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Givian A, Azizan A, Jamshidi A, Mahmoudi M, Farhadi E. Iron metabolism in rheumatic diseases. J Transl Autoimmun 2025; 10:100267. [PMID: 39867458 PMCID: PMC11763848 DOI: 10.1016/j.jtauto.2025.100267] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2024] [Revised: 12/24/2024] [Accepted: 01/03/2025] [Indexed: 01/28/2025] Open
Abstract
Iron is a crucial element for living organism in terms of oxygen transport, hematopoiesis, enzymatic activity, mitochondrial respiratory chain function and also immune system function. The human being has evolved a mechanism to regulate body iron. In some rheumatic diseases such as rheumatoid arthritis (RA), systemic lupus erythematous (SLE), systemic sclerosis (SSc), ankylosing spondylitis (AS), and gout, this balanced iron regulation is impaired. Altered iron homeostasis can contribute to disease progression through ROS production, fibrosis, inflammation, abnormal bone homeostasis, NETosis and cell senescence. In this review, we have focused on the iron metabolism in rheumatic disease and its role in disease progression.
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Affiliation(s)
- Aliakbar Givian
- Rheumatology Research Center, Tehran University of Medical Science, Tehran, Iran
- Department of Immunology, School of Medicine, Semnan University of Medical Science, Semnan, Iran
| | - Amin Azizan
- Rheumatology Research Center, Tehran University of Medical Science, Tehran, Iran
- Research Center for Chronic Inflammatory Diseases, Tehran University of Medical Sciences, Tehran, Iran
| | - Ahmadreza Jamshidi
- Rheumatology Research Center, Tehran University of Medical Science, Tehran, Iran
| | - Mahdi Mahmoudi
- Rheumatology Research Center, Tehran University of Medical Science, Tehran, Iran
- Research Center for Chronic Inflammatory Diseases, Tehran University of Medical Sciences, Tehran, Iran
| | - Elham Farhadi
- Rheumatology Research Center, Tehran University of Medical Science, Tehran, Iran
- Research Center for Chronic Inflammatory Diseases, Tehran University of Medical Sciences, Tehran, Iran
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Liu S, Tsyplenkova S, Fillebeen C, Pantopoulos K. Hypoferremic Response to Chronic Inflammation Is Controlled via the Hemojuvelin/Hepcidin/Ferroportin Axis and Does Not Involve Hepcidin-Independent Regulation of Fpn mRNA. Am J Hematol 2025. [PMID: 40347094 DOI: 10.1002/ajh.27710] [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: 12/16/2024] [Revised: 04/28/2025] [Accepted: 04/30/2025] [Indexed: 05/12/2025]
Abstract
The iron regulatory hormone hepcidin contributes to the pathogenesis of anemia of inflammation (AI) by inhibiting the iron exporter ferroportin in target cells, causing hypoferremia. Under acute inflammation, hepcidin induction requires hemojuvelin (Hjv), a bone morphogenetic protein co-receptor, while Fpn mRNA is also suppressed in a hepcidin-independent manner. However, it is unclear whether, during chronic inflammation, Hjv and hepcidin-independent Fpn mRNA regulation are critical for hypoferremia and AI. To address these questions, wild type and Hjv-/- mice, a model of hemochromatosis, were fed for 8 weeks an adenine-rich diet to develop chronic kidney disease (CKD). Renal inflammation, accessed by increased Il6 mRNA expression, did not differ among genotypes. Hjv disruption did not mitigate the severity of kidney injury but suppressed the inflammatory induction of liver hepcidin. CKD triggered hypoferremia and mild anemia in wild type mice; however, Hjv-/- littermates maintained high serum iron and normal hemoglobin, consistent with a protective effect of Hjv/hepcidin deficiency. Notably, tissue Fpn mRNA levels were not affected by the inflammatory milieu of CKD. Following injection of wild type or Hjv-/- mice with heat-killed Brucella abortus, Fpn mRNA was suppressed during the acute phase of inflammation but quickly recovered and persisted in the chronic phase. We conclude that Hjv deficiency reduces hepcidin levels and mitigates anemia in the CKD model, providing further support for pharmacological targeting of Hjv for the treatment of AI. Moreover, our data demonstrate that Fpn mRNA suppression only occurs under acute but not chronic inflammatory conditions and therefore cannot substantially contribute to AI pathogenesis.
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Affiliation(s)
- Siqi Liu
- Lady Davis Institute for Medical Research, Jewish General Hospital and Department of Medicine, McGill University, Montreal, Quebec, Canada
| | - Sofiya Tsyplenkova
- Lady Davis Institute for Medical Research, Jewish General Hospital and Department of Medicine, McGill University, Montreal, Quebec, Canada
| | - Carine Fillebeen
- Lady Davis Institute for Medical Research, Jewish General Hospital and Department of Medicine, McGill University, Montreal, Quebec, Canada
| | - Kostas Pantopoulos
- Lady Davis Institute for Medical Research, Jewish General Hospital and Department of Medicine, McGill University, Montreal, Quebec, Canada
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Marques O, Horvat NK, Zechner L, Colucci S, Sparla R, Zimmermann S, Neufeldt CJ, Altamura S, Qiu R, Müdder K, Weiss G, Hentze MW, Muckenthaler MU. Inflammation-driven NF-κB signaling represses ferroportin transcription in macrophages via HDAC1 and HDAC3. Blood 2025; 145:866-880. [PMID: 39656097 DOI: 10.1182/blood.2023023417] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2023] [Accepted: 10/25/2024] [Indexed: 02/21/2025] Open
Abstract
ABSTRACT Anemia of inflammation is a prevalent comorbidity in patients with chronic inflammatory disorders. Inflammation causes hypoferremia and iron-restricted erythropoiesis by limiting ferroportin (FPN)-mediated iron export from macrophages that recycle senescent erythrocytes. Macrophage cell surface expression of FPN is reduced by hepcidin-induced degradation and/or by repression of FPN (Slc40a1) transcription via cytokine and Toll-like receptor (TLR) stimulation. Although the mechanisms underlying hepcidin-mediated control of FPN have been extensively studied, those inhibiting Slc40a1 messenger RNA (mRNA) expression remain unknown. We applied targeted RNA interference and pharmacological screens in macrophages stimulated with the TLR2/6 ligand FSL1 and identified critical signaling regulators of Slc40a1 mRNA repression downstream of TLRs and NF-κB signaling. Interestingly, the NF-κB regulatory hub is equally relevant for Slc40a1 mRNA repression driven by the TLR4 ligand lipopolysaccharide, the cytokine tumor necrosis factor β/lymphotoxin-alpha (LTA), and heat-killed bacteria. Mechanistically, macrophage stimulation with heat-killed Staphylococcus aureus recruits the histone deacetylases (HDACs) HDAC1 and HDAC3 to the antioxidant response element (ARE) located in the Slc40a1 promoter. Accordingly, pretreatment with a pan-HDAC inhibitor abrogates Slc40a1 mRNA repression in response to inflammatory cues, suggesting that HDACs act downstream of NF-κB to repress Slc40a1 transcription. Consistently, recruitment of HDAC1 and HDAC3 to the Slc40a1 ARE after stimulation with heat-killed S aureus is dependent on NF-κB signaling. These results support a model in which the ARE integrates the transcriptional responses of Slc40a1 triggered by signals from redox, metabolic, and inflammatory pathways. This work identifies the long-sought mechanism of Slc40a1 transcriptional downregulation upon inflammation, paving the way for therapeutic interventions at this critical juncture.
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Affiliation(s)
- Oriana Marques
- Department of Pediatric Hematology, Oncology, and Immunology, University of Heidelberg, Heidelberg, Germany
- Molecular Medicine Partnership Unit, University of Heidelberg, Heidelberg, Germany
| | - Natalie K Horvat
- Department of Pediatric Hematology, Oncology, and Immunology, University of Heidelberg, Heidelberg, Germany
- Translational Lung Research Center Heidelberg, German Center for Lung Research, University of Heidelberg, Heidelberg, Germany
| | - Laura Zechner
- Department of Pediatric Hematology, Oncology, and Immunology, University of Heidelberg, Heidelberg, Germany
| | - Silvia Colucci
- Department of Pediatric Hematology, Oncology, and Immunology, University of Heidelberg, Heidelberg, Germany
- Molecular Medicine Partnership Unit, University of Heidelberg, Heidelberg, Germany
| | - Richard Sparla
- Department of Pediatric Hematology, Oncology, and Immunology, University of Heidelberg, Heidelberg, Germany
- Molecular Medicine Partnership Unit, University of Heidelberg, Heidelberg, Germany
| | - Stefan Zimmermann
- Department for Infectious Diseases, Microbiology and Hygiene, University Hospital Heidelberg, Heidelberg, Germany
| | - Christopher J Neufeldt
- Department of Infectious Diseases, Molecular Virology, University of Heidelberg, Heidelberg, Germany
- Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA
| | - Sandro Altamura
- Department of Pediatric Hematology, Oncology, and Immunology, University of Heidelberg, Heidelberg, Germany
- Molecular Medicine Partnership Unit, University of Heidelberg, Heidelberg, Germany
| | - Ruiyue Qiu
- Department of Pediatric Hematology, Oncology, and Immunology, University of Heidelberg, Heidelberg, Germany
| | - Katja Müdder
- Department of Pediatric Hematology, Oncology, and Immunology, University of Heidelberg, Heidelberg, Germany
- Molecular Medicine Partnership Unit, University of Heidelberg, Heidelberg, Germany
| | - Günter Weiss
- Department of Internal Medicine II, Medical University of Innsbruck, Innsbruck, Austria
- Christian Doppler Laboratory for Iron Metabolism and Anemia Research, Medical University of Innsbruck, Innsbruck, Austria
| | - Matthias W Hentze
- Molecular Medicine Partnership Unit, University of Heidelberg, Heidelberg, Germany
- European Molecular Biology Laboratory, Heidelberg, Germany
| | - Martina U Muckenthaler
- Department of Pediatric Hematology, Oncology, and Immunology, University of Heidelberg, Heidelberg, Germany
- Molecular Medicine Partnership Unit, University of Heidelberg, Heidelberg, Germany
- Translational Lung Research Center Heidelberg, German Center for Lung Research, University of Heidelberg, Heidelberg, Germany
- German Centre for Cardiovascular Research, Partner Site Heidelberg/Mannheim, Heidelberg/Mannheim, Germany
- Center for Translational Biomedical Iron Research, University of Heidelberg, Heidelberg, Germany
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Herpich C, Walter S, Ott C, Haß U, Grune T, Müller-Werdan U, Norman K. Pro-inflammatory diet affects markers of iron metabolism in healthy older adults. J Trace Elem Med Biol 2025; 87:127583. [PMID: 39708661 DOI: 10.1016/j.jtemb.2024.127583] [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: 09/09/2024] [Revised: 12/02/2024] [Accepted: 12/16/2024] [Indexed: 12/23/2024]
Abstract
BACKGROUND Inflammation and inadequate nutrition are common in older age and known to affect iron homeostasis. However, it is not known whether a pro-inflammatory diet affects iron status in older adults. We investigated the diet quality of healthy older adults considering markers of iron homeostasis and inflammation compared to a younger control. METHODS Serum markers of iron metabolism (iron, transferrin, ferritin, hepcidin, soluble transferrin receptor [sTfR]) and inflammation (interleukin-6 [IL-6], IL-10 high-sensitive C- reactive protein [hsCRP]) were quantified using immunosorbent assays. Insulin resistance was determined by calculating the homeostasis model assessment index (HOMA-IR). The Dietary Inflammatory Index® (DII) was computed based on dietary intake and inflammatory (ID) or less inflammatory diet (LID) groups were created by using median DII score specific to age group and sex. RESULTS DII did not differ by age (p = 0.668, n = 80, F: 75 %, >65 years, n = 60, F: 72 %, ≤35 years). Iron and inflammation status were different between age groups in terms of higher transferrin saturation, sTfR, ferritin and IL-6 concentrations in the old (all p ≤ 0.001). Only in older adults, BMI, HOMA-IR, hsCRP, ferritin and hepcidin concentrations were significantly higher in ID compared to LID (all p < 0.01). In addition, a risk-factor adjusted regression analysis showed that ID was independently associated with higher ferritin and hepcidin concentrations in older adults. CONCLUSION In older age, a pro-inflammatory diet is associated with systemic inflammation and disturbed iron homeostasis.
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Affiliation(s)
- Catrin Herpich
- Department of Nutrition and Gerontology, German Institute of Human Nutrition Potsdam-Rehbrücke, Nuthetal, Germany; Institute of Nutritional Science, University of Potsdam, Nuthetal, Germany; Department of Geriatrics and Medical Gerontology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany.
| | - Sophia Walter
- Department of Molecular Toxicology, German Institute of Human Nutrition Potsdam-Rehbrücke, Nuthetal, Germany; German Center for Cardiovascular Research (DZHK), Partner Site Berlin, Berlin, Germany; TraceAge-DFG Research Unit on Interactions of Essential Trace Elements in Healthy and Diseased Elderly, Potsdam-Berlin-Jena-Wuppertal, Germany
| | - Christiane Ott
- Department of Molecular Toxicology, German Institute of Human Nutrition Potsdam-Rehbrücke, Nuthetal, Germany; German Center for Cardiovascular Research (DZHK), Partner Site Berlin, Berlin, Germany; TraceAge-DFG Research Unit on Interactions of Essential Trace Elements in Healthy and Diseased Elderly, Potsdam-Berlin-Jena-Wuppertal, Germany
| | - Ulrike Haß
- Department of Rehabilitation Medicine, Faculty of Health Sciences, University of Potsdam, Potsdam, Germany
| | - Tilman Grune
- Institute of Nutritional Science, University of Potsdam, Nuthetal, Germany; Department of Molecular Toxicology, German Institute of Human Nutrition Potsdam-Rehbrücke, Nuthetal, Germany; German Center for Cardiovascular Research (DZHK), Partner Site Berlin, Berlin, Germany; TraceAge-DFG Research Unit on Interactions of Essential Trace Elements in Healthy and Diseased Elderly, Potsdam-Berlin-Jena-Wuppertal, Germany
| | - Ursula Müller-Werdan
- Department of Geriatrics and Medical Gerontology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany; Evangelisches Geriatriezentrum Berlin gGmbH, Berlin, Germany
| | - Kristina Norman
- Department of Nutrition and Gerontology, German Institute of Human Nutrition Potsdam-Rehbrücke, Nuthetal, Germany; Institute of Nutritional Science, University of Potsdam, Nuthetal, Germany; Department of Geriatrics and Medical Gerontology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany; German Center for Cardiovascular Research (DZHK), Partner Site Berlin, Berlin, Germany; TraceAge-DFG Research Unit on Interactions of Essential Trace Elements in Healthy and Diseased Elderly, Potsdam-Berlin-Jena-Wuppertal, Germany
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Zhang P, Liu W, Wang S, Wang Y, Han H. Ferroptosisand Its Role in the Treatment of Sepsis-Related Organ Injury: Mechanisms and Potential Therapeutic Approaches. Infect Drug Resist 2024; 17:5715-5727. [PMID: 39720615 PMCID: PMC11668052 DOI: 10.2147/idr.s496568] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2024] [Accepted: 12/12/2024] [Indexed: 12/26/2024] Open
Abstract
Sepsis is a complicated clinical disease caused by a defective host response to infection, leading to elevated morbidity and fatality globally. Sepsis patients have a significant risk of life-threatening organ damage, including hearts, brains, lungs, kidneys, and livers. Nevertheless, the molecular pathways driving organ injury in sepsis are not well known. Ferroptosis, a non-apoptotic cell death, occurs due to iron metabolism disturbance and lipid peroxide buildup. Multiple studies indicate that ferroptosis has a significant role in decreasing inflammation and lipid peroxidation during sepsis. Ferroptosis inhibitors and medications, aimed at the most studied ferroptosis process, including Xc-system, Nrf2/GPX4 axis, and NCOA4-FTH1-mediated ferritinophagy, alleviating sepsis effectively. However, few clinical trials demonstrated ferroptosis-targeted drugs's effectiveness in sepsis. Our study examines ferroptosis-targeted medicinal agents and their potential benefits for treating sepsis-associated organ impairment. This review indicates that ferroptosis suppression by pharmaceutical means may be a useful therapy for sepsis-associated organ injury.
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Affiliation(s)
- Pengyu Zhang
- The Medical College, Shandong University of Traditional Chinese Medicine, Jinan, Shandong, People’s Republic of China
| | - Wendi Liu
- School of Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, Shandong, People’s Republic of China
| | - Shu Wang
- School of Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, Shandong, People’s Republic of China
| | - Yuan Wang
- Department of Histology and Embryology, Shandong University of Traditional Chinese Medicine, Jinan, Shandong, People’s Republic of China
| | - Han Han
- School of Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, Shandong, People’s Republic of China
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Scholz GA, Xie S, Arsiwala T, Guggisberg D, Vogel M, Bachmann M, Möller B. Low Iron Diet Improves Clinical Arthritis in the Mouse Model of Collagen-Induced Arthritis. Cells 2024; 13:1792. [PMID: 39513899 PMCID: PMC11545767 DOI: 10.3390/cells13211792] [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: 05/29/2024] [Revised: 10/23/2024] [Accepted: 10/26/2024] [Indexed: 11/16/2024] Open
Abstract
Background: In response to inflammation, the absorption of nutritional iron is restricted. Since the pathophysiological significance of the presence and uptake of iron in chronic inflammation is still unknown, we tested the effect of a low iron diet on the clinical course of arthritis in the mouse model of collagen-induced arthritis (CIA). Methods: Six- to eight-week-old male DBA/1 mice were fed either a normal (51 mg/kg) or a low iron diet (5 mg/kg) starting four weeks before the first immunization. From day 4 after the second collagen booster made on day 25, the development of arthritis was regularly monitored until the end of the experiment (day 34), using a standard clinical arthritis score. Concentrations of mouse anti-bovine and anti-mouse collagen type 2 IgG antibodies were measured by ELISA; blood cell counts were performed and mediators of inflammation, tissue matrix degradation, oxygenation and oxidative stress were measured in the mouse sera of both diet groups at the end of the experiment by bead-based multiplex assay. Fe2+, Fe3+, oxidized and reduced glutathione (GSH and GSSG) and malondialdehyde (MDA) were quantified in whole paw tissue by ELISA. Quantitative PCR was performed in the tissues for glutathione peroxidase 4 and other key regulator genes of iron metabolism and ferroptosis. We used nonparametric tests to compare cross-sectional data. Nonlinear regression models were used for longitudinal data of the arthritis scores. Results: Mice fed a low iron diet showed a significantly less severe course of arthritis compared to mice fed a normal iron diet (p < 0.001). The immune response against bovine and mouse type 2 collagen did not differ between the two diet groups. Mice fed a low iron diet exhibited significantly lower serum levels of tissue inhibitor of metalloproteinase-1 (TIMP-1), a central regulator of inflammation and tissue matrix degradation (p < 0.05). In addition, a low iron diet led to a significant reduction in red blood cell indices, indicating restricted iron uptake and latent iron deficiency, but had no effect on hemoglobin concentrations or red blood cell counts. There were no differences between the dietary groups in Fe2+ or Fe3+ content in the paws. Based on calculation of the GSH/GSSG ratio and high MDA levels, high oxidative stress and lipid peroxidation were likewise detected in the paws of both diet groups of mice. Consequently, no differences associated with gene expression of key regulators of iron metabolism and ferroptosis could be detected between the paws of both diet groups. Conclusions: Restricted dietary iron intake alleviates immune-mediated inflammation in CIA without causing anemia. This finding suggests a promising option for dietary treatment of arthritis in inflammation. The underlying mechanism causing reduced arthritis may be linked to the complex regulatory network of TIMP-1 and appears to be independent from the local iron levels, oxidative stress and ferroptosis in the synovial tissues.
