023] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2021] [Revised: 06/01/2021] [Accepted: 06/28/2021] [Indexed: 12/24/2022]
Abstract
Macrophages are the dominant immune cell types in the adipose tissue, the liver or the aortic wall and they were originally believed to mainly derived from monocytes to fuel tissue inflammation in cardiometabolic diseases. However, over the last decade the identification of tissue resident macrophages (trMacs) from embryonic origin in these metabolic tissues has provided a breakthrough in the field forcing to better comprehend macrophage diversity during pathological states. Infiltrated monocyte-derived macrophages (moMacs), similar to trMacs, adapt to the local metabolic environment that eventually shapes their functions. In this review, we will summarize the emerging versatility of macrophages in cardiometabolic diseases with a focus in the control of adipose tissue, liver and large vessels homeostasis.
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Affiliation(s)
- Emmanuel L Gautier
- Institut National de la Santé et de la Recherche Médicale (Inserm) UMR-S 1166, Sorbonne Université, 75013 Paris, France.
| | - Haoussa Askia
- Institut National de la Santé et de la Recherche Médicale (Inserm) UMR-S 1166, Sorbonne Université, 75013 Paris, France
| | - Florent Murcy
- Institut National de la Santé et de la Recherche Médicale (Inserm) U1065, Université Côte d'Azur, Centre Méditerranéen de Médecine Moléculaire (C3M), Atip-Avenir, Fédération Hospitalo-Universitaire (FHU) Oncoage, 06204 Nice, France
| | - Laurent Yvan-Charvet
- Institut National de la Santé et de la Recherche Médicale (Inserm) U1065, Université Côte d'Azur, Centre Méditerranéen de Médecine Moléculaire (C3M), Atip-Avenir, Fédération Hospitalo-Universitaire (FHU) Oncoage, 06204 Nice, France.
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44
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Luque-Campos N, Bustamante-Barrientos FA, Pradenas C, García C, Araya MJ, Bohaud C, Contreras-López R, Elizondo-Vega R, Djouad F, Luz-Crawford P, Vega-Letter AM. The Macrophage Response Is Driven by Mesenchymal Stem Cell-Mediated Metabolic Reprogramming. Front Immunol 2021; 12:624746. [PMID: 34149687 PMCID: PMC8213396 DOI: 10.3389/fimmu.2021.624746] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2020] [Accepted: 05/13/2021] [Indexed: 12/17/2022] Open
Abstract
Mesenchymal stem cells (MSCs) are multipotent adult stromal cells widely studied for their regenerative and immunomodulatory properties. They are capable of modulating macrophage plasticity depending on various microenvironmental signals. Current studies have shown that metabolic changes can also affect macrophage fate and function. Indeed, changes in the environment prompt phenotype change. Therefore, in this review, we will discuss how MSCs orchestrate macrophage’s metabolic plasticity and the impact on their function. An improved understanding of the crosstalk between macrophages and MSCs will improve our knowledge of MSC’s therapeutic potential in the context of inflammatory diseases, cancer, and tissue repair processes in which macrophages are pivotal.
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Affiliation(s)
- Noymar Luque-Campos
- Laboratorio de Inmunología Celular y Molecular, Facultad de Medicina, Universidad de los Andes, Santiago, Chile.,Centro de Investigación e Innovación Biomédica, Universidad de los Andes, Santiago, Chile.,Programa de Doctorado en Biomedicina, Facultad de Medicina, Universidad de los Andes, Santiago, Chile
| | - Felipe A Bustamante-Barrientos
- Laboratorio de Inmunología Celular y Molecular, Facultad de Medicina, Universidad de los Andes, Santiago, Chile.,Centro de Investigación e Innovación Biomédica, Universidad de los Andes, Santiago, Chile
| | - Carolina Pradenas
- Laboratorio de Inmunología Celular y Molecular, Facultad de Medicina, Universidad de los Andes, Santiago, Chile.,Centro de Investigación e Innovación Biomédica, Universidad de los Andes, Santiago, Chile.,Facultad de Ciencias, Universidad de Chile, Santiago, Chile
| | - Cynthia García
- Laboratorio de Inmunología Celular y Molecular, Facultad de Medicina, Universidad de los Andes, Santiago, Chile.,Centro de Investigación e Innovación Biomédica, Universidad de los Andes, Santiago, Chile.,Escuela de Biotecnología, Facultad de Ciencias, Universidad Mayor, Santiago, Chile