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Affiliation(s)
| | | | | | | | | | - Martin Bachmann
- Department for Rheumatology and Immunology, Inselspital, University Hospital Bern, 3010 Bern, Switzerland
| | - Burkhard Möller
- Department for Rheumatology and Immunology, Inselspital, University Hospital Bern, 3010 Bern, Switzerland
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Silva-Gomes R, Caldeira I, Fernandes R, Cunha C, Carvalho A. Metabolic regulation of the host-fungus interaction: from biological principles to therapeutic opportunities. J Leukoc Biol 2024; 116:469-486. [PMID: 38498599 DOI: 10.1093/jleuko/qiae045] [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: 01/01/2024] [Revised: 02/11/2024] [Accepted: 02/19/2024] [Indexed: 03/20/2024] Open
Abstract
Fungal infections present a significant global public health concern, impacting over 1 billion individuals worldwide and resulting in more than 3 million deaths annually. Despite considerable progress in recent years, the management of fungal infections remains challenging. The limited development of novel diagnostic and therapeutic approaches is largely attributed to our incomplete understanding of the pathogenetic mechanisms involved in these diseases. Recent research has highlighted the pivotal role of cellular metabolism in regulating the interaction between fungi and their hosts. In response to fungal infection, immune cells undergo complex metabolic adjustments to meet the energy demands necessary for an effective immune response. A comprehensive understanding of the metabolic circuits governing antifungal immunity, combined with the integration of individual host traits, holds the potential to inform novel medical interventions for fungal infections. This review explores recent insights into the immunometabolic regulation of host-fungal interactions and the infection outcome and discusses how the metabolic repurposing of immune cell function could be exploited in innovative and personalized therapeutic approaches.
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Affiliation(s)
- Rita Silva-Gomes
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Campus de Gualtar, 4710-057 Braga, Portugal
- ICVS/3B's-PT Government Associate Laboratory, Braga/Guimarães, Portugal
| | - Inês Caldeira
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Campus de Gualtar, 4710-057 Braga, Portugal
- ICVS/3B's-PT Government Associate Laboratory, Braga/Guimarães, Portugal
| | - Raquel Fernandes
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Campus de Gualtar, 4710-057 Braga, Portugal
- ICVS/3B's-PT Government Associate Laboratory, Braga/Guimarães, Portugal
| | - Cristina Cunha
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Campus de Gualtar, 4710-057 Braga, Portugal
- ICVS/3B's-PT Government Associate Laboratory, Braga/Guimarães, Portugal
| | - Agostinho Carvalho
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Campus de Gualtar, 4710-057 Braga, Portugal
- ICVS/3B's-PT Government Associate Laboratory, Braga/Guimarães, Portugal
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Zhou Y, Cheng T, Tang K, Li H, Luo C, Yu F, Xiao F, Jin L, Hung IFN, Lu L, Yuen KY, Chan JFW, Yuan S, Sun H. Integration of metalloproteome and immunoproteome reveals a tight link of iron-related proteins with COVID-19 pathogenesis and immunity. Clin Immunol 2024; 263:110205. [PMID: 38575044 DOI: 10.1016/j.clim.2024.110205] [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: 11/17/2023] [Revised: 03/23/2024] [Accepted: 04/01/2024] [Indexed: 04/06/2024]
Abstract
Increasing clinical data show that the imbalance of host metallome is closely associated with different kinds of disease, however, the intrinsic mechanisms of action of metals in immunity and pathogenesis of disease remain largely undefined. There is lack of multiplexed profiling system to integrate the metalloproteome-immunoproteome information at systemic level for exploring the roles of metals in immunity and disease pathogenesis. In this study, we build up a metal-coding assisted multiplexed proteome assay platform for serum metalloproteomic and immunoproteomic profiling. By taking COVID-19 as a showcase, we unbiasedly uncovered the most evident modulation of iron-related proteins, i.e., Ft and Tf, in serum of severe COVID-19 patients, and the value of Ft/Tf could work as a robust biomarker for COVID-19 severity stratification, which overtakes the well-established clinical risk factors (cytokines). We further uncovered a tight association of transferrin with inflammation mediator IL-10 in COVID-19 patients, which was proved to be mainly governed by the monocyte/macrophage of liver, shedding light on new pathophysiological and immune regulatory mechanisms of COVID-19 disease. We finally validated the beneficial effects of iron chelators as anti-viral agents in SARS-CoV-2-infected K18-hACE2 mice through modulation of iron dyshomeostasis and alleviating inflammation response. Our findings highlight the critical role of liver-mediated iron dysregulation in COVID-19 disease severity, providing solid evidence on the involvement of iron-related proteins in COVID-19 pathophysiology and immunity.
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Affiliation(s)
- Ying Zhou
- Department of Chemistry, State Key Laboratory of Synthetic Chemistry, CAS-HKU Joint Laboratory of Metallomics for Health and Environment, The University of Hong Kong, Pokfulam, Hong Kong Special Administrative Region, PR China
| | - Tianfan Cheng
- Faculty of Dentistry, The University of Hong Kong, Pokfulam, Hong Kong, PR China
| | - Kaiming Tang
- State Key Laboratory of Emerging Infectious Diseases, Carol Yu Centre for Infection, Department of Microbiology, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong Special Administrative Region, PR China
| | - Hongyan Li
- Department of Chemistry, State Key Laboratory of Synthetic Chemistry, CAS-HKU Joint Laboratory of Metallomics for Health and Environment, The University of Hong Kong, Pokfulam, Hong Kong Special Administrative Region, PR China
| | - Cuiting Luo
- State Key Laboratory of Emerging Infectious Diseases, Carol Yu Centre for Infection, Department of Microbiology, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong Special Administrative Region, PR China
| | - Fu Yu
- State Key Laboratory of Emerging Infectious Diseases, Carol Yu Centre for Infection, Department of Microbiology, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong Special Administrative Region, PR China
| | - Fan Xiao
- Department of Pathology and Shenzhen Institute of Research and Innovation, The University of Hong Kong, Hong Kong Special Administrative Region, PR China
| | - Lijian Jin
- Faculty of Dentistry, The University of Hong Kong, Pokfulam, Hong Kong, PR China
| | - Ivan Fan-Ngai Hung
- Division of Infectious Diseases, Department of Medicine, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong Special Administrative Region, PR China
| | - Liwei Lu
- Department of Pathology and Shenzhen Institute of Research and Innovation, The University of Hong Kong, Hong Kong Special Administrative Region, PR China
| | - Kwok-Yung Yuen
- State Key Laboratory of Emerging Infectious Diseases, Carol Yu Centre for Infection, Department of Microbiology, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong Special Administrative Region, PR China; Department of Infectious Diseases and Microbiology, The University of Hong Kong-Shenzhen Hospital, Shenzhen, Guangdong Province, PR China; Centre for Virology, Vaccinology and Therapeutics, Hong Kong Science and Technology Park, Hong Kong Special Administrative Region, PR China; Department of Microbiology, Queen Mary Hospital, Pokfulam, Hong Kong Special Administrative Region, PR China; Academician Workstation of Hainan Province, Hainan Medical University-The University of Hong Kong Joint Laboratory of Tropical Infectious Diseases, The University of Hong Kong, Pokfulam, Hong Kong Special Administrative Region, PR China; Guangzhou Laboratory, Guangdong Province, China
| | - Jasper Fuk-Woo Chan
- State Key Laboratory of Emerging Infectious Diseases, Carol Yu Centre for Infection, Department of Microbiology, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong Special Administrative Region, PR China; Department of Infectious Diseases and Microbiology, The University of Hong Kong-Shenzhen Hospital, Shenzhen, Guangdong Province, PR China; Centre for Virology, Vaccinology and Therapeutics, Hong Kong Science and Technology Park, Hong Kong Special Administrative Region, PR China; Department of Microbiology, Queen Mary Hospital, Pokfulam, Hong Kong Special Administrative Region, PR China; Academician Workstation of Hainan Province, Hainan Medical University-The University of Hong Kong Joint Laboratory of Tropical Infectious Diseases, The University of Hong Kong, Pokfulam, Hong Kong Special Administrative Region, PR China; Guangzhou Laboratory, Guangdong Province, China.
| | - Shuofeng Yuan
- State Key Laboratory of Emerging Infectious Diseases, Carol Yu Centre for Infection, Department of Microbiology, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong Special Administrative Region, PR China; Department of Infectious Diseases and Microbiology, The University of Hong Kong-Shenzhen Hospital, Shenzhen, Guangdong Province, PR China; Centre for Virology, Vaccinology and Therapeutics, Hong Kong Science and Technology Park, Hong Kong Special Administrative Region, PR China.
| | - Hongzhe Sun
- Department of Chemistry, State Key Laboratory of Synthetic Chemistry, CAS-HKU Joint Laboratory of Metallomics for Health and Environment, The University of Hong Kong, Pokfulam, Hong Kong Special Administrative Region, PR China.
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Kulkarni S, Arunachala S, Chaya SK, ShankaraSetty RV, Karnik M, Bansal N, Ravindran S, Lokesh KS, Mohan M, Kaleem Ullah M, Siddaiah JB, Mahesh PA. The Assessment of Serum Fibronectin Levels as a Potential Biomarker for the Severity of Drug-Sensitive Pulmonary Tuberculosis: A Pilot Study. Diagnostics (Basel) 2023; 14:50. [PMID: 38201359 PMCID: PMC10804257 DOI: 10.3390/diagnostics14010050] [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: 11/27/2023] [Revised: 12/18/2023] [Accepted: 12/22/2023] [Indexed: 01/12/2024] Open
Abstract
BACKGROUND Tuberculosis (TB) is a global health burden caused by Mycobacterium tuberculosis (Mtb) infection. Fibronectin (Fn) facilitates Mtb attachment to host cells. We studied the Fn levels in smear-positive TB patients to assess its correlation with disease severity based on sputum smears and chest X-rays. METHODS Newly detected consecutive sputum AFB-positive pulmonary TB patients (n = 78) and healthy control subjects (n = 11) were included. The mycobacterial load in the sputum smear was assessed by IUATLD classification, ranging from 0 to 3. The severity of pulmonary involvement was assessed radiologically in terms of both the number of zones involved (0-6) and as localized (up to 2 zones), moderate (3-4 zones), or extensive (5-6 zones). The serum human fibronectin levels were measured by using a commercially available enzyme-linked immunosorbent assay (ELISA) kit (Catalogue No: CK-bio-11486, Shanghai Coon Koon Biotech Co., Ltd., Shanghai, China). RESULTS The PTB patients showed lower Fn levels (102.4 ± 26.7) compared with the controls (108.8 ± 6.8), but they were not statistically significant. Higher AFB smear grades had lower Fn levels. The chest X-ray zones involved were inversely correlated with Fn levels. The Fn levels, adjusted for age and gender, decreased with increased mycobacterial load and the number of chest radiograph zones affected. A Fn level <109.39 g/mL predicted greater TB severity (sensitivity of 67.57% and specificity of 90.38%), while a level <99.32 pg/mL predicted severity based on the chest radiology (sensitivity of 84.21% and specificity of 100%). CONCLUSIONS The Fn levels are lower in tuberculosis patients and are negatively correlated with severity based on sputum mycobacterial load and chest radiographs. The Fn levels may serve as a potential biomarker for assessing TB severity, which could have implications for early diagnosis and treatment monitoring.
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Affiliation(s)
- Shreedhar Kulkarni
- Department of Respiratory Medicine, JSS Medical College, JSS Academy of Higher Education and Research, Mysore 570015, India (S.A.); (R.V.S.); (S.R.)
| | - Sumalatha Arunachala
- Department of Respiratory Medicine, JSS Medical College, JSS Academy of Higher Education and Research, Mysore 570015, India (S.A.); (R.V.S.); (S.R.)
- Public Health Research Institute of India, Mysore 570020, India
- Department of Critical Care Medicine, Adichunchanagiri Institute of Medical Sciences, Bellur 571448, India
| | - Sindaghatta Krishnarao Chaya
- Department of Respiratory Medicine, JSS Medical College, JSS Academy of Higher Education and Research, Mysore 570015, India (S.A.); (R.V.S.); (S.R.)
| | - Rekha Vaddarahalli ShankaraSetty
- Department of Respiratory Medicine, JSS Medical College, JSS Academy of Higher Education and Research, Mysore 570015, India (S.A.); (R.V.S.); (S.R.)
| | - Medha Karnik
- Centre for Excellence in Molecular Biology and Regenerative Medicine (A DST-FIST Supported Center), Department of Biochemistry (A DST-FIST Supported Department), JSS Medical College, JSS Academy of Higher Education and Research, Mysore 570015, India; (M.K.)
| | - Nidhi Bansal
- Department of Respiratory Medicine, JSS Medical College, JSS Academy of Higher Education and Research, Mysore 570015, India (S.A.); (R.V.S.); (S.R.)
| | - Sukanya Ravindran
- Department of Respiratory Medicine, JSS Medical College, JSS Academy of Higher Education and Research, Mysore 570015, India (S.A.); (R.V.S.); (S.R.)
| | - Komarla Sundararaja Lokesh
- Department of Respiratory Medicine, JSS Medical College, JSS Academy of Higher Education and Research, Mysore 570015, India (S.A.); (R.V.S.); (S.R.)
| | - Mikash Mohan
- Department of Respiratory Medicine, JSS Medical College, JSS Academy of Higher Education and Research, Mysore 570015, India (S.A.); (R.V.S.); (S.R.)
| | - Mohammed Kaleem Ullah
- Centre for Excellence in Molecular Biology and Regenerative Medicine (A DST-FIST Supported Center), Department of Biochemistry (A DST-FIST Supported Department), JSS Medical College, JSS Academy of Higher Education and Research, Mysore 570015, India; (M.K.)
- Division of Infectious Disease and Vaccinology, School of Public Health, University of California, Berkeley, CA 94720, USA
| | - Jayaraj Biligere Siddaiah
- Department of Respiratory Medicine, JSS Medical College, JSS Academy of Higher Education and Research, Mysore 570015, India (S.A.); (R.V.S.); (S.R.)
| | - Padukudru Anand Mahesh
- Department of Respiratory Medicine, JSS Medical College, JSS Academy of Higher Education and Research, Mysore 570015, India (S.A.); (R.V.S.); (S.R.)
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Tang H, Li P, Guo X. Ferroptosis-Mediated Immune Microenvironment and Therapeutic Response in Inflammatory Bowel Disease. DNA Cell Biol 2023; 42:720-734. [PMID: 37943983 DOI: 10.1089/dna.2023.0260] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2023] Open
Abstract
Inflammatory bowel disease (IBD) is a chronic inflammatory disorder characterized by dysregulated immune responses in the gastrointestinal tract. One intriguing aspect of IBD is the potential involvement of ferroptosis, but the mechanism remains incompletely understood. In this study, 27 ferroptosis-related genes (FRGs) were identified differentially expressed between IBD and non-IBD control samples. We used CIBERSORT to compare alterations in the mucosal immune microenvironment between the above two group samples, and found that M1 macrophages and neutrophil infiltration increased in IBD. Two clusters based on consensus clustering of 27 FRGs led to significant changes in the abundance of CD4 memory resting T cells, M2 macrophages, and resting mast cells. Subsequently, 23 hub genes were identified, which could distinguish IBD samples into two distinct clusters with noticeable differences in immune therapy response. Furthermore, scRNA sequencing data based on these 23 hub genes uncovered the highest ferroptosis scores in CD8+ T effector memory (Tem) cells, and their expression underwent significant changes along the differentiation trajectory of CD8+ Tem cells. The random forest model identified eight decisive genes, out of which ferroptosis-related hub genes (SEMA3E, SLC46A1, AC092652.1, DACT2, IL17C, and KRTAP5.2) were confirmed by RT-qPCR in the IBD mouse model. This study reveals ferroptosis-mediated immune microenvironment in IBD and provides multiple potential targets for IBD treatment.