| | - María Jesús Araya
- Laboratorio de Inmunología Celular y Molecular, Facultad de Medicina, Universidad de los Andes, Santiago, Chile.,Centro de Investigación e Innovación Biomédica, Universidad de los Andes, Santiago, Chile.,Escuela de Biotecnología, Facultad de Ciencias, Universidad Mayor, Santiago, Chile
| | | | | | - Roberto Elizondo-Vega
- Laboratorio de Biología Celular, Departamento de Biología Celular, Facultad de Ciencias Biológicas, Universidad de Concepción, Concepción, Chile
| | | | - Patricia Luz-Crawford
- Laboratorio de Inmunología Celular y Molecular, Facultad de Medicina, Universidad de los Andes, Santiago, Chile.,Centro de Investigación e Innovación Biomédica, Universidad de los Andes, Santiago, Chile
| | - Ana María Vega-Letter
- Centro de Investigación e Innovación Biomédica, Universidad de los Andes, Santiago, Chile.,Cells for Cells, Regenero, Las Condes, Santiago, Chile.,Laboratory of Nano-Regenerative Medicine, Facultad de Medicina, Universidad de los Andes, Santiago, Chile
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45
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Geisberger S, Bartolomaeus H, Neubert P, Willebrand R, Zasada C, Bartolomaeus T, McParland V, Swinnen D, Geuzens A, Maifeld A, Krampert L, Vogl M, Mähler A, Wilck N, Markó L, Tilic E, Forslund SK, Binger KJ, Stegbauer J, Dechend R, Kleinewietfeld M, Jantsch J, Kempa S, Müller DN. Salt Transiently Inhibits Mitochondrial Energetics in Mononuclear Phagocytes. Circulation 2021; 144:144-158. [PMID: 33906377 PMCID: PMC8270232 DOI: 10.1161/circulationaha.120.052788] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Supplemental Digital Content is available in the text. Background: Dietary high salt (HS) is a leading risk factor for mortality and morbidity. Serum sodium transiently increases postprandially but can also accumulate at sites of inflammation affecting differentiation and function of innate and adaptive immune cells. Here, we focus on how changes in extracellular sodium, mimicking alterations in the circulation and tissues, affect the early metabolic, transcriptional, and functional adaption of human and murine mononuclear phagocytes. Methods: Using Seahorse technology, pulsed stable isotope-resolved metabolomics, and enzyme activity assays, we characterize the central carbon metabolism and mitochondrial function of human and murine mononuclear phagocytes under HS in vitro. HS as well as pharmacological uncoupling of the electron transport chain under normal salt is used to analyze mitochondrial function on immune cell activation and function (as determined by Escherichiacoli killing and CD4+ T cell migration capacity). In 2 independent clinical studies, we analyze the effect of a HS diet during 2 weeks (URL: http://www.clinicaltrials.gov. Unique identifier: NCT02509962) and short-term salt challenge by a single meal (URL: http://www.clinicaltrials.gov. Unique identifier: NCT04175249) on mitochondrial function of human monocytes in vivo. Results: Extracellular sodium was taken up into the intracellular compartment, followed by the inhibition of mitochondrial respiration in murine and human macrophages. Mechanistically, HS reduces mitochondrial membrane potential, electron transport chain complex II activity, oxygen consumption, and ATP production independently of the polarization status of macrophages. Subsequently, cell activation is altered with improved bactericidal function in HS-treated M1-like macrophages and diminished CD4+ T cell migration in HS-treated M2-like macrophages. Pharmacological uncoupling of the electron transport chain under normal salt phenocopies HS-induced transcriptional changes and bactericidal function of human and murine mononuclear phagocytes. Clinically, also in vivo, rise in plasma sodium concentration within the physiological range reversibly reduces mitochondrial function in human monocytes. In both a 14-day and single meal HS challenge, healthy volunteers displayed a plasma sodium increase of and respectively, that correlated with decreased monocytic mitochondrial oxygen consumption. Conclusions: Our data identify the disturbance of mitochondrial respiration as the initial step by which HS mechanistically influences immune cell function. Although these functional changes might help to resolve bacterial infections, a shift toward proinflammation could accelerate inflammatory cardiovascular disease.
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Affiliation(s)
- Sabrina Geisberger
- Experimental and Clinical Research Center, a joint cooperation of Max-Delbrück-Center for Molecular Medicine and Charité-Universitätsmedizin Berlin, Germany (S.G., H.B., V.M., A. Maifeld, A. Mähler, N.W., L.M., S.K.F., R.D., D.N.M.).,Integrative Proteomics and Metabolomics, Berlin Institute for Medical Systems Biology, Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association, Germany (S.G., C.Z., S.K.).,German Center for Cardiovascular Research, partner site Berlin (S.G., H.B., A. Maifeld, A. Mähler, N.W., L.M., S.K.F., R.D., D.N.M.).,Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany (S.G., H.B., V.M., A. Maifeld, A. Mähler, N.W., L.M., S.K.F., R.D., D.N.M.)
| | - Hendrik Bartolomaeus
- Experimental and Clinical Research Center, a joint cooperation of Max-Delbrück-Center for Molecular Medicine and Charité-Universitätsmedizin Berlin, Germany (S.G., H.B., V.M., A. Maifeld, A. Mähler, N.W., L.M., S.K.F., R.D., D.N.M.).,German Center for Cardiovascular Research, partner site Berlin (S.G., H.B., A. Maifeld, A. Mähler, N.W., L.M., S.K.F., R.D., D.N.M.).,Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Germany (H.B., V.M., A. Maifeld, A. Mähler, L.M., S.K.F., R.D., D.N.M.).,Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany (S.G., H.B., V.M., A. Maifeld, A. Mähler, N.W., L.M., S.K.F., R.D., D.N.M.)
| | - Patrick Neubert
- Institute of Clinical Microbiology and Hygiene, University Hospital of Regensburg, University of Regensburg, Germany (P.N., L.K., M.V., J.J.)
| | - Ralf Willebrand
- VIB Laboratory of Translational Immunomodulation, VIB Center for Inflammation Research, UHasselt, Campus Diepenbeek, Belgium (R.W., D.S., A.G., M.K.)
| | - Christin Zasada
- Integrative Proteomics and Metabolomics, Berlin Institute for Medical Systems Biology, Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association, Germany (S.G., C.Z., S.K.)
| | | | - Victoria McParland
- Experimental and Clinical Research Center, a joint cooperation of Max-Delbrück-Center for Molecular Medicine and Charité-Universitätsmedizin Berlin, Germany (S.G., H.B., V.M., A. Maifeld, A. Mähler, N.W., L.M., S.K.F., R.D., D.N.M.).,Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Germany (H.B., V.M., A. Maifeld, A. Mähler, L.M., S.K.F., R.D., D.N.M.).,Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany (S.G., H.B., V.M., A. Maifeld, A. Mähler, N.W., L.M., S.K.F., R.D., D.N.M.)
| | - Dries Swinnen
- VIB Laboratory of Translational Immunomodulation, VIB Center for Inflammation Research, UHasselt, Campus Diepenbeek, Belgium (R.W., D.S., A.G., M.K.)
| | - Anneleen Geuzens
- VIB Laboratory of Translational Immunomodulation, VIB Center for Inflammation Research, UHasselt, Campus Diepenbeek, Belgium (R.W., D.S., A.G., M.K.)
| | - András Maifeld
- Experimental and Clinical Research Center, a joint cooperation of Max-Delbrück-Center for Molecular Medicine and Charité-Universitätsmedizin Berlin, Germany (S.G., H.B., V.M., A. Maifeld, A. Mähler, N.W., L.M., S.K.F., R.D., D.N.M.).,Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Germany (H.B., V.M., A. Maifeld, A. Mähler, L.M., S.K.F., R.D., D.N.M.).,Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany (S.G., H.B., V.M., A. Maifeld, A. Mähler, N.W., L.M., S.K.F., R.D., D.N.M.)
| | - Luka Krampert
- Institute of Clinical Microbiology and Hygiene, University Hospital of Regensburg, University of Regensburg, Germany (P.N., L.K., M.V., J.J.)
| | - Marion Vogl
- Institute of Clinical Microbiology and Hygiene, University Hospital of Regensburg, University of Regensburg, Germany (P.N., L.K., M.V., J.J.)