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Affiliation(s)
- Haiming Tang
- Department of Anorectal Surgery, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Peng Li
- Department of Anorectal Surgery, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Xiutian Guo
- Department of Anorectal Surgery, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
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11
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Chang J, Debreli Coskun M, Kim J. Inflammation alters iron distribution in bone and spleen in mice. Metallomics 2023; 15:mfad055. [PMID: 37738439 PMCID: PMC10563149 DOI: 10.1093/mtomcs/mfad055] [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: 04/09/2023] [Accepted: 09/15/2023] [Indexed: 09/24/2023]
Abstract
Anemia of inflammation (or inflammation-associated anemia) decreases the quality of life in billions of patients suffering from various inflammatory diseases, such as infection, autoimmune diseases, and cancer, associated with a prolonged state of immune activation. While proper utilization of iron, a nutrient metal essential for erythropoiesis, is important for the prevention of anemia, the alteration of body iron homeostasis upon inflammation, which can contribute to the development of anemia, is not completely understood. Thus, we sought to examine temporal and spatial changes in the distribution of iron and iron-associated molecules during inflammation in mice. To induce inflammation, C57BL/6J mice were injected with turpentine oil weekly for 3 weeks, which resulted in anemia, decreased protein expression of ferroportin, a cellular iron exporter, in the spleen, duodenum, and liver, and increased iron stores in the duodenum and spleen. Tracer kinetic studies after oral administration of 59Fe revealed that more iron was found in the spleen and less in the femur bone in turpentine oil-injected mice compared to the saline-injected mice, indicating tissue-specific abnormalities in iron distribution during inflammation. However, there was no difference in the utilization of iron for red blood cell production after turpentine oil injection; instead, serum hemopexin level and lactate dehydrogenase activity were increased, suggesting increased red blood cell destruction upon inflammation. Our findings provide an improved understanding of temporal and spatial changes in the distribution and utilization of iron during inflammation.
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Affiliation(s)
- JuOae Chang
- Department of Pharmaceutical Sciences, Northeastern University, Boston, MA, USA
- School of Pharmacy, Sungkyunkwan University, 2066 Seobu-ro, Jangan-gu, Suwon-si, Gyeonggi-do, South Korea
| | - Melis Debreli Coskun
- Department of Pharmaceutical Sciences, Northeastern University, Boston, MA, USA
- Department of Biomedical & Nutritional Sciences, University of Massachusetts Lowell, 3 Solomont Way, Suite 4, Lowell, MA 01854, USA
| | - Jonghan Kim
- Department of Pharmaceutical Sciences, Northeastern University, Boston, MA, USA
- Department of Biomedical & Nutritional Sciences, University of Massachusetts Lowell, 3 Solomont Way, Suite 4, Lowell, MA 01854, USA
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12
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Chibanda Y, Brookes M, Churchill D, Al-Hassi H. The Ferritin, Hepcidin and Cytokines Link in the Diagnoses of Iron Deficiency Anaemia during Pregnancy: A Review. Int J Mol Sci 2023; 24:13323. [PMID: 37686128 PMCID: PMC10488244 DOI: 10.3390/ijms241713323] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2023] [Revised: 08/21/2023] [Accepted: 08/23/2023] [Indexed: 09/10/2023] Open
Abstract
Following a diagnosis of iron deficiency anaemia in pregnancy, iron supplements are prescribed using UK guidelines; however, despite this, the condition remains highly prevalent, affecting up to 30% of pregnant women in the UK. According to the World Health Organisation, it globally accounts for 45% in the most vulnerable groups of pregnant women and infants (<5 years old). Recently, the efficacy of iron replacement therapy and the effectiveness of current standard testing of iron parameters have been reviewed in order to evaluate whether a more accurate diagnosis can be made using alternative and/or supplementary markers. Furthermore, many questions remain about the mechanisms involved in iron metabolism during pregnancy. The most recent studies have shed more light on serum hepcidin and raised questions on the significance of pregnancy related inflammatory markers including cytokines in iron deficiency anaemia. However, research into this is still scarce, and this review aims to contribute to further understanding and elucidating these areas.
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Affiliation(s)
- Yvonne Chibanda
- Research Institute in Healthcare Science, University of Wolverhampton, Wolverhampton WV1 1LY, UK
| | - Matthew Brookes
- Gastroenterology, The Royal Wolverhampton NHS Trust, Wolverhampton WV10 0QP, UK
| | - David Churchill
- Obstetrics, The Royal Wolverhampton NHS Trust, Wolverhampton WV10 0QP, UK
| | - Hafid Al-Hassi
- Research Institute in Healthcare Science, University of Wolverhampton, Wolverhampton WV1 1LY, UK
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13
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Grubwieser P, Hilbe R, Gehrer CM, Grander M, Brigo N, Hoffmann A, Seifert M, Berger S, Theurl I, Nairz M, Weiss G. Klebsiella pneumoniae manipulates human macrophages to acquire iron. Front Microbiol 2023; 14:1223113. [PMID: 37637102 PMCID: PMC10451090 DOI: 10.3389/fmicb.2023.1223113] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2023] [Accepted: 07/17/2023] [Indexed: 08/29/2023] Open
Abstract
Background Klebsiella pneumoniae (KP) is a major cause of hospital-acquired infections, such as pneumonia. Moreover, it is classified as a pathogen of concern due to sprawling anti-microbial resistance. During infection, the gram-negative pathogen is capable of establishing an intracellular niche in macrophages by altering cellular metabolism. One factor critically affecting the host-pathogen interaction is the availability of essential nutrients, like iron, which is required for KP to proliferate but which also modulates anti-microbial immune effector pathways. We hypothesized, that KP manipulates macrophage iron homeostasis to acquire this crucial nutrient for sustained proliferation. Methods We applied an in-vitro infection model, in which human macrophage-like PMA-differentiated THP1 cells were infected with KP (strain ATCC 43816). During a 24-h course of infection, we quantified the number of intracellular bacteria via serial plating of cell lysates and evaluated the effects of different stimuli on intracellular bacterial numbers and iron acquisition. Furthermore, we analyzed host and pathogen specific gene and protein expression of key iron metabolism molecules. Results Viable bacteria are recovered from macrophage cell lysates during the course of infection, indicative of persistence of bacteria within host cells and inefficient pathogen clearing by macrophages. Strikingly, following KP infection macrophages strongly induce the expression of the main cellular iron importer transferrin-receptor-1 (TFR1). Accordingly, intracellular KP proliferation is further augmented by the addition of iron loaded transferrin. The induction of TFR1 is mediated via the STAT-6-IL-10 axis, and pharmacological inhibition of this pathway reduces macrophage iron uptake, elicits bacterial iron starvation, and decreases bacterial survival. Conclusion Our results suggest, that KP manipulates macrophage iron metabolism to acquire iron once confined inside the host cell and enforces intracellular bacterial persistence. This is facilitated by microbial mediated induction of TFR1 via the STAT-6-IL-10 axis. Mechanistic insights into immune metabolism will provide opportunities for the development of novel antimicrobial therapies.
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Affiliation(s)
- Philipp Grubwieser
- Department of Internal Medicine II, Infectious Diseases, Immunology, Rheumatology, Pulmonology, Medical University of Innsbruck, Innsbruck, Austria
| | - Richard Hilbe
- Department of Internal Medicine II, Infectious Diseases, Immunology, Rheumatology, Pulmonology, Medical University of Innsbruck, Innsbruck, Austria
| | - Clemens Michael Gehrer
- Department of Internal Medicine II, Infectious Diseases, Immunology, Rheumatology, Pulmonology, Medical University of Innsbruck, Innsbruck, Austria
| | - Manuel Grander
- Department of Internal Medicine II, Infectious Diseases, Immunology, Rheumatology, Pulmonology, Medical University of Innsbruck, Innsbruck, Austria
- Christian Doppler Laboratory for Iron Metabolism and Anemia Research, Medical University of Innsbruck, Innsbruck, Austria
| | - Natascha Brigo
- Department of Internal Medicine II, Infectious Diseases, Immunology, Rheumatology, Pulmonology, Medical University of Innsbruck, Innsbruck, Austria
| | - Alexander Hoffmann
- Department of Internal Medicine II, Infectious Diseases, Immunology, Rheumatology, Pulmonology, Medical University of Innsbruck, Innsbruck, Austria
- Christian Doppler Laboratory for Iron Metabolism and Anemia Research, Medical University of Innsbruck, Innsbruck, Austria
| | - Markus Seifert
- Department of Internal Medicine II, Infectious Diseases, Immunology, Rheumatology, Pulmonology, Medical University of Innsbruck, Innsbruck, Austria
- Christian Doppler Laboratory for Iron Metabolism and Anemia Research, Medical University of Innsbruck, Innsbruck, Austria
| | - Sylvia Berger
- Department of Internal Medicine II, Infectious Diseases, Immunology, Rheumatology, Pulmonology, Medical University of Innsbruck, Innsbruck, Austria
| | - Igor Theurl
- Department of Internal Medicine II, Infectious Diseases, Immunology, Rheumatology, Pulmonology, Medical University of Innsbruck, Innsbruck, Austria
| | - Manfred Nairz
- Department of Internal Medicine II, Infectious Diseases, Immunology, Rheumatology, Pulmonology, Medical University of Innsbruck, Innsbruck, Austria
| | - Günter Weiss
- Department of Internal Medicine II, Infectious Diseases, Immunology, Rheumatology, Pulmonology, Medical University of Innsbruck, Innsbruck, Austria
- Christian Doppler Laboratory for Iron Metabolism and Anemia Research, Medical University of Innsbruck, Innsbruck, Austria
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14
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Jung DK, Tan ST, Hemlock C, Mertens AN, Stewart CP, Rahman MZ, Ali S, Raqib R, Grembi JA, Karim MR, Shahriar S, Roy AK, Abdelrahman S, Shoab AK, Famida SL, Hossen MS, Mutsuddi P, Akther S, Rahman M, Unicomb L, Hester L, Granger DA, Erhardt J, Naved RT, Al Mamun MM, Parvin K, Colford JM, Fernald LC, Luby SP, Dhabhar FS, Lin A. Micronutrient status during pregnancy is associated with child immune status in rural Bangladesh. Curr Dev Nutr 2023; 7:101969. [PMID: 37560460 PMCID: PMC10407622 DOI: 10.1016/j.cdnut.2023.101969] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2023] [Revised: 06/26/2023] [Accepted: 06/30/2023] [Indexed: 08/11/2023] Open
Abstract
Background Poor immune function increases children's risk of infection and mortality. Several maternal factors during pregnancy may affect infant immune function during the postnatal period. Objectives We aimed to evaluate whether maternal micronutrients, stress, estriol, and immune status during the first or second trimester of pregnancy were associated with child immune status in the first two years after birth. Methods We conducted observational analyses within the water, sanitation, and hygiene (WASH) Benefits Bangladesh randomized controlled trial. We measured biomarkers in 575 pregnant women and postnatally in their children. Maternal biomarkers measured during the first and second trimester of pregnancy included nutrition status via vitamin D (25-hydroxy-D [25(OH)D]), ferritin, soluble transferrin receptor (sTfR), and retinol-binding protein (RBP); cortisol; estriol. Immune markers were assessed in pregnant women at enrollment and their children at ages 14 and 28 mo, including C-reactive protein (CRP), alpha-1-acid glycoprotein (AGP), and 13 cytokines (including IFN-γ). We generated a standardized sum score of log-transformed cytokines. We analyzed IFN-γ individually because it is a critical immunoregulatory cytokine. All outcomes were prespecified. We used generalized additive models and reported the mean difference and 95% confidence intervals at the 25th and 75th percentiles of exposure distribution. Results At child age 14 mo, concentrations of maternal RBP were inversely associated with the cytokine sum score in children (-0.34 adjusted difference between the 25th and 75th percentile [95% confidence interval -0.61, -0.07]), and maternal vitamin A deficiency was positively associated with the cytokine sum score in children (1.02 [0.13, 1.91]). At child age of 28 mo, maternal RBP was positively associated with IFN-γ in children (0.07 [0.01, 0.14]), whereas maternal vitamin A deficiency was negatively associated with child AGP (-0.07 [-0.13, -0.02]). Maternal iron deficiency was associated with higher AGP concentrations in children at age 14 mo (0.13 [0.04, 0.23]), and maternal sTfR concentrations were positively associated with child CRP concentrations at age 28 mo (0.18 [0, 0.36]). Conclusion Maternal deficiencies in vitamin A or iron during the first 2 trimesters of pregnancy may shape the trajectory of a child's immune status.
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Affiliation(s)
- Da Kyung Jung
- Division of Epidemiology and Biostatistics, School of Public Health, University of California Berkeley, Berkeley, CA, United States
| | - Sophia T. Tan
- Division of Infectious Diseases and Geographic Medicine, Stanford University, Stanford, CA, United States
| | - Caitlin Hemlock
- Division of Epidemiology and Biostatistics, School of Public Health, University of California Berkeley, Berkeley, CA, United States
| | - Andrew N. Mertens
- Division of Epidemiology and Biostatistics, School of Public Health, University of California Berkeley, Berkeley, CA, United States
| | - Christine P. Stewart
- Institute for Global Nutrition, University of California Davis, Davis, CA, United States
| | - Md Ziaur Rahman
- Environmental Interventions Unit, Infectious Diseases Division, icddr,b, Dhaka 1212, Bangladesh
| | - Shahjahan Ali
- Environmental Interventions Unit, Infectious Diseases Division, icddr,b, Dhaka 1212, Bangladesh
| | - Rubhana Raqib
- Environmental Interventions Unit, Infectious Diseases Division, icddr,b, Dhaka 1212, Bangladesh
| | - Jessica A. Grembi
- Division of Infectious Diseases and Geographic Medicine, Stanford University, Stanford, CA, United States
| | - Mohammed Rabiul Karim
- Environmental Interventions Unit, Infectious Diseases Division, icddr,b, Dhaka 1212, Bangladesh
| | - Sunny Shahriar
- Environmental Interventions Unit, Infectious Diseases Division, icddr,b, Dhaka 1212, Bangladesh
| | - Anjan Kumar Roy
- Environmental Interventions Unit, Infectious Diseases Division, icddr,b, Dhaka 1212, Bangladesh
| | - Sarah Abdelrahman
- Division of Epidemiology and Biostatistics, School of Public Health, University of California Berkeley, Berkeley, CA, United States
| | - Abul K. Shoab
- Environmental Interventions Unit, Infectious Diseases Division, icddr,b, Dhaka 1212, Bangladesh
| | - Syeda L. Famida
- Environmental Interventions Unit, Infectious Diseases Division, icddr,b, Dhaka 1212, Bangladesh
| | - Md Saheen Hossen
- Environmental Interventions Unit, Infectious Diseases Division, icddr,b, Dhaka 1212, Bangladesh
| | - Palash Mutsuddi
- Environmental Interventions Unit, Infectious Diseases Division, icddr,b, Dhaka 1212, Bangladesh
| | - Salma Akther
- Environmental Interventions Unit, Infectious Diseases Division, icddr,b, Dhaka 1212, Bangladesh
| | - Mahbubur Rahman
- Environmental Interventions Unit, Infectious Diseases Division, icddr,b, Dhaka 1212, Bangladesh
| | - Leanne Unicomb
- Environmental Interventions Unit, Infectious Diseases Division, icddr,b, Dhaka 1212, Bangladesh
| | - Lisa Hester
- Department of Medicine, University of Maryland, Baltimore, MD USA
| | - Douglas A. Granger
- Institute for Interdisciplinary Salivary Bioscience Research, University of California Irvine, Irvine, CA, United States
| | | | | | - Md Mahfuz Al Mamun
- Health System and Population Studies Division, icddr,b, Dhaka, Bangladesh
| | - Kausar Parvin
- Health System and Population Studies Division, icddr,b, Dhaka, Bangladesh
| | - John M. Colford
- Division of Epidemiology and Biostatistics, School of Public Health, University of California Berkeley, Berkeley, CA, United States
| | - Lia C.H. Fernald
- Division of Community Health Sciences, School of Public Health, University of California, Berkeley, Berkeley, CA, United States
| | - Stephen P. Luby
- Division of Infectious Diseases and Geographic Medicine, Stanford University, Stanford, CA, United States
| | - Firdaus S. Dhabhar
- Department of Psychiatry & Behavioral Sciences, Department of Microbiology and Immunology, Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL, United States
| | - Audrie Lin
- Department of Microbiology and Environmental Toxicology, University of California, Santa Cruz, CA, United States
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15
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Abstract
COVID-19 can cause detrimental effects on health. Vaccines have helped in reducing disease severity and transmission but their long-term effects on health and effectiveness against future viral variants remain unknown. COVID-19 pathogenesis involves alteration in iron homeostasis. Thus, a contextual understanding of iron-related parameters would be very valuable for disease prognosis and therapeutics.Accordingly, we reviewed the status of iron and iron-related proteins in COVID-19. Iron-associated alterations in COVID-19 reported hitherto include anemia of inflammation, low levels of serum iron (hypoferremia), transferrin and transferrin saturation, and high levels of serum ferritin (hyperferritinemia), hepcidin, lipocalin-2, catalytic iron, and soluble transferrin receptor (in ICU patients). Hemoglobin levels can be low or normal, and compromised hemoglobin function has been proposed. Membrane-bound transferrin receptor may facilitate viral entry, so it acts as a potential target for antiviral therapy. Lactoferrin can provide natural defense by preventing viral entry and/or inhibiting viral replication. Serum iron and ferritin levels can predict COVID-19-related hospitalization, severity, and mortality. Serum hepcidin and ferritin/transferrin ratio can predict COVID-19 severity. Here, serum levels of these iron-related parameters are provided, caveats of iron chelation for therapy are discussed and the interplay of these iron-related parameters in COVID-19 is explained.This synopsis is crucial as it clearly presents the iron picture of COVID-19. The information may assist in disease prognosis and/or in formulating iron-related adjunctive strategies that can help reduce infection/inflammation and better manage COVID-19 caused by future variants. Indeed, the current picture will augment as more is revealed about these iron-related parameters in COVID-19.
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Affiliation(s)
- Erin Suriawinata
- Faculty of Life Sciences and Medicine, King's College London, London, UK
| | - Kosha J Mehta
- Centre for Education, Faculty of Life Sciences and Medicine, King's College London, London, UK.
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16
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Prajapati R, Mehta R, Kabrawala M, Nandwani S, Patel N, Sethia M, Magnani K, Tandel R, Kumar A. Dengue hepatitis: Incidence, spectrum and outcome. Indian J Gastroenterol 2023; 42:355-360. [PMID: 37335522 DOI: 10.1007/s12664-023-01405-0] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/15/2021] [Accepted: 05/22/2023] [Indexed: 06/21/2023]
Abstract
BACKGROUND AND AIMS While dengue infection is common in India, there is scarce information on dengue hepatitis. The aim of this study was to analyze the incidence, spectrum and outcome of dengue hepatitis. METHODS We retrospectively analyzed consecutive patients, who had hepatitis among those with dengue infection admitted to two tertiary care hospitals in western India from January 2016 to March 2021. Diagnosis of dengue infection was made by serology. Dengue hepatitis was diagnosed and the severity of dengue was categorized by standard criteria. RESULTS Of 1664 patients admitted with dengue fever during the study period, 199 patients had hepatitis (i.e. incidence of dengue hepatitis was 11.9%). Of the 199 dengue hepatitis patients (age: 29 [13 - 80] years, median [range], 67% males), 100 patients (50%) had severe dengue, 73 (36%) had severe dengue hepatitis, 32 (16%) had dengue shock syndrome and eight (4%) had acute liver failure. Forty-five patients (23%) had acute lung injury and 32 (16%) had acute kidney injury. The dengue hepatitis patients were treated with standard medical care, including vital organ support, as needed-166 (83%) patients survived, while 33 patients (17%) died (cause of death: multi-organ failure: 24 patients, septic shock: nine patients). The presence of shock independently predicted mortality (odds ratio 6.4, 95% confidence interval: 1.2 - 34). Among patients with dengue hepatitis, mortality rate was higher in those with severe dengue (23%), dengue shock syndrome (47%), severe dengue hepatitis (24%) and acute liver failure (38%). CONCLUSION In this large series of hospitalized patients with dengue infection, the incidence of dengue hepatitis was 11.9%. Among 199 dengue hepatitis, 17% died; multi-organ failure was the commonest cause for death and death rate was higher in patients with more severe disease. The presence of shock at presentation independently predicted mortality.
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Affiliation(s)
- Ritesh Prajapati
- Department of Gastroenterology, Surat Institute of Digestive Sciences, Majura Gate, Ring Road, Surat, 395 002, India.
- Department of Gastroenterology, Smt. R. B. Shah Mahavir Super Speciality Hospital, Surat, 395 001, India.
| | - Rajiv Mehta
- Department of Gastroenterology, Surat Institute of Digestive Sciences, Majura Gate, Ring Road, Surat, 395 002, India
- Department of Gastroenterology, Smt. R. B. Shah Mahavir Super Speciality Hospital, Surat, 395 001, India
| | - Mayank Kabrawala
- Department of Gastroenterology, Surat Institute of Digestive Sciences, Majura Gate, Ring Road, Surat, 395 002, India
- Department of Gastroenterology, Smt. R. B. Shah Mahavir Super Speciality Hospital, Surat, 395 001, India
| | - Subhash Nandwani
- Department of Gastroenterology, Surat Institute of Digestive Sciences, Majura Gate, Ring Road, Surat, 395 002, India
- Department of Gastroenterology, Smt. R. B. Shah Mahavir Super Speciality Hospital, Surat, 395 001, India
| | - Nisharg Patel
- Department of Gastroenterology, Surat Institute of Digestive Sciences, Majura Gate, Ring Road, Surat, 395 002, India
| | - Mohit Sethia
- Department of Gastroenterology, Surat Institute of Digestive Sciences, Majura Gate, Ring Road, Surat, 395 002, India
| | - Kamlesh Magnani
- Department of Gastroenterology, Surat Institute of Digestive Sciences, Majura Gate, Ring Road, Surat, 395 002, India
| | - Raj Tandel
- Department of Gastroenterology, Surat Institute of Digestive Sciences, Majura Gate, Ring Road, Surat, 395 002, India
| | - Ashish Kumar
- Department of Gastroenterology, Sir Ganga Ram Hospital, New Delhi, 110 060, India
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Gao M, Zhao T, Zhang C, Li P, Wang J, Han J, Zhang N, Pang B, Liu S. Ferritinophagy-mediated iron competition in RUTIs: Tug-of-war between UPEC and host. Biomed Pharmacother 2023; 163:114859. [PMID: 37167722 DOI: 10.1016/j.biopha.2023.114859] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2023] [Revised: 04/24/2023] [Accepted: 05/06/2023] [Indexed: 05/13/2023] Open
Abstract
Uropathogenic Escherichia coli (UPEC) is the main pathogen of recurrent urinary tract infections (RUTIs). Urinary tract infection is a complicated interaction between UPEC and the host. During infection, UPEC can evade the host's immune response and retain in bladder epithelial cells, which requires adequate nutritional support. Iron is the first necessary trace element in life and a key nutritional factor, making it an important part of the competition between UPEC and the host. On the one hand, UPEC grabs iron to satisfy its reproduction, on the other hand, the host relies on iron to build nutritional immunity defenses against UPEC. Ferritinophagy is a selective autophagy of ferritin mediated by nuclear receptor coactivator 4, which is not only a way for the host to regulate iron metabolism to maintain iron homeostasis, but also a key point of competition between the host and UPEC. Although recent studies have confirmed the role of ferritinophagy in the progression of many diseases, the mechanism of potential interactions between ferritinophagy in UPEC and the host is poorly understood. In this paper, we reviewed the potential mechanisms of ferritinophagy-mediated iron competition in the UPEC-host interactions. This competitive relationship, like a tug-of-war, is a confrontation between the capability of UPEC to capture iron and the host's nutritional immunity defense, which could be the trigger for RUTIs. Therefore, understanding ferritinophagy-mediated iron competition may provide new strategies for exploring effective antibiotic alternative therapies to prevent and treat RUTIs.
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Affiliation(s)
- Mengqi Gao
- Department of Nephrology and Endocrinology, Wangjing Hospital, China Academy of Chinese Medical Sciences, Beijing 100102, China
| | - Tingting Zhao
- Department of Nephrology, Beijing Key Laboratory for Immune-Mediated Inflammatory 9 Diseases, China-Japan Friendship Hospital, Beijing 100029, China
| | - Chuanlong Zhang
- Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, China
| | - Ping Li
- Department of Nephrology, Beijing Key Laboratory for Immune-Mediated Inflammatory 9 Diseases, China-Japan Friendship Hospital, Beijing 100029, China
| | - Jiazhe Wang
- Beijing University of Chinese Medicine, Beijing 100029, China
| | - Jiatong Han
- Department of Nephrology and Endocrinology, Wangjing Hospital, China Academy of Chinese Medical Sciences, Beijing 100102, China
| | - Ning Zhang
- Department of Nephrology and Endocrinology, Wangjing Hospital, China Academy of Chinese Medical Sciences, Beijing 100102, China
| | - Bo Pang
- International Medical Department of Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, China.
| | - Shiwei Liu
- Department of Nephrology and Endocrinology, Wangjing Hospital, China Academy of Chinese Medical Sciences, Beijing 100102, China.
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18
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Leischner C, Marongiu L, Piotrowsky A, Niessner H, Venturelli S, Burkard M, Renner O. Relevant Membrane Transport Proteins as Possible Gatekeepers for Effective Pharmacological Ascorbate Treatment in Cancer. Antioxidants (Basel) 2023; 12:antiox12040916. [PMID: 37107291 PMCID: PMC10135768 DOI: 10.3390/antiox12040916] [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: 01/31/2023] [Revised: 03/23/2023] [Accepted: 04/06/2023] [Indexed: 04/29/2023] Open
Abstract
Despite the increasing number of newly diagnosed malignancies worldwide, therapeutic options for some tumor diseases are unfortunately still limited. Interestingly, preclinical but also some clinical data suggest that the administration of pharmacological ascorbate seems to respond well, especially in some aggressively growing tumor entities. The membrane transport and channel proteins are highly relevant for the use of pharmacological ascorbate in cancer therapy and are involved in the transfer of active substances such as ascorbate, hydrogen peroxide, and iron that predominantly must enter malignant cells to induce antiproliferative effects and especially ferroptosis. In this review, the relevant conveying proteins from cellular surfaces are presented as an integral part of the efficacy of pharmacological ascorbate, considering the already known genetic and functional features in tumor tissues. Accordingly, candidates for diagnostic markers and therapeutic targets are mentioned.
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Affiliation(s)
- Christian Leischner
- Institute of Nutritional Sciences, Department of Nutritional Biochemistry, University of Hohenheim, Garbenstraße 30, 70599 Stuttgart, Germany
| | - Luigi Marongiu
- Institute of Nutritional Sciences, Department of Nutritional Biochemistry, University of Hohenheim, Garbenstraße 30, 70599 Stuttgart, Germany
- Department of Internal Medicine VIII, University Hospital Tuebingen, Otfried-Mueller-Straße 10, 72076 Tuebingen, Germany
| | - Alban Piotrowsky
- Institute of Nutritional Sciences, Department of Nutritional Biochemistry, University of Hohenheim, Garbenstraße 30, 70599 Stuttgart, Germany
| | - Heike Niessner
- Department of Dermatology, Division of Dermatooncology, University of Tuebingen, Liebermeisterstraße 25, 72076 Tuebingen, Germany
- Cluster of Excellence iFIT (EXC 2180) "Image Guided and Functionally Instructed Tumor Therapies", 72076 Tuebingen, Germany
| | - Sascha Venturelli
- Institute of Nutritional Sciences, Department of Nutritional Biochemistry, University of Hohenheim, Garbenstraße 30, 70599 Stuttgart, Germany
- Institute of Physiology, Department of Vegetative and Clinical Physiology, University of Tuebingen, Wilhelmstraße 56, 72074 Tuebingen, Germany
| | - Markus Burkard
- Institute of Nutritional Sciences, Department of Nutritional Biochemistry, University of Hohenheim, Garbenstraße 30, 70599 Stuttgart, Germany
| | - Olga Renner
- Institute of Nutritional Sciences, Department of Nutritional Biochemistry, University of Hohenheim, Garbenstraße 30, 70599 Stuttgart, Germany
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19
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Wu Q, Sacomboio E, Valente de Souza L, Martins R, Kitoko J, Cardoso S, Ademolue TW, Paixão T, Lehtimäki J, Figueiredo A, Norden C, Tharaux PL, Weiss G, Wang F, Ramos S, Soares MP. Renal control of life-threatening malarial anemia. Cell Rep 2023; 42:112057. [PMID: 36735532 DOI: 10.1016/j.celrep.2023.112057] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2022] [Revised: 11/30/2022] [Accepted: 01/17/2023] [Indexed: 02/04/2023] Open
Abstract
Iron recycling prevents the development of anemia under homeostatic conditions. Whether iron recycling was co-opted as a defense strategy to prevent the development of anemia in response to infection is unclear. We find that in severe Plasmodium falciparum malaria, the onset of life-threatening anemia is associated with acute kidney injury (AKI), irrespective of parasite load. Using a well-established experimental rodent model of malaria anemia, we identify a transcriptional response that endows renal proximal tubule epithelial cells (RPTECs) with the capacity to store and recycle iron during P. chabaudi chabaudi (Pcc) infection. This response encompasses the induction of ferroportin 1/SLC40A1, which exports iron from RPTECs and counteracts AKI while supporting compensatory erythropoiesis and preventing the onset of life-threatening malarial anemia. Iron recycling by myeloid cells is dispensable to this protective response, suggesting that RPTECs provide an iron-recycling salvage pathway that prevents the pathogenesis of life-threatening malarial anemia.
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Affiliation(s)
- Qian Wu
- Instituto Gulbenkian de Ciência, Oeiras, Portugal
| | | | - Lara Valente de Souza
- Department of Internal Medicine II, Infectious Diseases, Immunology, Rheumatology, Medical University of Innsbruck, Innsbruck, Austria; Christian Doppler Laboratory for Iron Metabolism and Anemia Research, Medical University of Innsbruck, Innsbruck, Austria
| | - Rui Martins
- Instituto Gulbenkian de Ciência, Oeiras, Portugal
| | - Jamil Kitoko
- Instituto Gulbenkian de Ciência, Oeiras, Portugal
| | | | | | - Tiago Paixão
- Instituto Gulbenkian de Ciência, Oeiras, Portugal
| | | | | | - Caren Norden
- Instituto Gulbenkian de Ciência, Oeiras, Portugal
| | - Pierre-Louis Tharaux
- Paris Cardiovascular Center (PARCC), Institut National de la Santé et de la Recherche Médicale (Inserm), Université Paris Cité, Paris, France
| | - Guenter Weiss
- Department of Internal Medicine II, Infectious Diseases, Immunology, Rheumatology, Medical University of Innsbruck, Innsbruck, Austria; Christian Doppler Laboratory for Iron Metabolism and Anemia Research, Medical University of Innsbruck, Innsbruck, Austria
| | - Fudi Wang
- The First Affiliated Hospital, Institute of Translational Medicine, School of Public Health, Zhejiang University School of Medicine, Hangzhou, China
| | - Susana Ramos
- Instituto Gulbenkian de Ciência, Oeiras, Portugal.
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20
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Dassanayake PSB, Prajapati R, Gelman N, Thompson RT, Prato FS, Goldhawk DE. Monocyte MRI Relaxation Rates Are Regulated by Extracellular Iron and Hepcidin. Int J Mol Sci 2023; 24:ijms24044036. [PMID: 36835448 PMCID: PMC9962677 DOI: 10.3390/ijms24044036] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2022] [Revised: 02/08/2023] [Accepted: 02/09/2023] [Indexed: 02/19/2023] Open
Abstract
Many chronic inflammatory conditions are mediated by an increase in the number of monocytes in peripheral circulation, differentiation of monocytes to macrophages, and different macrophage subpopulations during pro- and anti-inflammatory stages of tissue injury. When hepcidin secretion is stimulated during inflammation, the iron export protein ferroportin is targeted for degradation on a limited number of cell types, including monocytes and macrophages. Such changes in monocyte iron metabolism raise the possibility of non-invasively tracking the activity of these immune cells using magnetic resonance imaging (MRI). We hypothesized that hepcidin-mediated changes in monocyte iron regulation influence both cellular iron content and MRI relaxation rates. In response to varying conditions of extracellular iron supplementation, ferroportin protein levels in human THP-1 monocytes decreased two- to eightfold, consistent with paracrine/autocrine regulation of iron export. Following hepcidin treatment, ferroportin protein levels further decreased two- to fourfold. This was accompanied by an approximately twofold increase in total transverse relaxation rate, R2*, compared to non-supplemented cells. A positive correlation between total cellular iron content and R2* improved from moderate to strong in the presence of hepcidin. These findings suggest that hepcidin-mediated changes detected in monocytes using MRI could be valuable for in vivo cell tracking of inflammatory responses.
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Affiliation(s)
- Praveen S. B. Dassanayake
- Imaging Program, Lawson Health Research Institute, London, ON N6A 4V2, Canada
- Medical Biophysics, Western University, London, ON N6A 5C1, Canada
- Collaborative Graduate Program in Molecular Imaging, Western University, London, ON N6A 5C1, Canada
| | - Rahil Prajapati
- Imaging Program, Lawson Health Research Institute, London, ON N6A 4V2, Canada
| | - Neil Gelman
- Imaging Program, Lawson Health Research Institute, London, ON N6A 4V2, Canada
- Medical Biophysics, Western University, London, ON N6A 5C1, Canada
| | - R. Terry Thompson
- Imaging Program, Lawson Health Research Institute, London, ON N6A 4V2, Canada
- Medical Biophysics, Western University, London, ON N6A 5C1, Canada
| | - Frank S. Prato
- Imaging Program, Lawson Health Research Institute, London, ON N6A 4V2, Canada
- Medical Biophysics, Western University, London, ON N6A 5C1, Canada
- Collaborative Graduate Program in Molecular Imaging, Western University, London, ON N6A 5C1, Canada
| | - Donna E. Goldhawk
- Imaging Program, Lawson Health Research Institute, London, ON N6A 4V2, Canada
- Medical Biophysics, Western University, London, ON N6A 5C1, Canada
- Collaborative Graduate Program in Molecular Imaging, Western University, London, ON N6A 5C1, Canada
- Correspondence:
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21
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Han Y, Luo Z, Yue Z, Miao L, Xv M, Chang S, Zhan Y, Hou J. The tendency of anemia of inflammation in periodontal diseases. Clin Sci (Lond) 2023; 137:251-264. [PMID: 36705427 PMCID: PMC9908573 DOI: 10.1042/cs20220524] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2022] [Revised: 01/18/2023] [Accepted: 01/27/2023] [Indexed: 01/28/2023]
Abstract
Anemia of inflammation (AI) is associated with inflammatory diseases, and inflammation-induced iron metabolism disorder is the major pathogenic factor. Earlier studies have reported a tendency of AI in periodontitis patients, but the explicit relationship and possible pathological mechanisms remain unclear. Here, the analyses of both periodontitis patients and a mouse model of ligature-induced experimental periodontitis showed that periodontitis was associated with lower levels of hemoglobin and hematocrit with evidence of systemic inflammation (increased white blood cell levels) and evidence of iron restriction (low serum iron along with a high serum hepcidin and ferritin levels), in accordance with the current diagnosis criteria for AI. Moreover, periodontal therapy improved the anemia status and iron metabolism disorders. Furthermore, the increased level of hepcidin and significant correlation between hepcidin and key indicators of iron metabolism emphasized the pivotal role of hepcidin in the pathogenesis of periodontitis-related AI. Administration of the signal transducer and activator of transcription 3 (STAT3) inhibitors Stattic suggested that the IL-6-STAT3-hepcidin signaling pathway participated in this regulatory process. Together, these findings demonstrated that periodontitis should be considered an inflammatory disease that contributes to the development of AI; furthermore, IL-6-STAT3-hepcidin signaling pathway plays a key regulatory role in the pathogenesis of periodontitis-related AI. Our study will provide new insights into the systemic effects of periodontitis, while meaningfully expanding the spectrum of inflammatory diseases that contribute to AI.