| | - Anja Mähler
- Experimental and Clinical Research Center, a joint cooperation of Max-Delbrück-Center for Molecular Medicine and Charité-Universitätsmedizin Berlin, Germany (S.G., H.B., V.M., A. Maifeld, A. Mähler, N.W., L.M., S.K.F., R.D., D.N.M.).,German Center for Cardiovascular Research, partner site Berlin (S.G., H.B., A. Maifeld, A. Mähler, N.W., L.M., S.K.F., R.D., D.N.M.).,Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Germany (H.B., V.M., A. Maifeld, A. Mähler, L.M., S.K.F., R.D., D.N.M.).,Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany (S.G., H.B., V.M., A. Maifeld, A. Mähler, N.W., L.M., S.K.F., R.D., D.N.M.)
| | - Nicola Wilck
- Experimental and Clinical Research Center, a joint cooperation of Max-Delbrück-Center for Molecular Medicine and Charité-Universitätsmedizin Berlin, Germany (S.G., H.B., V.M., A. Maifeld, A. Mähler, N.W., L.M., S.K.F., R.D., D.N.M.).,German Center for Cardiovascular Research, partner site Berlin (S.G., H.B., A. Maifeld, A. Mähler, N.W., L.M., S.K.F., R.D., D.N.M.).,Berlin Institute of Health at Charité-Universitätsmedizin Berlin, Germany (N.W.).,Department of Nephrology and Internal Intensive Care Medicine (N.W.).,Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany (S.G., H.B., V.M., A. Maifeld, A. Mähler, N.W., L.M., S.K.F., R.D., D.N.M.)
| | - Lajos Markó
- Experimental and Clinical Research Center, a joint cooperation of Max-Delbrück-Center for Molecular Medicine and Charité-Universitätsmedizin Berlin, Germany (S.G., H.B., V.M., A. Maifeld, A. Mähler, N.W., L.M., S.K.F., R.D., D.N.M.).,German Center for Cardiovascular Research, partner site Berlin (S.G., H.B., A. Maifeld, A. Mähler, N.W., L.M., S.K.F., R.D., D.N.M.).,Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Germany (H.B., V.M., A. Maifeld, A. Mähler, L.M., S.K.F., R.D., D.N.M.).,Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany (S.G., H.B., V.M., A. Maifeld, A. Mähler, N.W., L.M., S.K.F., R.D., D.N.M.)
| | - Ekin Tilic
- Institute of Evolutionary Biology, University of Bonn, Germany (T.B., E.T.)
| | - Sofia K Forslund
- Experimental and Clinical Research Center, a joint cooperation of Max-Delbrück-Center for Molecular Medicine and Charité-Universitätsmedizin Berlin, Germany (S.G., H.B., V.M., A. Maifeld, A. Mähler, N.W., L.M., S.K.F., R.D., D.N.M.).,German Center for Cardiovascular Research, partner site Berlin (S.G., H.B., A. Maifeld, A. Mähler, N.W., L.M., S.K.F., R.D., D.N.M.).,Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Germany (H.B., V.M., A. Maifeld, A. Mähler, L.M., S.K.F., R.D., D.N.M.).,Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany (S.G., H.B., V.M., A. Maifeld, A. Mähler, N.W., L.M., S.K.F., R.D., D.N.M.)
| | - Katrina J Binger
- Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Bundoora, Australia (K.J.B.)
| | - Johannes Stegbauer
- Department of Nephrology, Medical Faculty, University Hospital Düsseldorf, Heinrich-Heine-University Düsseldorf, Germany (J.S.)
| | - Ralf Dechend
- Experimental and Clinical Research Center, a joint cooperation of Max-Delbrück-Center for Molecular Medicine and Charité-Universitätsmedizin Berlin, Germany (S.G., H.B., V.M., A. Maifeld, A. Mähler, N.W., L.M., S.K.F., R.D., D.N.M.).,German Center for Cardiovascular Research, partner site Berlin (S.G., H.B., A. Maifeld, A. Mähler, N.W., L.M., S.K.F., R.D., D.N.M.).,Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Germany (H.B., V.M., A. Maifeld, A. Mähler, L.M., S.K.F., R.D., D.N.M.).,Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany (S.G., H.B., V.M., A. Maifeld, A. Mähler, N.W., L.M., S.K.F., R.D., D.N.M.).,Department of Cardiology and Nephrology, HELIOS-Klinikum, Berlin, Germany (R.D.)
| | - Markus Kleinewietfeld
- VIB Laboratory of Translational Immunomodulation, VIB Center for Inflammation Research, UHasselt, Campus Diepenbeek, Belgium (R.W., D.S., A.G., M.K.)
| | - Jonathan Jantsch
- Institute of Clinical Microbiology and Hygiene, University Hospital of Regensburg, University of Regensburg, Germany (P.N., L.K., M.V., J.J.)