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Affiliation(s)
- Ye Han
- Department of Periodontology, Peking University School and Hospital of Stomatology and National Center of Stomatology and National Clinical Research Center for Oral Diseases and National Engineering Laboratory for Digital and Material Technology of Stomatology and Beijing Key Laboratory of Digital Stomatology and Research Center of Engineering and Technology for Computerized Dentistry Ministry of Health and NMPA Key Laboratory for Dental Materials, Beijing, China
| | - Zhiqiang Luo
- One stop dental, Beijing, PR China, Beijing, China
| | - Zhao Guo Yue
- Department of Periodontology, Peking University School and Hospital of Stomatology and National Center of Stomatology and National Clinical Research Center for Oral Diseases and National Engineering Laboratory for Digital and Material Technology of Stomatology and Beijing Key Laboratory of Digital Stomatology and Research Center of Engineering and Technology for Computerized Dentistry Ministry of Health and NMPA Key Laboratory for Dental Materials, Beijing, China
| | - Li Li Miao
- Department of Periodontology, Peking University School and Hospital of Stomatology and National Center of Stomatology and National Clinical Research Center for Oral Diseases and National Engineering Laboratory for Digital and Material Technology of Stomatology and Beijing Key Laboratory of Digital Stomatology and Research Center of Engineering and Technology for Computerized Dentistry Ministry of Health and NMPA Key Laboratory for Dental Materials, Beijing, China
| | - Min Xv
- Department of Periodontology, Peking University School and Hospital of Stomatology and National Center of Stomatology and National Clinical Research Center for Oral Diseases and National Engineering Laboratory for Digital and Material Technology of Stomatology and Beijing Key Laboratory of Digital Stomatology and Research Center of Engineering and Technology for Computerized Dentistry Ministry of Health and NMPA Key Laboratory for Dental Materials, Beijing, China
| | - Shu Chang
- Department of Periodontology, Peking University School and Hospital of Stomatology and National Center of Stomatology and National Clinical Research Center for Oral Diseases and National Engineering Laboratory for Digital and Material Technology of Stomatology and Beijing Key Laboratory of Digital Stomatology and Research Center of Engineering and Technology for Computerized Dentistry Ministry of Health and NMPA Key Laboratory for Dental Materials, Beijing, China
| | - Yalin Zhan
- First Clinical Division, Peking University School and Hospital of Stomatology and National Center of Stomatology and National Clinical Research Center for Oral Diseases and National Engineering Laboratory for Digital and Material Technology of Stomatology and Beijing Key Laboratory of Digital Stomatology and Research Center of Engineering and Technology for Computerized Dentistry Ministry of Health and NMPA Key Laboratory for Dental Materials, Beijing, China
| | - Jianxia Hou
- Department of Periodontology, Peking University School and Hospital of Stomatology and National Center of Stomatology and National Clinical Research Center for Oral Diseases and National Engineering Laboratory for Digital and Material Technology of Stomatology and Beijing Key Laboratory of Digital Stomatology and Research Center of Engineering and Technology for Computerized Dentistry Ministry of Health and NMPA Key Laboratory for Dental Materials, Beijing, China
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22
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De Souza LV, Hoffmann A, Fischer C, Petzer V, Asshoff M, Theurl I, Tymoszuk P, Seifert M, Brigo N, Hilbe R, Demetz E, Von Raffay L, Berger S, Barros-Pinkelnig M, Weiss G. Comparative analysis of oral and intravenous iron therapy in rat models of inflammatory anemia and iron deficiency. Haematologica 2023; 108:135-149. [PMID: 35796011 PMCID: PMC9827174 DOI: 10.3324/haematol.2022.281149] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2022] [Accepted: 06/29/2022] [Indexed: 02/05/2023] Open
Abstract
Anemia is a major health issue and associated with increased morbidity. Iron deficiency anemia (IDA) is the most prevalent, followed by anemia of chronic disease (ACD). IDA and ACD often co-exist, challenging diagnosis and treatment. While iron supplementation is the first-line therapy for IDA, its optimal route of administration and the efficacy of different repletion strategies in ACD are elusive. Female Lewis rats were injected with group A streptococcal peptidoglycan-polysaccharide (PG-APS) to induce inflammatory arthritis with associated ACD and/or repeatedly phlebotomized and fed with a low iron diet to induce IDA, or a combination thereof (ACD/IDA). Iron was either supplemented by daily oral gavage of ferric maltol or by weekly intravenous (i.v.) injection of ferric carboxymaltose for up to 4 weeks. While both strategies reversed IDA, they remained ineffective to improve hemoglobin (Hb) levels in ACD, although oral iron showed slight amelioration of various erythropoiesis-associated parameters. In contrast, both iron treatments significantly increased Hb in ACD/IDA. In ACD and ACD/IDA animals, i.v. iron administration resulted in iron trapping in liver and splenic macrophages, induction of ferritin expression and increased circulating levels of the iron hormone hepcidin and the inflammatory cytokine interleukin-6, while oral iron supplementation reduced interleukin-6 levels. Thus, oral and i.v. iron resulted in divergent effects on systemic and tissue iron homeostasis and inflammation. Our results indicate that both iron supplements improve Hb in ACD/IDA, but are ineffective in ACD with pronounced inflammation, and that under the latter condition, i.v. iron is trapped in macrophages and may enhance inflammation.
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Affiliation(s)
- Lara Valente De Souza
- Department of Internal Medicine II, Infectious Diseases, Immunology, Rheumatology, Medical University of Innsbruck, Austria; Christian Doppler Laboratory for Iron Metabolism and Anemia research, Medical University of Innsbruck
| | - Alexander Hoffmann
- Department of Internal Medicine II, Infectious Diseases, Immunology, Rheumatology, Medical University of Innsbruck, Austria; Christian Doppler Laboratory for Iron Metabolism and Anemia research, Medical University of Innsbruck
| | - Christine Fischer
- Department of Internal Medicine II, Infectious Diseases, Immunology, Rheumatology, Medical University of Innsbruck
| | - Verena Petzer
- Department of Internal Medicine II, Infectious Diseases, Immunology, Rheumatology, Medical University of Innsbruck
| | - Malte Asshoff
- Department of Internal Medicine II, Infectious Diseases, Immunology, Rheumatology, Medical University of Innsbruck
| | - Igor Theurl
- Department of Internal Medicine II, Infectious Diseases, Immunology, Rheumatology, Medical University of Innsbruck
| | - Piotr Tymoszuk
- Department of Internal Medicine II, Infectious Diseases, Immunology, Rheumatology, Medical University of Innsbruck
| | - Markus Seifert
- Department of Internal Medicine II, Infectious Diseases, Immunology, Rheumatology, Medical University of Innsbruck, Austria; Christian Doppler Laboratory for Iron Metabolism and Anemia research, Medical University of Innsbruck
| | - Natascha Brigo
- Department of Internal Medicine II, Infectious Diseases, Immunology, Rheumatology, Medical University of Innsbruck
| | - Richard Hilbe
- Department of Internal Medicine II, Infectious Diseases, Immunology, Rheumatology, Medical University of Innsbruck
| | - Egon Demetz
- Department of Internal Medicine II, Infectious Diseases, Immunology, Rheumatology, Medical University of Innsbruck
| | - Laura Von Raffay
- Department of Internal Medicine II, Infectious Diseases, Immunology, Rheumatology, Medical University of Innsbruck
| | - Sylvia Berger
- Department of Internal Medicine II, Infectious Diseases, Immunology, Rheumatology, Medical University of Innsbruck
| | - Marina Barros-Pinkelnig
- Department of Internal Medicine II, Infectious Diseases, Immunology, Rheumatology, Medical University of Innsbruck
| | - Guenter Weiss
- Department of Internal Medicine II, Infectious Diseases, Immunology, Rheumatology, Medical University of Innsbruck, Austria; Christian Doppler Laboratory for Iron Metabolism and Anemia research, Medical University of Innsbruck.
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23
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Li LH, Hou SK, Chen CT, Chang YI, Kao WF, Chiu YH, Juan CC, How CK. Effect of ultramarathon running on iron metabolism. J Chin Med Assoc 2023; 86:80-87. [PMID: 36194166 DOI: 10.1097/jcma.0000000000000818] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/28/2023] Open
Abstract
BACKGROUND Iron is a vital trace element for energy production and oxygen transportation; importantly, it is essential to athletic performance. Maintaining iron balance is tightly controlled at systemic and cellular levels. This study aimed to determine serum iron tests, hepcidin levels, and cellular iron import and export activities in peripheral blood mononuclear cells (PBMCs) in ultramarathon runners to elucidate the association of systemic inflammation response and iron metabolism. METHODS Sixteen amateur runners were enrolled. Blood samples were taken 1 week before, immediately, and 24 h after the run. Plasma hepcidin levels were measured by enzyme-linked immunosorbent assay. The expression levels of divalent metal iron transporter 1 (DMT1), ZRT/IRT-like protein 14 (ZIP14), transferrin receptor 1 (TfR1), and ferroportin (FPN) in PBMCs were measured using real-time quantitative reverse transcription-polymerase chain reaction. RESULTS Serum iron concentrations and transferrin saturation significantly decreased immediately after the race and dramatically recovered 24 h post-race. Serum ferritin levels had a statistically significant rise immediately after the race and remained high 24 h after the completion of the race. Ultramarathons were associated with increased plasma interleukin-6 concentrations corresponding to the state of severe systemic inflammation and therefore boosted plasma hepcidin levels. The expression levels of DMT1 and FPN mRNA were markedly decreased immediately and 24 h after the race. The ZIP14 and TfR1 mRNA expression in PBMCs significantly decreased immediately after the race and returned to the baseline level at 24 h post-race. Positive significant correlations were observed between plasma hepcidin and ferritin levels. CONCLUSION Iron homeostasis and systemic inflammatory response are closely interconnected. Cellular iron import and export mRNA activities in PBMCs were acutely inhibited during an ultramarathon.
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Affiliation(s)
- Li-Hua Li
- Department of Pathology and Laboratory Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
- Ph.D. Program of Medical Biotechnology, Taipei Medical University, Taipei, Taiwan, ROC
| | - Sen-Kuang Hou
- Department of Emergency, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan, ROC
- Department of Emergency and Critical Care Medicine, Taipei Medical University Hospital, Taipei, Taiwan, ROC
| | - Chung-Ting Chen
- Emergency Department, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
- Department of Emergency Medicine, School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
| | - Yuan-I Chang
- Institute of Physiology, School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
| | - Wei-Fong Kao
- Department of Emergency, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan, ROC
- Department of Emergency and Critical Care Medicine, Taipei Medical University Hospital, Taipei, Taiwan, ROC
| | - Yu-Hui Chiu
- Department of Emergency, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan, ROC
- Department of Emergency Medicine, Mackay Memorial Hospital, Taipei, Taiwan, ROC
- Department of Medicine, Mackay Medical College, New Taipei City, Taiwan, ROC
| | - Chi-Chang Juan
- Institute of Physiology, School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
| | - Chorng-Kuang How
- Emergency Department, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
- Department of Emergency Medicine, School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
- Kinmen Hospital, Ministry of Health and Welfare, Kinmen, Taiwan, ROC
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24
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The role of iron in chronic inflammatory diseases: from mechanisms to treatment options in anemia of inflammation. Blood 2022; 140:2011-2023. [PMID: 35994752 DOI: 10.1182/blood.2021013472] [Citation(s) in RCA: 52] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2022] [Accepted: 08/09/2022] [Indexed: 11/20/2022] Open
Abstract
Anemia of inflammation (AI) is a highly prevalent comorbidity in patients affected by chronic inflammatory disorders, such as chronic kidney disease, inflammatory bowel disease, or cancer, that negatively affect disease outcome and quality of life. The pathophysiology of AI is multifactorial, with inflammatory hypoferremia and iron-restricted erythropoiesis playing a major role in the context of disease-specific factors. Here, we review the recent progress in our understanding of the molecular mechanisms contributing to iron dysregulation in AI, the impact of hypoferremia and anemia on the course of the underlying disease, and (novel) therapeutic strategies applied to treat AI.
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25
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Charlebois E, Fillebeen C, Katsarou A, Rabinovich A, Wisniewski K, Venkataramani V, Michalke B, Velentza A, Pantopoulos K. A crosstalk between hepcidin and IRE/IRP pathways controls ferroportin expression and determines serum iron levels in mice. eLife 2022; 11:81332. [PMID: 36066082 PMCID: PMC9499557 DOI: 10.7554/elife.81332] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2022] [Accepted: 08/30/2022] [Indexed: 11/13/2022] Open
Abstract
The iron hormone hepcidin is transcriptionally activated by iron or inflammation via distinct, partially overlapping pathways. We addressed how iron affects inflammatory hepcidin levels and the ensuing hypoferremic response. Dietary iron overload did not mitigate hepcidin induction in lipopolysaccharide (LPS)-treated wild type mice but prevented effective inflammatory hypoferremia. Likewise, LPS modestly decreased serum iron in hepcidin-deficient Hjv-/- mice, model of hemochromatosis. Synthetic hepcidin triggered hypoferremia in control but not iron-loaded wild type animals. Furthermore, it dramatically decreased hepatic and splenic ferroportin in Hjv-/- mice on standard or iron-deficient diet, but only triggered hypoferremia in the latter. Mechanistically, iron antagonized hepcidin responsiveness by inactivating IRPs in the liver and spleen to stimulate ferroportin mRNA translation. Prolonged LPS treatment eliminated ferroportin mRNA and permitted hepcidin-mediated hypoferremia in iron-loaded mice. Thus, de novo ferroportin synthesis is a critical determinant of serum iron and finetunes hepcidin-dependent functional outcomes. Our data uncover a crosstalk between hepcidin and IRE/IRP systems that controls tissue ferroportin expression and determines serum iron levels. Moreover, they suggest that hepcidin supplementation therapy is more efficient when combined with iron depletion.
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Affiliation(s)
| | | | | | | | | | - Vivek Venkataramani
- Department of Medicine II, University Hospital Frankfurt, Frankfurt, Germany
| | - Bernhard Michalke
- Research Unit Analytical BioGeoChemistry, Helmholtz Zentrum München, Neuherberg, Germany
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26
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Dasaradhan T, Koneti J, Kalluru R, Gadde S, Cherukuri SP, Chikatimalla R. Tuberculosis-Associated Anemia: A Narrative Review. Cureus 2022; 14:e27746. [PMID: 36106202 PMCID: PMC9447415 DOI: 10.7759/cureus.27746] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/07/2022] [Indexed: 11/25/2022] Open
Abstract
Tuberculosis (TB) is an airborne illness that induces systemic inflammation. It often affects the lungs causing cough, fever, and chest pain. A commonly associated comorbid condition in TB is anemia. This review article has summarized various studies with an aim to gain a better understanding of pathogenesis and the role of cytokines that contribute to the development of anemia in TB. The study has gathered risk factors that enhance the likelihood of TB patients acquiring anemia. It has reviewed therapeutic modalities such as antitubercular therapy and iron therapy in an attempt to find which of them are effective in reducing the severity of anemia. This review article has also emphasized the importance of measuring hepcidin and ferritin and has touched upon the investigations that can be easily implemented.
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Perng V, Navazesh SE, Park J, Arballo JR, Ji P. Iron Deficiency and Overload Modulate the Inflammatory Responses and Metabolism of Alveolar Macrophages. Nutrients 2022; 14:nu14153100. [PMID: 35956279 PMCID: PMC9370601 DOI: 10.3390/nu14153100] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2022] [Revised: 07/16/2022] [Accepted: 07/26/2022] [Indexed: 02/04/2023] Open
Abstract
Alveolar macrophages (AM) are critical to defense against respiratory pathogens. This study evaluated cellular iron imbalance to immunometabolism in endotoxin-polarized porcine AMs (PAMs). PAMs collected from five 6-week-old pigs were treated with a basal media, iron chelator, or ferric ammonium citrate to maintain iron replete or induce iron deficiency or overload, respectively. After 24 h treatment, PAMs were challenged with saline or lipopolysaccharide (LPS) for 6 h. Cells were analyzed for gene, protein, and untargeted metabolome. Cytokines were determined in culture media. Data were assessed using two-way ANOVA. Treatments successfully induced iron deficiency and overload. The mRNA of DMT1 and ZIP14 was increased up to 300-fold by LPS, but unaffected by iron. Surprisingly, both iron deprivation and overload attenuated LPS-induced inflammation, showing less TNFα production and lower mRNA of pro- and anti-inflammatory cytokines than iron-replete PAMs. Forty-eight metabolites were altered by either or both main effects. LPS enhanced the glycolysis and polyol pathways. Iron deprivation disrupted the TCA cycle. Iron overload increased intracellular cholesterol. Interestingly, iron deprivation augmented, whereas iron overload diminished, LPS-induced itaconic acid production, which has anti-microbial and anti-inflammatory properties. Therefore, iron-deficient PAMs may be more resistant to intracellular pathogens which use PAMs as a conduit for infection.
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Affiliation(s)
| | | | | | | | - Peng Ji
- Correspondence: ; Tel.: +1-530-752-6469
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Gonçalves SM, Ferreira AV, Cunha C, Carvalho A. Targeting immunometabolism in host-directed therapies to fungal disease. Clin Exp Immunol 2022; 208:158-166. [PMID: 35641161 PMCID: PMC9188340 DOI: 10.1093/cei/uxab014] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2021] [Revised: 10/03/2021] [Accepted: 10/29/2021] [Indexed: 01/21/2024] Open
Abstract
Fungal infections affect over a billion people and are responsible for more than 1.5 million deaths each year. Despite progress in diagnostic and therapeutic approaches, the management of severe fungal infections remains a challenge. Recently, the reprogramming of cellular metabolism has emerged as a central mechanism through which the effector functions of immune cells are supported to promote antifungal activity. An improved understanding of the immunometabolic signatures that orchestrate antifungal immunity, together with the dissection of the mechanisms that underlie heterogeneity in individual immune responses, may therefore unveil new targets amenable to adjunctive host-directed therapies. In this review, we highlight recent advances in the metabolic regulation of host-fungus interactions and antifungal immune responses, and outline targetable pathways and mechanisms with promising therapeutic potential.
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Affiliation(s)
- Samuel M Gonçalves
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal
- ICVS/3B's - PT Government Associate Laboratory, Guimarães/Braga, Portugal
| | - Anaísa V Ferreira
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal
- ICVS/3B's - PT Government Associate Laboratory, Guimarães/Braga, Portugal
- Department of Internal Medicine and Radboud Center for Infectious Diseases (RCI), Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands
- Instituto de Ciências Biomédicas Abel Salazar (ICBAS), Universidade do Porto, Porto, Portugal
| | - Cristina Cunha
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal
- ICVS/3B's - PT Government Associate Laboratory, Guimarães/Braga, Portugal
| | - Agostinho Carvalho
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal
- ICVS/3B's - PT Government Associate Laboratory, Guimarães/Braga, Portugal
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Grubwieser P, Hoffmann A, Hilbe R, Seifert M, Sonnweber T, Böck N, Theurl I, Weiss G, Nairz M. Airway Epithelial Cells Differentially Adapt Their Iron Metabolism to Infection With Klebsiella pneumoniae and Escherichia coli In Vitro. Front Cell Infect Microbiol 2022; 12:875543. [PMID: 35663465 PMCID: PMC9157649 DOI: 10.3389/fcimb.2022.875543] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2022] [Accepted: 04/22/2022] [Indexed: 12/13/2022] Open
Abstract
Background Pneumonia is often elicited by bacteria and can be associated with a severe clinical course, respiratory failure and the need for mechanical ventilation. In the alveolus, type-2-alveolar-epithelial-cells (AECII) contribute to innate immune functions. We hypothesized that AECII actively adapt cellular iron homeostasis to restrict this essential nutrient from invading pathogens - a defense strategy termed 'nutritional immunity', hitherto mainly demonstrated for myeloid cells. Methods We established an in-vitro infection model using the human AECII-like cell line A549. We infected cells with Klebsiella pneumoniae (K. pneumoniae) and Escherichia coli (E. coli), two gram-negative bacteria with different modes of infection and frequent causes of hospital-acquired pneumonia. We followed the entry and intracellular growth of these gram-negative bacteria and analyzed differential gene expression and protein levels of key inflammatory and iron metabolism molecules. Results Both, K. pneumoniae and E. coli are able to invade A549 cells, whereas only K. pneumoniae is capable of proliferating intracellularly. After peak bacterial burden, the number of intracellular pathogens declines, suggesting that epithelial cells initiate antimicrobial immune effector pathways to combat bacterial proliferation. The extracellular pathogen E. coli induces an iron retention phenotype in A549 cells, mainly characterized by the downregulation of the pivotal iron exporter ferroportin, the upregulation of the iron importer transferrin-receptor-1 and corresponding induction of the iron storage protein ferritin. In contrast, cells infected with the facultative intracellular bacterium K. pneumoniae exhibit an iron export phenotype indicated by ferroportin upregulation. This differential regulation of iron homeostasis and the pathogen-specific inflammatory reaction is likely mediated by oxidative stress. Conclusion AECII-derived A549 cells show pathogen-specific innate immune functions and adapt their iron handling in response to infection. The differential regulation of iron transporters depends on the preferential intra- or extracellular localization of the pathogen and likely aims at limiting bacterial iron availability.
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Affiliation(s)
- Philipp Grubwieser
- Department of Internal Medicine II, Infectious Diseases, Immunology, Rheumatology, Medical University of Innsbruck, Innsbruck, Austria
| | - Alexander Hoffmann
- Department of Internal Medicine II, Infectious Diseases, Immunology, Rheumatology, Medical University of Innsbruck, Innsbruck, Austria
- Christian Doppler Laboratory for Iron Metabolism and Anemia Research, Medical University of Innsbruck, Innsbruck, Austria
| | - Richard Hilbe
- Department of Internal Medicine II, Infectious Diseases, Immunology, Rheumatology, Medical University of Innsbruck, Innsbruck, Austria
| | - Markus Seifert
- Department of Internal Medicine II, Infectious Diseases, Immunology, Rheumatology, Medical University of Innsbruck, Innsbruck, Austria
| | - Thomas Sonnweber
- Department of Internal Medicine II, Infectious Diseases, Immunology, Rheumatology, Medical University of Innsbruck, Innsbruck, Austria
| | - Nina Böck
- Biocenter, Institute of Bioinformatics, Medical University of Innsbruck, Innsbruck, Austria
| | - Igor Theurl
- Department of Internal Medicine II, Infectious Diseases, Immunology, Rheumatology, Medical University of Innsbruck, Innsbruck, Austria
| | - Günter Weiss
- Department of Internal Medicine II, Infectious Diseases, Immunology, Rheumatology, Medical University of Innsbruck, Innsbruck, Austria
- Christian Doppler Laboratory for Iron Metabolism and Anemia Research, Medical University of Innsbruck, Innsbruck, Austria
| | - Manfred Nairz
- Department of Internal Medicine II, Infectious Diseases, Immunology, Rheumatology, Medical University of Innsbruck, Innsbruck, Austria
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Wijekoon S, Sunaga T, Wang Y, Mwale C, Kim S, Okumura M. Pentosan polysulfate regulates hepcidin 1-facilitated formation and function of osteoclast derived from canine bone marrow. PLoS One 2022; 17:e0265596. [PMID: 35299233 PMCID: PMC8929557 DOI: 10.1371/journal.pone.0265596] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2021] [Accepted: 03/01/2022] [Indexed: 12/03/2022] Open
Abstract
Hepcidin which is the crucial regulator of iron homeostasis, produced in the liver in response to anemia, hypoxia, or inflammation. Recent studies have suggested that hepcidin and iron metabolism are involved in osteoporosis by inhibiting osteoblast function and promoting osteoclastogenesis. Pentosan polysulfate (PPS) is a heparin analogue and promising novel therapeutic for osteoarthritis (OA). This study was undertaken to determine whether PPS inhibits hepcidin-facilitated osteoclast (OC) differentiation and iron overload. Canine (n = 3) bone marrow mononuclear cells were differentiated to OC by macrophage colony-stimulating factor and receptor-activator of nuclear factor kappaB ligand with the treatment of hepcidin1 (200, 400, 800, 1200 nmol/L) and PPS (1, 5, 10, 20, 40 μg/mL). Differentiation and function of OC were accessed using tartrate-resistant acid phosphate staining and bone resorption assay while monitoring ferroportin1 (FPN1) and iron concentration by immunocytochemistry. Gene expression of OC for cathepsin K (CTK), matrix metallopeptidase-9, nuclear factor of activated-T-cells cytoplasmic 1 and FPN1 was examined. Hepcidin1 showed significant enhancement of OC number at 800 nmol/L (p<0.01). PPS impeded hepcidin-facilitated OC at 1, 5 and 10 μg/mL and reduction of resorption pits at 5 and 10 μg/mL (p< 0.01). All OC specific genes were downregulated with PPS, specifically in significant manner with CTK at higher concentrations. However, heparin induced FPN1 internalization and degradation was inhibited at higher concentrations of PPS while restoring iron-releasing capability of OC. We demonstrate for the first time that PPS is a novel-inhibitor of hepcidin-facilitated OC formation/function which might be beneficial for treatment of OA and osteoporosis.
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Affiliation(s)
- Suranji Wijekoon
- Laboratory of Veterinary Surgery, Department of Veterinary Clinical Sciences, Graduate School of Veterinary Medicine, Sapporo, Hokkaido, Japan
| | - Takafumi Sunaga
- Laboratory of Veterinary Surgery, Department of Veterinary Clinical Sciences, Graduate School of Veterinary Medicine, Sapporo, Hokkaido, Japan
| | - Yanlin Wang
- Laboratory of Veterinary Surgery, Department of Veterinary Clinical Sciences, Graduate School of Veterinary Medicine, Sapporo, Hokkaido, Japan
| | - Carol Mwale
- Laboratory of Veterinary Surgery, Department of Veterinary Clinical Sciences, Graduate School of Veterinary Medicine, Sapporo, Hokkaido, Japan
| | - Sangho Kim
- Laboratory of Veterinary Surgery, Department of Veterinary Clinical Sciences, Graduate School of Veterinary Medicine, Sapporo, Hokkaido, Japan
| | - Masahiro Okumura
- Laboratory of Veterinary Surgery, Department of Veterinary Clinical Sciences, Graduate School of Veterinary Medicine, Sapporo, Hokkaido, Japan
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Lin J, Tan B, Li Y, Feng H, Chen Y. Sepsis-Exacerbated Brain Dysfunction After Intracerebral Hemorrhage. Front Cell Neurosci 2022; 15:819182. [PMID: 35126060 PMCID: PMC8814659 DOI: 10.3389/fncel.2021.819182] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2021] [Accepted: 12/27/2021] [Indexed: 12/28/2022] Open
Abstract
Sepsis susceptibility is significantly increased in patients with intracerebral hemorrhage (ICH), owing to immunosuppression and intestinal microbiota dysbiosis. To date, ICH with sepsis occurrence is still difficult for clinicians to deal with, and the mortality, as well as long-term cognitive disability, is still increasing. Actually, intracerebral hemorrhage and sepsis are mutually exacerbated via similar pathophysiological mechanisms, mainly consisting of systemic inflammation and circulatory dysfunction. The main consequence of these two processes is neural dysfunction and multiple organ damages, notably, via oxidative stress and neurotoxic mediation under the mediation of central nervous system activation and blood-brain barrier disruption. Besides, the comorbidity-induced multiple organ damages will produce numerous damage-associated molecular patterns and consequently exacerbate the severity of the disease. At present, the prospective views are about operating artificial restriction for the peripheral immune system and achieving cross-tolerance among organs via altering immune cell composition to reduce inflammatory damage.
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Affiliation(s)
- Jie Lin
- State Key Laboratory of Trauma, Burn and Combined Injury, Department of Neurosurgery, Southwest Hospital, Third Military Medical University, Army Medical University, Chongqing, China
- Chongqing Clinical Research Center for Neurosurgery, Southwest Hospital, Third Military Medical University, Army Medical University, Chongqing, China
- Chongqing Key Laboratory of Precision Neuromedicine and Neuroregenaration, Southwest Hospital, Third Military Medical University, Army Medical University, Chongqing, China
| | - Binbin Tan
- State Key Laboratory of Trauma, Burn and Combined Injury, Department of Neurosurgery, Southwest Hospital, Third Military Medical University, Army Medical University, Chongqing, China
- Chongqing Clinical Research Center for Neurosurgery, Southwest Hospital, Third Military Medical University, Army Medical University, Chongqing, China
- Chongqing Key Laboratory of Precision Neuromedicine and Neuroregenaration, Southwest Hospital, Third Military Medical University, Army Medical University, Chongqing, China
| | - Yuhong Li
- State Key Laboratory of Trauma, Burn and Combined Injury, Department of Neurosurgery, Southwest Hospital, Third Military Medical University, Army Medical University, Chongqing, China
- Chongqing Clinical Research Center for Neurosurgery, Southwest Hospital, Third Military Medical University, Army Medical University, Chongqing, China
- Chongqing Key Laboratory of Precision Neuromedicine and Neuroregenaration, Southwest Hospital, Third Military Medical University, Army Medical University, Chongqing, China
| | - Hua Feng
- State Key Laboratory of Trauma, Burn and Combined Injury, Department of Neurosurgery, Southwest Hospital, Third Military Medical University, Army Medical University, Chongqing, China
- Chongqing Clinical Research Center for Neurosurgery, Southwest Hospital, Third Military Medical University, Army Medical University, Chongqing, China
- Chongqing Key Laboratory of Precision Neuromedicine and Neuroregenaration, Southwest Hospital, Third Military Medical University, Army Medical University, Chongqing, China
| | - Yujie Chen
- State Key Laboratory of Trauma, Burn and Combined Injury, Department of Neurosurgery, Southwest Hospital, Third Military Medical University, Army Medical University, Chongqing, China
- Chongqing Clinical Research Center for Neurosurgery, Southwest Hospital, Third Military Medical University, Army Medical University, Chongqing, China
- Chongqing Key Laboratory of Precision Neuromedicine and Neuroregenaration, Southwest Hospital, Third Military Medical University, Army Medical University, Chongqing, China
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Daher R, Ducrot N, Lefebvre T, Zineeddine S, Ausseil J, Puy H, Karim Z. Crosstalk between Acidosis and Iron Metabolism: Data from In Vivo Studies. Metabolites 2022; 12:metabo12020089. [PMID: 35208164 PMCID: PMC8874512 DOI: 10.3390/metabo12020089] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2021] [Revised: 01/05/2022] [Accepted: 01/12/2022] [Indexed: 01/27/2023] Open
Abstract
Iron absorption requires an acidic environment that is generated by the activity of the proton pump gastric H(+)/K(+)ATPase (ATP4), expressed in gastric parietal cells. However, hepcidin, the iron regulatory peptide that inhibits iron absorption, unexpectedly upregulates ATP4 and increases gastric acidity. Thus, a concept of link between acidosis and alterations in iron metabolism, needs to be explored. We investigated this aspect in-vivo using experimental models of NH4Cl-induced acidosis and of an iron-rich diet. Under acidosis, gastric ATP4 was augmented. Serum hepcidin was induced and its mRNA level was increased in the liver but not in the stomach, a tissue where hepcidin is also expressed. mRNA and protein levels of intestinal DMT1(Divalent Metal Transporter 1) and ferroportin were downregulated. Serum iron level and transferrin saturation remained unchanged, but serum ferritin was significantly increased. Under iron-rich diet, the protein expression of ATP4A was increased and serum, hepatic and gastric hepcidin were all induced. Taken together, these results provide evidence of in-vivo relationship between iron metabolism and acidosis. For clinical importance, we speculate that metabolic acidosis may contribute in part to the pathologic elevation of serum hepcidin levels seen in patients with chronic kidney disease. The regulation of ATP4 by iron metabolism may also be of interest for patients with hemochromatosis.
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Affiliation(s)
- Raêd Daher
- Centre de Recherche sur l’Inflammation (CRI), Université de Paris, INSERM, CNRS, F-75018 Paris, France; (R.D.); (N.D.); (T.L.); (S.Z.); (H.P.)
| | - Nicolas Ducrot
- Centre de Recherche sur l’Inflammation (CRI), Université de Paris, INSERM, CNRS, F-75018 Paris, France; (R.D.); (N.D.); (T.L.); (S.Z.); (H.P.)
| | - Thibaud Lefebvre
- Centre de Recherche sur l’Inflammation (CRI), Université de Paris, INSERM, CNRS, F-75018 Paris, France; (R.D.); (N.D.); (T.L.); (S.Z.); (H.P.)
- Centre Français des Porphyries, Hôpital Louis Mourier, APHP, Nord-Université de Paris, F-75014 Colombes, France
| | - Sofia Zineeddine
- Centre de Recherche sur l’Inflammation (CRI), Université de Paris, INSERM, CNRS, F-75018 Paris, France; (R.D.); (N.D.); (T.L.); (S.Z.); (H.P.)
- Institut Toulousain des Maladies Infectieuses et Inflammatoires (Infinity), Université de Toulouse, INSERM, CNRS, F-31024 Toulouse, France;
| | - Jérome Ausseil
- Institut Toulousain des Maladies Infectieuses et Inflammatoires (Infinity), Université de Toulouse, INSERM, CNRS, F-31024 Toulouse, France;
| | - Hervé Puy
- Centre de Recherche sur l’Inflammation (CRI), Université de Paris, INSERM, CNRS, F-75018 Paris, France; (R.D.); (N.D.); (T.L.); (S.Z.); (H.P.)
- Centre Français des Porphyries, Hôpital Louis Mourier, APHP, Nord-Université de Paris, F-75014 Colombes, France
| | - Zoubida Karim
- Centre de Recherche sur l’Inflammation (CRI), Université de Paris, INSERM, CNRS, F-75018 Paris, France; (R.D.); (N.D.); (T.L.); (S.Z.); (H.P.)
- Institut Toulousain des Maladies Infectieuses et Inflammatoires (Infinity), Université de Toulouse, INSERM, CNRS, F-31024 Toulouse, France;
- Correspondence:
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He Y, Shang Y, Li Y, Wang M, Yu D, Yang Y, Ning S, Chen H. An 8-ferroptosis-related genes signature from Bronchoalveolar Lavage Fluid for prognosis in patients with idiopathic pulmonary fibrosis. BMC Pulm Med 2022; 22:15. [PMID: 34983465 PMCID: PMC8728942 DOI: 10.1186/s12890-021-01799-7] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2021] [Accepted: 12/14/2021] [Indexed: 12/12/2022] Open
Abstract
Background With the rapid advances of genetic and genomic technologies, the pathophysiological mechanisms of idiopathic pulmonary fibrosis (IPF) were gradually becoming clear, however, the prognosis of IPF was still poor. This study aimed to systematically explore the ferroptosis-related genes model associated with prognosis in IPF patients. Methods Datasets were collected from the Gene Expression Omnibus (GEO). The least absolute shrinkage and selection operator (LASSO) Cox regression analysis was applied to create a multi-gene predicted model from patients with IPF in the Freiburg cohort of the GSE70866 dataset. The Siena cohort and the Leuven cohort were used for validation. Results Nineteen differentially expressed genes (DEGs) between the patients with IPF and control were associated with poor prognosis based on the univariate Cox regression analysis (all P < 0.05). According to the median value of the risk score derived from an 8-ferroptosis-related genes signature, the three cohorts’ patients were stratified into two risk groups. Prognosis of high-risk group (high risk score) was significantly poorer compared with low-risk group in the three cohorts. According to multivariate Cox regression analyses, the risk score was an independently predictor for poor prognosis in the three cohorts. Receiver operating characteristic (ROC) curve analysis and decision curve analysis (DCA) confirmed the signature's predictive value in the three cohorts. According to functional analysis, inflammation- and immune-related pathways and biological process could participate in the progression of IPF. Conclusions These results imply that the 8-ferroptosis-related genes signature in the bronchoalveolar lavage samples might be an effective model to predict the poor prognosis of IPF. Supplementary Information The online version contains supplementary material available at 10.1186/s12890-021-01799-7.
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Affiliation(s)
- Yaowu He
- Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital of Harbin Medical University, Harbin, 150086, China
| | - Yu Shang
- Department of Respiration, The First Hospital of Harbin, Harbin, 150010, China
| | - Yupeng Li
- Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital of Harbin Medical University, Harbin, 150086, China
| | - Menghan Wang
- Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital of Harbin Medical University, Harbin, 150086, China
| | - Dongping Yu
- Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital of Harbin Medical University, Harbin, 150086, China
| | - Yi Yang
- Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital of Harbin Medical University, Harbin, 150086, China
| | - Shangwei Ning
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, 150086, China.
| | - Hong Chen
- Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital of Harbin Medical University, Harbin, 150086, China.