| | - Stefan Kempa
- Integrative Proteomics and Metabolomics, Berlin Institute for Medical Systems Biology, Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association, Germany (S.G., C.Z., S.K.)
| | - Dominik N Müller
- Experimental and Clinical Research Center, a joint cooperation of Max-Delbrück-Center for Molecular Medicine and Charité-Universitätsmedizin Berlin, Germany (S.G., H.B., V.M., A. Maifeld, A. Mähler, N.W., L.M., S.K.F., R.D., D.N.M.).,German Center for Cardiovascular Research, partner site Berlin (S.G., H.B., A. Maifeld, A. Mähler, N.W., L.M., S.K.F., R.D., D.N.M.).,Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Germany (H.B., V.M., A. Maifeld, A. Mähler, L.M., S.K.F., R.D., D.N.M.).,Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany (S.G., H.B., V.M., A. Maifeld, A. Mähler, N.W., L.M., S.K.F., R.D., D.N.M.)
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Sullivan KD, Galbraith MD, Kinning KT, Bartsch K, Levinsky N, Araya P, Smith KP, Granrath RE, Shaw JR, Baxter R, Jordan KR, Russell S, Dzieciatkowska M, Reisz JA, Gamboni F, Cendali F, Ghosh T, Monte AA, Bennett TD, Miller MG, Hsieh EW, D’Alessandro A, Hansen KC, Espinosa JM. The COVIDome Explorer Researcher Portal. MEDRXIV : THE PREPRINT SERVER FOR HEALTH SCIENCES 2021:2021.03.04.21252945. [PMID: 33758879 PMCID: PMC7987038 DOI: 10.1101/2021.03.04.21252945] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/08/2023]
Abstract
COVID-19 pathology involves dysregulation of diverse molecular, cellular, and physiological processes. In order to expedite integrated and collaborative COVID-19 research, we completed multi-omics analysis of hospitalized COVID-19 patients including matched analysis of the whole blood transcriptome, plasma proteomics with two complementary platforms, cytokine profiling, plasma and red blood cell metabolomics, deep immune cell phenotyping by mass cytometry, and clinical data annotation. We refer to this multidimensional dataset as the COVIDome. We then created the COVIDome Explorer, an online researcher portal where the data can be analyzed and visualized in real time. We illustrate here the use of the COVIDome dataset through a multi-omics analysis of biosignatures associated with C-reactive protein (CRP), an established marker of poor prognosis in COVID-19, revealing associations between CRP levels and damage-associated molecular patterns, depletion of protective serpins, and mitochondrial metabolism dysregulation. We expect that the COVIDome Explorer will rapidly accelerate data sharing, hypothesis testing, and discoveries worldwide.
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Affiliation(s)
- Kelly D. Sullivan
- Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
- Department of Pediatrics, Section of Developmental Biology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Matthew D. Galbraith
- Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
- Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Kohl T. Kinning
- Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Kyle Bartsch
- Information Services, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Nik Levinsky
- Information Services, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Paula Araya
- Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Keith P. Smith
- Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Ross E. Granrath
- Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Jessica R. Shaw
- Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Ryan Baxter
- Department of Immunology and Microbiology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Kimberly R. Jordan
- Department of Immunology and Microbiology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Seth Russell
- Data Science to Patient Value, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Monika Dzieciatkowska
- Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Julie A. Reisz
- Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Fabia Gamboni
- Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Francesca Cendali
- Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Tusharkanti Ghosh
- Department of Biostatistics and Informatics, Colorado School of Public Health, Aurora, CO, USA
| | - Andrew A. Monte
- Department of Emergency Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Tellen D. Bennett
- Department of Pediatrics, Sections of Informatics and Data Science and Critical Care Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Michael G. Miller
- Information Services, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Elena W.Y. Hsieh
- Department of Immunology and Microbiology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
- Department of Pediatrics, Division of Allergy/Immunology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Angelo D’Alessandro
- Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Kirk C. Hansen
- Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Joaquin M. Espinosa
- Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
- Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
- Correspondence to:
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47