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Li W, Zhou X, Xu S, Cao N, Li B, Chen W, Yang B, Yuan M, Xu D. Lipopolysaccharide-induced Splenic Ferroptosis in Goslings was Alleviated by Polysaccharide of Atractylodes macrocephala Koidz Associated with Pro-inflammatory Factors. Poult Sci 2022; 101:101725. [PMID: 35299067 PMCID: PMC8927836 DOI: 10.1016/j.psj.2022.101725] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2021] [Revised: 01/07/2022] [Accepted: 01/08/2022] [Indexed: 12/22/2022] Open
Abstract
Ferroptosis is a newly discovered form of cell death due to iron-dependent lipid peroxidation. In animal breeding, many environmental factors could lead to oxidative stress, which in turn reduce animal immunity and production performance. Polysaccharide of Atractylodes macrocephala Koidz (PAMK) has antioxidation, immunomodulatory, and inflammatory modulating effects. For investigating the effect of PAMK on splenic ferroptosis in gosling caused by lipopolysaccharide (LPS), 40 one-day-old Magang goslings were randomly divided into 4 groups (CON group, LPS group, PAMK group, and LPS+PAMK group). The protein expression of the ferroptosis marker Glutathione Peroxidase 4 (GPX4), the relative mRNA expression of ferroptosis-related genes and cytokines, and the oxidative stress and iron content of spleen tissues were examined. The correlation between ferroptosis and inflammatory factors was further analyzed by principal component analysis. The results showed that, compared with CON group, LPS caused alterations in the expression of the ferroptosis pathway genes and cytokines, which could upregulate levels of ferroptosis and inflammation. However, after treated with PAMK, the inflammation and ferroptosis was alleviated. Meanwhile, PAMK restored the expression and distribution of GPX4. In addition, PAMK alleviated the oxidative stress caused by LPS and reduced the iron content in spleen. Principal component analysis showed that cytokines were more closely related to antioxidant indexes. The CON, PAMK and LPS+PAMK groups had similar effects on the four components, with the LPS and PAMK groups showing the furthest difference in results. The result indicated that PAMK could reduce the level of oxidative stress and inflammatory cytokines in spleen of gosling caused by LPS, and jointly alleviate ferroptosis by regulating genes related to the ferroptosis pathway.
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Affiliation(s)
- Wanyan Li
- College of Animal Science & Technology, Zhongkai University of Agriculture and Engineering, Guangzhou 510225, China; Guangdong Province Key Laboratory of Waterfowl Healthy Breeding, Guangzhou 510225, China
| | - Xiangying Zhou
- College of Animal Science & Technology, Zhongkai University of Agriculture and Engineering, Guangzhou 510225, China; Guangdong Province Key Laboratory of Waterfowl Healthy Breeding, Guangzhou 510225, China
| | - Shiwen Xu
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, China
| | - Nan Cao
- College of Animal Science & Technology, Zhongkai University of Agriculture and Engineering, Guangzhou 510225, China; Guangdong Province Key Laboratory of Waterfowl Healthy Breeding, Guangzhou 510225, China
| | - Bingxin Li
- College of Animal Science & Technology, Zhongkai University of Agriculture and Engineering, Guangzhou 510225, China; Guangdong Province Key Laboratory of Waterfowl Healthy Breeding, Guangzhou 510225, China
| | - Wenbin Chen
- College of Animal Science & Technology, Zhongkai University of Agriculture and Engineering, Guangzhou 510225, China; Guangdong Province Key Laboratory of Waterfowl Healthy Breeding, Guangzhou 510225, China
| | - Baohe Yang
- Yunnan Kuaidaduo Animal Husbandry Technology Co., Ltd, Yuxi 653100, China
| | - Mingfeng Yuan
- Yunnan Kuaidaduo Animal Husbandry Technology Co., Ltd, Yuxi 653100, China
| | - Danning Xu
- College of Animal Science & Technology, Zhongkai University of Agriculture and Engineering, Guangzhou 510225, China; Guangdong Province Key Laboratory of Waterfowl Healthy Breeding, Guangzhou 510225, China.
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Monocyte Subsets in Patients with Chronic Heart Failure Treated with Cardiac Resynchronization Therapy. Cells 2021; 10:cells10123482. [PMID: 34943990 PMCID: PMC8700101 DOI: 10.3390/cells10123482] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2021] [Revised: 11/24/2021] [Accepted: 12/06/2021] [Indexed: 02/06/2023] Open
Abstract
Background: The exact role of individual inflammatory factor in heart failure with reduced ejection fraction (HFrEF) remains elusive. The study aimed to evaluate three monocyte subsets (classical-CD14++CD16−, intermediate-CD14++CD16+, and nonclassical-CD14+CD16++) in HFrEF patients and to assess the effect of the cardiac resynchronization therapy (CRT) on the changes in monocyte compartment. Methods: The study included 85 patients with stable HFrEF. Twenty-five of them underwent CRT device implantation with subsequent 6-month assessment. The control group consisted of 23 volunteers without HFrEF. Results: The analysis revealed that frequencies of non-classical-CD14+CD16++ monocytes were lower in HFrEF patients compared to the control group (6.98 IQR: 4.95–8.65 vs. 8.37 IQR: 6.47–9.94; p = 0.021), while CD14++CD16+ and CD14++CD16− did not differ. The analysis effect of CRT on the frequency of analysed monocyte subsets 6 months after CRT device implantation showed a significant increase in CD14+CD16++ (from 7 IQR: 4.5–8.4 to 7.9 IQR: 6.5–9.5; p = 0.042) and CD14++CD16+ (from 5.1 IQR: 3.7–6.5 to 6.8 IQR: 5.4–7.4; p = 0.017) monocytes, while the frequency of steady-state CD14++CD16− monocytes was decreased (from 81.4 IQR: 78–86.2 to 78.2 IQR: 76.1–81.7; p = 0.003). Conclusions: HFrEF patients present altered monocyte composition. CRT-related changes in the monocyte compartment achieve levels observed in controls without HFrEF.
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Dechanuwong P, Phuan-Udom R. Hematological parameters as a predictor of disease remission in patients with rheumatoid arthritis. Ann Med Surg (Lond) 2021; 72:103085. [PMID: 34868575 PMCID: PMC8626573 DOI: 10.1016/j.amsu.2021.103085] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2021] [Revised: 11/16/2021] [Accepted: 11/16/2021] [Indexed: 12/29/2022] Open
Abstract
Background Alterations in the hematological profile have been linked to disease activity in rheumatoid arthritis (RA). We aimed to evaluate the levels of hematological parameters in different phases of rheumatoid arthritis (RA) and determine whether hematological parameters could be used to predict RA remission. Materials and methods The medical records of 365 RA patients were reviewed. Multivariate logistic regression analysis was used to compare hematological parameters among RA patients who were categorized into 4 groups according to disease activity: disease remission or low, moderate or high disease activity. Receiver operating characteristic curves were used to determine the predictive performances of significant parameters for RA remission. Results Complete data were obtained from 325 patients. The 4 groups of patients had different levels of hemoglobin (Hb), red blood cell, white blood cell, and platelet values. In multivariate analysis, Hb level, neutrophil-to-lymphocyte ratio (NLR), and mean platelet volume (MPV) were independent factors associated with disease activity. The combination of these 3 parameters yielded a sensitivity of 95.2% (95% confidence interval [CI] 88.7-98.2), specificity of 23.6% (95% CI 18.3-29.9), positive predictive value of 37.3% (95% CI 31.6-43.4), and negative predictive value of 91.2% (95% CI 80.0-96.7) in predicting disease remission. Conclusion Hb level, NLR and MPV were independently associated with RA disease activity. The high sensitivity and negative predictive value of the model consisting of Hb level, NLR and MPV may serve as a simple and inexpensive tool to identify patients who are less likely to have disease remission.
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Affiliation(s)
- Pornchai Dechanuwong
- Department of Medicine, Faculty of Medicine Vajira Hospital, Navamindradhiraj University, Bangkok, Thailand
| | - Ratanapha Phuan-Udom
- Department of Medicine, Faculty of Medicine Vajira Hospital, Navamindradhiraj University, Bangkok, Thailand
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Handono K, Wahono CS, Pratama MZ, Kalim H. Association of the premature immunosenescence with the presence and severity of anemia among patients with systemic lupus erythematosus. Lupus 2021; 30:1906-1914. [PMID: 34720016 DOI: 10.1177/09612033211038057] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
INTRODUCTION One of the possible mechanisms that contribute to the development of anemia in systemic lupus erythematosus (SLE) is the presence of premature immunosenescence in SLE. This study aimed to observe the correlation between immunosenescence with anemia in SLE. METHODS This research was a cross-sectional study with the subject was 60 women with SLE aged 16-45 years old. Subjects were recorded for the demographic and clinical data, complete blood counts, iron status (iron serum, total iron-binding capacity, and transferrin saturation), ferritin, inflammatory markers (erythrocyte sedimentation rate [ESR] and C-reactive protein [CRP]), and anti-dsDNA levels. Immunosenescence was observed by measuring the senescent T cells from peripheral blood mononuclear cells (PBMC) by flow cytometry, counted as CD4+CD57+ and CD8+CD57+ T cells. Serum IL-2 and IFNγ as the cytokines associated with immunosenescence were also measured from all subjects. Subjects were divided into anemic and non-anemic groups according to the classification of anemia from WHO (Hb < 12 gr/dl). RESULTS Anemic SLE patients had higher CD4+CD57+, CD8+CD57+, and IFNγ, while IL-2 was lower in SLE patients with anemia. Multivariate linear regression revealed that the decreasing levels of Hb were associated with the increase of CD8+CD57+ percentages and IFNγ levels. Anti-dsDNA, ESR, CRP, ferritin, iron serum, and transferrin saturation were correlated with CD8+CD57+. IFNγ level also correlated with the anti-dsDNA, iron serum, and ferritin levels. No correlation was found between the iron status and inflammatory markers with CD4+CD57+ percentages and IL-2 levels. Multivariate regression analysis showed that IFNγ was positively associated with anti-dsDNA and negatively associated with iron serum and transferrin saturation, while CD8+CD57+ percentages were positively associated with the ferritin levels. CONCLUSION Immunosenescence is associated with anemia by modulating the inflammatory response and causing iron dysregulation in SLE.
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Affiliation(s)
- Kusworini Handono
- Department of Clinical Pathology, Faculty of Medicine Universitas Brawijaya - Saiful Anwar General Hospital, Malang, Indonesia
| | - Cesarius Singgih Wahono
- Rheumatology and Immunology Division, Department of Internal Medicine, Facuty of Medicine Universitas Brawijaya - Saiful Anwar General Hospital, Malang, Indonesia
| | - Mirza Zaka Pratama
- Rheumatology and Immunology Division, Department of Internal Medicine, Facuty of Medicine Universitas Brawijaya - Saiful Anwar General Hospital, Malang, Indonesia
| | - Handono Kalim
- Rheumatology and Immunology Division, Department of Internal Medicine, Facuty of Medicine Universitas Brawijaya - Saiful Anwar General Hospital, Malang, Indonesia
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Lanser L, Fuchs D, Kurz K, Weiss G. Physiology and Inflammation Driven Pathophysiology of Iron Homeostasis-Mechanistic Insights into Anemia of Inflammation and Its Treatment. Nutrients 2021; 13:3732. [PMID: 34835988 PMCID: PMC8619077 DOI: 10.3390/nu13113732] [Citation(s) in RCA: 66] [Impact Index Per Article: 16.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2021] [Revised: 10/18/2021] [Accepted: 10/19/2021] [Indexed: 02/07/2023] Open
Abstract
Anemia is very common in patients with inflammatory disorders. Its prevalence is associated with severity of the underlying disease, and it negatively affects quality of life and cardio-vascular performance of patients. Anemia of inflammation (AI) is caused by disturbances of iron metabolism resulting in iron retention within macrophages, a reduced erythrocyte half-life, and cytokine mediated inhibition of erythropoietin function and erythroid progenitor cell differentiation. AI is mostly mild to moderate, normochromic and normocytic, and characterized by low circulating iron, but normal and increased levels of the storage protein ferritin and the iron hormone hepcidin. The primary therapeutic approach for AI is treatment of the underlying inflammatory disease which mostly results in normalization of hemoglobin levels over time unless other pathologies such as vitamin deficiencies, true iron deficiency on the basis of bleeding episodes, or renal insufficiency are present. If the underlying disease and/or anemia are not resolved, iron supplementation therapy and/or treatment with erythropoietin stimulating agents may be considered whereas blood transfusions are an emergency treatment for life-threatening anemia. New treatments with hepcidin-modifying strategies and stabilizers of hypoxia inducible factors emerge but their therapeutic efficacy for treatment of AI in ill patients needs to be evaluated in clinical trials.
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Affiliation(s)
- Lukas Lanser
- Department of Internal Medicine II, Medical University of Innsbruck, 6020 Innsbruck, Austria; (L.L.); (K.K.)
| | - Dietmar Fuchs
- Division of Biological Chemistry, Biocenter, Medical University of Innsbruck, 6020 Innsbruck, Austria;
| | - Katharina Kurz
- Department of Internal Medicine II, Medical University of Innsbruck, 6020 Innsbruck, Austria; (L.L.); (K.K.)
| | - Günter Weiss
- Department of Internal Medicine II, Medical University of Innsbruck, 6020 Innsbruck, Austria; (L.L.); (K.K.)
- Christian Doppler Laboratory for Iron Metabolism and Anemia Research, Medical University of Innsbruck, 6020 Innsbruck, Austria
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Dynamics in Anemia Development and Dysregulation of Iron Homeostasis in Hospitalized Patients with COVID-19. Metabolites 2021; 11:metabo11100653. [PMID: 34677368 PMCID: PMC8540370 DOI: 10.3390/metabo11100653] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Revised: 09/13/2021] [Accepted: 09/23/2021] [Indexed: 01/08/2023] Open
Abstract
Anemia and disturbances of iron metabolism are frequently encountered in patients with COVID-19 and associated with an adverse clinical course. We retrospectively analyzed 645 consecutive COVID-19 patients hospitalized at the Innsbruck University Hospital. Pre-existing anemia was associated with increased risk for in-hospital death. We further found that the decline in hemoglobin levels during hospital stay is more pronounced in patients with signs of hyperinflammation upon admission, the latter being associated with a nearly two-fold higher risk for new onset anemia within one week. Anemia prevalence increased from 44.3% upon admission to 87.8% in patients who were still hospitalized after two weeks. A more distinct decrease in hemoglobin levels was observed in subjects with severe disease, and new-onset anemia was associated with a higher risk for ICU admission. Transferrin levels decreased within the first week of hospitalization in all patients, however, a continuous decline was observed in subjects who died. Hemoglobin, ferritin, and transferrin levels normalized in a median of 122 days after discharge from hospital. This study uncovers pre-existing anemia as well as low transferrin concentrations as risk factors for mortality in hospitalized COVID-19 patients, whereas new-onset anemia during hospitalization is a risk factor for ICU admission. Anemia and iron disturbances are mainly driven by COVID-19 associated inflammation, and cure from infection results in resolution of anemia and normalization of dysregulated iron homeostasis.
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The role of iron homeostasis in remodeling immune function and regulating inflammatory disease. Sci Bull (Beijing) 2021; 66:1806-1816. [PMID: 36654387 DOI: 10.1016/j.scib.2021.02.010] [Citation(s) in RCA: 105] [Impact Index Per Article: 26.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2020] [Revised: 12/31/2020] [Accepted: 01/28/2021] [Indexed: 02/03/2023]
Abstract
The essential trace element iron regulates a wide range of biological processes in virtually all living organisms. Because both iron deficiency and iron overload can lead to various pathological conditions, iron homeostasis is tightly regulated, and understanding this complex process will help pave the way to developing new therapeutic strategies for inflammatory disease. In recent years, significant progress has been made with respect to elucidating the roles of iron and iron-related genes in the development and maintenance of the immune system. Here, we review the timing and mechanisms by which systemic and cellular iron metabolism are regulated during the inflammatory response and during infectious disease, processes in which both the host and the pathogen compete for iron. We also discuss the evidence and implications that immune cells such as macrophages, T cells, and B cells require sufficient amounts of iron for their proliferation and for mediating their effector functions, in which iron serves as a co-factor in toll-like receptor 4 (TLR4) signaling, mitochondrial respiration, posttranslational regulation, and epigenetic modification. In addition, we discuss the therapeutic implications of targeting ferroptosis, iron homeostasis and/or iron metabolism with respect to conferring protection against pathogen infection, controlling inflammation, and improving the efficacy of immunotherapy.
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The Role of Copper in the Regulation of Ferroportin Expression in Macrophages. Cells 2021; 10:cells10092259. [PMID: 34571908 PMCID: PMC8469096 DOI: 10.3390/cells10092259] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2021] [Revised: 08/22/2021] [Accepted: 08/24/2021] [Indexed: 11/17/2022] Open
Abstract
The critical function of ferroportin (Fpn) in maintaining iron homeostasis requires complex and multilevel control of its expression. Besides iron-dependent cellular and systemic control of Fpn expression, other metals also seem to be involved in regulating the Fpn gene. Here, we found that copper loading significantly enhanced Fpn transcription in an Nrf2-dependent manner in primary bone-marrow-derived macrophages (BMDMs). However, prolonged copper loading resulted in decreased Fpn protein abundance. Moreover, CuCl2 treatment induced Fpn expression in RAW 264.7 macrophages at both the mRNA and protein level. These data suggest that cell-type-specific regulations have an impact on Fpn protein stability after copper loading. Transcriptional suppression of Fpn after lipopolysaccharide (LPS) treatment contributes to increased iron storage inside macrophages and may result in anemia of inflammation. Here, we observed that in both primary BMDMs and RAW 264.7 macrophages, LPS treatment significantly decreased Fpn mRNA levels, but concomitant CuCl2 stimulation counteracted the transcriptional suppression of Fpn and restored its expression to the control level. Overall, we show that copper loading significantly enhances Fpn transcription in macrophages, while Fpn protein abundance in response to CuCl2 treatment, depending on macrophage type and factors specific to the macrophage population, can influence Fpn regulation in response to copper loading.