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Lipid Metabolism in Regulation of Macrophage Functions. Trends Cell Biol 2020; 30:979-989. [DOI: 10.1016/j.tcb.2020.09.006] [Citation(s) in RCA: 69] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2020] [Revised: 09/08/2020] [Accepted: 09/09/2020] [Indexed: 01/04/2023]
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48
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Ko JH, Olona A, Papathanassiu AE, Buang N, Park KS, Costa ASH, Mauro C, Frezza C, Behmoaras J. BCAT1 affects mitochondrial metabolism independently of leucine transamination in activated human macrophages. J Cell Sci 2020; 133:jcs247957. [PMID: 33148611 PMCID: PMC7116427 DOI: 10.1242/jcs.247957] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2020] [Accepted: 10/26/2020] [Indexed: 12/21/2022] Open
Abstract
In response to environmental stimuli, macrophages change their nutrient consumption and undergo an early metabolic adaptation that progressively shapes their polarization state. During the transient, early phase of pro-inflammatory macrophage activation, an increase in tricarboxylic acid (TCA) cycle activity has been reported, but the relative contribution of branched-chain amino acid (BCAA) leucine remains to be determined. Here, we show that glucose but not glutamine is a major contributor of the increase in TCA cycle metabolites during early macrophage activation in humans. We then show that, although uptake of BCAAs is not altered, their transamination by BCAT1 is increased following 8 h lipopolysaccharide (LPS) stimulation. Of note, leucine is not metabolized to integrate into the TCA cycle in basal or stimulated human macrophages. Surprisingly, the pharmacological inhibition of BCAT1 reduced glucose-derived itaconate, α-ketoglutarate and 2-hydroxyglutarate levels without affecting succinate and citrate levels, indicating a partial inhibition of the TCA cycle. This indirect effect is associated with NRF2 (also known as NFE2L2) activation and anti-oxidant responses. These results suggest a moonlighting role of BCAT1 through redox-mediated control of mitochondrial function during early macrophage activation.
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Affiliation(s)
- Jeong-Hun Ko
- Centre for Inflammatory Disease, Imperial College London, London W12 0NN, UK
| | - Antoni Olona
- Centre for Inflammatory Disease, Imperial College London, London W12 0NN, UK
| | | | - Norzawani Buang
- Centre for Inflammatory Disease, Imperial College London, London W12 0NN, UK
| | - Kwon-Sik Park
- Department of Microbiology, Immunology, and Cancer Biology, University of Virginia School of Medicine, Charlottesville, VA 22908, USA
| | - Ana S H Costa
- Medical Research Council Cancer Unit, University of Cambridge, Cambridge CB2 0XZ, UK
| | - Claudio Mauro
- Institute of Inflammation and Ageing, College of Medical and Dental Sciences, University of Birmingham, Mindelsohn Way, Birmingham B15 2WB, UK
| | - Christian Frezza
- Medical Research Council Cancer Unit, University of Cambridge, Cambridge CB2 0XZ, UK
| | - Jacques Behmoaras
- Centre for Inflammatory Disease, Imperial College London, London W12 0NN, UK
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49
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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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50
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Runtsch MC, Ferrara G, Angiari S. Metabolic determinants of leukocyte pathogenicity in neurological diseases. J Neurochem 2020; 158:36-58. [PMID: 32880969 DOI: 10.1111/jnc.15169] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2020] [Revised: 07/31/2020] [Accepted: 08/26/2020] [Indexed: 12/15/2022]
Abstract
Neuroinflammatory and neurodegenerative diseases are characterized by the recruitment of circulating blood-borne innate and adaptive immune cells into the central nervous system (CNS). These leukocytes sustain the detrimental response in the CNS by releasing pro-inflammatory mediators that induce activation of local glial cells, blood-brain barrier (BBB) dysfunction, and neural cell death. However, infiltrating peripheral immune cells could also dampen CNS inflammation and support tissue repair. Recent advances in the field of immunometabolism demonstrate the importance of metabolic reprogramming for the activation and functionality of such innate and adaptive immune cell populations. In particular, an increasing body of evidence suggests that the activity of metabolites and metabolic enzymes could influence the pathogenic potential of immune cells during neuroinflammatory and neurodegenerative disorders. In this review, we discuss the role of intracellular metabolic cues in regulating leukocyte-mediated CNS damage in Alzheimer's and Parkinson's disease, multiple sclerosis and stroke, highlighting the therapeutic potential of drugs targeting metabolic pathways for the treatment of neurological diseases.
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Affiliation(s)
- Marah C Runtsch
- School of Biochemistry and Immunology, Trinity College Dublin, Dublin, Ireland
| | | | - Stefano Angiari
- School of Biochemistry and Immunology, Trinity College Dublin, Dublin, Ireland
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