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Lanser L, Fuchs D, Scharnagl H, Grammer T, Kleber ME, März W, Weiss G, Kurz K. Anemia of Chronic Disease in Patients With Cardiovascular Disease. Front Cardiovasc Med 2021; 8:666638. [PMID: 34458328 PMCID: PMC8387678 DOI: 10.3389/fcvm.2021.666638] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2021] [Accepted: 07/23/2021] [Indexed: 12/28/2022] Open
Abstract
Objective: Anemia is often found in patients with coronary artery disease (CAD) or acute coronary syndrome (ACS) and related to disease severity. Our study investigated the relationship between anemia, iron homeostasis and inflammation in CAD and examined their influence on the outcome of patients. Patients and Methods: Markers of immune activation (neopterin, interleukin [IL]-12, IL-6, high sensitive C-reactive protein (hsCRP), fibrinogen, serum amyloid A [SAA]) and iron metabolism (ferritin, transferrin saturation, hemoglobin) were determined in 2,082 patients (68.7 % men, median age 63 years) from the Ludwigshafen Risk and cardiovascular Health (LURIC) cohort. Patients were followed-up for a median of 9.81 years. Results: 960 patients (46.1 %) presented with chronic CAD, 645 patients (31.0 %) had an ACS, and 477 patients (22.9 %) presented with no CAD in coronary angiography (CAG). Anemia (n = 357, 17.1 %) was associated with disease severity (reflected by more progressed stenosis in CAG, CCS, and NYHA classes, and a lower LV-EF), a higher cardio-cerebrovascular event rate and higher levels of inflammatory markers. Interestingly, anemia was only predictive for an adverse outcome in patients with elevated inflammatory markers. Accordingly, anemia of chronic disease (ACD) was associated with a higher cardio-cerebrovascular event-rate in the subsequent 2 years as compared to patients with other types of anemia or without anemia (14.3 vs. 6.1 vs. 4.0%, p < 0.001). Conclusions: This study confirms that anemia and immune activation are strongly related to cardiovascular disease progression and an adverse outcome. Our data suggest that the association of anemia with disease severity and outcome might mainly be due to underlying inflammation.
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Affiliation(s)
- Lukas Lanser
- Department of Internal Medicine II, Innsbruck Medical University, Innsbruck, Austria
| | - Dietmar Fuchs
- Institute of Biological Chemistry, Biocenter, Innsbruck Medical University, Innsbruck, Austria
| | - Hubert Scharnagl
- Clinical Institute of Medical and Chemical Laboratory Diagnostics, Graz Medical University, Graz, Austria
| | - Tanja Grammer
- Medical CIinic V, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany
| | - Marcus E Kleber
- Medical CIinic V, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany
| | - Winfried März
- Medical CIinic V, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.,SYNLAB Academy, SYNLAB Holding Deutschland GmbH, Augsburg and Mannheim, Germany
| | - Günter Weiss
- Department of Internal Medicine II, Innsbruck Medical University, Innsbruck, Austria
| | - Katharina Kurz
- Department of Internal Medicine II, Innsbruck Medical University, Innsbruck, Austria
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Foka P, Dimitriadis A, Karamichali E, Kochlios E, Eliadis P, Valiakou V, Koskinas J, Mamalaki A, Georgopoulou U. HCV-Induced Immunometabolic Crosstalk in a Triple-Cell Co-Culture Model Capable of Simulating Systemic Iron Homeostasis. Cells 2021; 10:2251. [PMID: 34571900 PMCID: PMC8465420 DOI: 10.3390/cells10092251] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2021] [Revised: 08/26/2021] [Accepted: 08/26/2021] [Indexed: 11/16/2022] Open
Abstract
Iron is crucial to the regulation of the host innate immune system and the outcome of many infections. Hepatitis C virus (HCV), one of the major viral human pathogens that depends on iron to complete its life cycle, is highly skilled in evading the immune system. This study presents the construction and validation of a physiologically relevant triple-cell co-culture model that was used to investigate the input of iron in HCV infection and the interplay between HCV, iron, and determinants of host innate immunity. We recorded the expression patterns of key proteins of iron homeostasis involved in iron import, export and storage and examined their relation to the iron regulatory hormone hepcidin in hepatocytes, enterocytes and macrophages in the presence and absence of HCV. We then assessed the transcriptional profiles of pro-inflammatory cytokines Interleukin-6 (IL-6) and interleukin-15 (IL-15) and anti-inflammatory interleukin-10 (IL-10) under normal or iron-depleted conditions and determined how these were affected by infection. Our data suggest the presence of a link between iron homeostasis and innate immunity unfolding among liver, intestine, and macrophages, which could participate in the deregulation of innate immune responses observed in early HCV infection. Coupled with iron-assisted enhanced viral propagation, such a mechanism may be important for the establishment of viral persistence and the ensuing chronic liver disease.
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Affiliation(s)
- Pelagia Foka
- Molecular Virology Laboratory, Hellenic Pasteur Institute, 11521 Athens, Greece; (E.K.); (E.K.); (U.G.)
| | - Alexios Dimitriadis
- Molecular Biology and Immunobiotechnology Laboratory, Hellenic Pasteur Institute, 11521 Athens, Greece; (A.D.); (P.E.); (V.V.); (A.M.)
| | - Eirini Karamichali
- Molecular Virology Laboratory, Hellenic Pasteur Institute, 11521 Athens, Greece; (E.K.); (E.K.); (U.G.)
| | - Emmanouil Kochlios
- Molecular Virology Laboratory, Hellenic Pasteur Institute, 11521 Athens, Greece; (E.K.); (E.K.); (U.G.)
| | - Petros Eliadis
- Molecular Biology and Immunobiotechnology Laboratory, Hellenic Pasteur Institute, 11521 Athens, Greece; (A.D.); (P.E.); (V.V.); (A.M.)
| | - Vaia Valiakou
- Molecular Biology and Immunobiotechnology Laboratory, Hellenic Pasteur Institute, 11521 Athens, Greece; (A.D.); (P.E.); (V.V.); (A.M.)
| | - John Koskinas
- 2nd Department of Internal Medicine, Hippokration Hospital, Medical School of Athens, 11527 Athens, Greece;
| | - Avgi Mamalaki
- Molecular Biology and Immunobiotechnology Laboratory, Hellenic Pasteur Institute, 11521 Athens, Greece; (A.D.); (P.E.); (V.V.); (A.M.)
| | - Urania Georgopoulou
- Molecular Virology Laboratory, Hellenic Pasteur Institute, 11521 Athens, Greece; (E.K.); (E.K.); (U.G.)
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Hoffmann A, de Souza LV, Seifert M, von Raffay L, Haschka D, Grubwieser P, Grander M, Mitterstiller AM, Nairz M, Poli M, Weiss G. Pharmacological Targeting of BMP6-SMAD Mediated Hepcidin Expression Does Not Improve the Outcome of Systemic Infections With Intra-Or Extracellular Gram-Negative Bacteria in Mice. Front Cell Infect Microbiol 2021; 11:705087. [PMID: 34368018 PMCID: PMC8342937 DOI: 10.3389/fcimb.2021.705087] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2021] [Accepted: 07/05/2021] [Indexed: 12/21/2022] Open
Abstract
Introduction Hepcidin is the systemic master regulator of iron metabolism as it degrades the cellular iron exporter ferroportin. In bacterial infections, hepcidin is upregulated to limit circulating iron for pathogens, thereby increasing iron retention in macrophages. This mechanism withholds iron from extracellular bacteria but could be of disadvantage in infections with intracellular bacteria. We aimed to understand the role of hepcidin in infections with intra- or extracellular bacteria using different hepcidin inhibitors. Methods For the experiments LDN-193189 and oversulfated heparins were used, which interact with the BMP6-SMAD pathway thereby inhibiting hepcidin expression. We infected male C57BL/6N mice with either the intracellular bacterium Salmonella Typhimurium or the extracellular bacterium Escherichia coli and treated these mice with the different hepcidin inhibitors. Results Both inhibitors effectively reduced hepcidin levels in vitro under steady state conditions and upon stimulation with the inflammatory signals interleukin-6 or lipopolysaccharide. The inhibitors also reduced hepcidin levels and increased circulating iron concentration in uninfected mice. However, both compounds failed to decrease liver- and circulating hepcidin levels in infected mice and did not affect ferroportin expression in the spleen or impact on serum iron levels. Accordingly, both BMP-SMAD signaling inhibitors did not influence bacterial numbers in different organs in the course of E.coli or S.Tm sepsis. Conclusion These data indicate that targeting the BMP receptor or the BMP-SMAD pathway is not sufficient to suppress hepcidin expression in the course of infection with both intra- or extracellular bacteria. This suggests that upon pharmacological inhibition of the central SMAD-BMP pathways during infection, other signaling cascades are compensatorily induced to ensure sufficient hepcidin formation and iron restriction to circulating microbes.
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Affiliation(s)
- Alexander Hoffmann
- Department of Internal Medicine II, Infectious Diseases, Immunology, Rheumatology, Medical University of Innsbruck, Innsbruck, Austria.,Christian Doppler Laboratory for Iron Metabolism and Anemia Research, Medical University of Innsbruck, Innsbruck, Austria
| | - Lara Valente de Souza
- Department of Internal Medicine II, Infectious Diseases, Immunology, Rheumatology, Medical University of Innsbruck, Innsbruck, Austria.,Christian Doppler Laboratory for Iron Metabolism and Anemia Research, Medical University of Innsbruck, Innsbruck, Austria
| | - Markus Seifert
- Department of Internal Medicine II, Infectious Diseases, Immunology, Rheumatology, Medical University of Innsbruck, Innsbruck, Austria.,Christian Doppler Laboratory for Iron Metabolism and Anemia Research, Medical University of Innsbruck, Innsbruck, Austria
| | - Laura von Raffay
- Department of Internal Medicine II, Infectious Diseases, Immunology, Rheumatology, Medical University of Innsbruck, Innsbruck, Austria.,Christian Doppler Laboratory for Iron Metabolism and Anemia Research, Medical University of Innsbruck, Innsbruck, Austria
| | - David Haschka
- Department of Internal Medicine II, Infectious Diseases, Immunology, Rheumatology, Medical University of Innsbruck, Innsbruck, Austria
| | - Philipp Grubwieser
- Department of Internal Medicine II, Infectious Diseases, Immunology, Rheumatology, Medical University of Innsbruck, Innsbruck, Austria
| | - Manuel Grander
- Department of Internal Medicine II, Infectious Diseases, Immunology, Rheumatology, Medical University of Innsbruck, Innsbruck, Austria
| | - Anna-Maria Mitterstiller
- Department of Internal Medicine II, Infectious Diseases, Immunology, Rheumatology, Medical University of Innsbruck, Innsbruck, Austria
| | - Manfred Nairz
- Department of Internal Medicine II, Infectious Diseases, Immunology, Rheumatology, Medical University of Innsbruck, Innsbruck, Austria
| | - Maura Poli
- Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy
| | - Günter Weiss
- Department of Internal Medicine II, Infectious Diseases, Immunology, Rheumatology, Medical University of Innsbruck, Innsbruck, Austria.,Christian Doppler Laboratory for Iron Metabolism and Anemia Research, Medical University of Innsbruck, Innsbruck, Austria
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Saha P, Xiao X, Li Y, Golonka RM, Abokor AA, Yeoh BS, Vijay-Kumar M. Distinct iron homeostasis in C57BL/6 and Balb/c mouse strains. Physiol Rep 2021; 8:e14441. [PMID: 32385968 PMCID: PMC7210116 DOI: 10.14814/phy2.14441] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2020] [Revised: 04/18/2020] [Accepted: 04/20/2020] [Indexed: 12/17/2022] Open
Abstract
C57BL/6 (BL6) and Balb/c mice exhibit prototypical Th1- and Th2-dominant immune predispositions, respectively. Iron is a proinflammatory metal ion; however, limited information is documented on the differences in iron homeostasis between BL6 and Balb/c strains. The objective of this study was to investigate the extent to which strain-level differences in these mice dictates the regulation of iron homeostasis during physiologic and inflammatory conditions. At basal levels, Balb/c mice displayed significantly higher levels of iron in systemic circulation and tissue compared to BL6 mice. Moreover, Balb/c mice had greater iron absorption as indicated by higher gene expressions of duodenal DcytB, DMT1, Fpn, SFT, and Heph. Similarly, hepatic Tf, TfR1, TfR2, and DMT1 expressions were augmented in Balb/c mice. Interestingly, there was no change in hepatic Hamp expression between the two strains, suggesting that the disparity in their maintenance of iron is independent of hepcidin. Additionally, the basal levels of intracellular labile iron pool in Balb/c intestinal epithelial cells, and bone marrow-derived macrophages and neutrophils, were higher compared to BL6 mice. When mice were challenged with lipopolysaccharide, the acute inflammatory response in BL6 mice was more pronounced than in Balb/c mice, as indicated by the more rapid development of hypoferremia and upregulation of serum IL-6 and TNF-α levels in BL6 mice. In conclusion, this study underscores that iron homeostasis is distinct between BL6 and Balb/c strains under both physiologic and inflammatory conditions.
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Affiliation(s)
- Piu Saha
- Department of Physiology & Pharmacology, University of Toledo College of Medicine and Life Sciences, Toledo, OH, USA
| | - Xia Xiao
- Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Yaqi Li
- Department of Nutritional Sciences, The Pennsylvania State University, University Park, PA, USA
| | - Rachel M Golonka
- Department of Physiology & Pharmacology, University of Toledo College of Medicine and Life Sciences, Toledo, OH, USA
| | - Ahmed A Abokor
- Department of Physiology & Pharmacology, University of Toledo College of Medicine and Life Sciences, Toledo, OH, USA
| | - Beng San Yeoh
- Department of Physiology & Pharmacology, University of Toledo College of Medicine and Life Sciences, Toledo, OH, USA
| | - Matam Vijay-Kumar
- Department of Physiology & Pharmacology, University of Toledo College of Medicine and Life Sciences, Toledo, OH, USA.,Department of Medical Microbiology & Immunology, University of Toledo College of Medicine and Life Sciences, Toledo, OH, USA
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Bjørklund G, Peana M, Pivina L, Dosa A, Aaseth J, Semenova Y, Chirumbolo S, Medici S, Dadar M, Costea DO. Iron Deficiency in Obesity and after Bariatric Surgery. Biomolecules 2021; 11:biom11050613. [PMID: 33918997 PMCID: PMC8142987 DOI: 10.3390/biom11050613] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2020] [Revised: 04/10/2021] [Accepted: 04/16/2021] [Indexed: 02/06/2023] Open
Abstract
Iron deficiency (ID) is particularly frequent in obese patients due to increased circulating levels of acute-phase reactant hepcidin and adiposity-associated inflammation. Inflammation in obese subjects is closely related to ID. It induces reduced iron absorption correlated to the inhibition of duodenal ferroportin expression, parallel to the increased concentrations of hepcidin. Obese subjects often get decreased inflammatory response after bariatric surgery, accompanied by decreased serum hepcidin and therefore improved iron absorption. Bariatric surgery can induce the mitigation or resolution of obesity-associated complications, such as hypertension, insulin resistance, diabetes mellitus, and hyperlipidemia, adjusting many parameters in the metabolism. However, gastric bypass surgery and sleeve gastrectomy can induce malabsorption and may accentuate ID. The present review explores the burden and characteristics of ID and anemia in obese patients after bariatric surgery, accounting for gastric bypass technique (Roux-en-Y gastric bypass-RYGB) and sleeve gastrectomy (SG). After bariatric surgery, obese subjects' iron status should be monitored, and they should be motivated to use adequate and recommended iron supplementation.
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Affiliation(s)
- Geir Bjørklund
- Council for Nutritional and Environmental Medicine, Toften 24, 8610 Mo i Rana, Norway
- Correspondence: (G.B.); (M.P.)
| | - Massimiliano Peana
- Department of Chemistry and Pharmacy, University of Sassari, Via Vienna 2, 07100 Sassari, Italy;
- Correspondence: (G.B.); (M.P.)
| | - Lyudmila Pivina
- Department of Neurology, Ophthalmology and Otolaryngology, Semey Medical University, 071400 Semey, Kazakhstan; (L.P.); (Y.S.)
- CONEM Kazakhstan Environmental Health and Safety Research Group, Semey Medical University, 071400 Semey, Kazakhstan
| | - Alexandru Dosa
- Faculty of Medicine, Ovidius University of Constanta, 900470 Constanta, Romania; (A.D.); (D.-O.C.)
| | - Jan Aaseth
- Research Department, Innlandet Hospital Trust, 2380 Brumunddal, Norway;
| | - Yuliya Semenova
- Department of Neurology, Ophthalmology and Otolaryngology, Semey Medical University, 071400 Semey, Kazakhstan; (L.P.); (Y.S.)
- CONEM Kazakhstan Environmental Health and Safety Research Group, Semey Medical University, 071400 Semey, Kazakhstan
| | - Salvatore Chirumbolo
- Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona, 37134 Verona, Italy;
- CONEM Scientific Secretary, 37134 Verona, Italy
| | - Serenella Medici
- Department of Chemistry and Pharmacy, University of Sassari, Via Vienna 2, 07100 Sassari, Italy;
| | - Maryam Dadar
- Razi Vaccine and Serum Research Institute, Agricultural Research, Education and Extension Organization (AREEO), Karaj 31975/148, Iran;
| | - Daniel-Ovidiu Costea
- Faculty of Medicine, Ovidius University of Constanta, 900470 Constanta, Romania; (A.D.); (D.-O.C.)
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Merli P, Quintarelli C, Strocchio L, Locatelli F. The role of interferon-gamma and its signaling pathway in pediatric hematological disorders. Pediatr Blood Cancer 2021; 68:e28900. [PMID: 33484058 DOI: 10.1002/pbc.28900] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2020] [Revised: 12/28/2020] [Accepted: 12/29/2020] [Indexed: 12/15/2022]
Abstract
Interferon-gamma (IFN-γ) plays a key role in the pathophysiology of hemophagocytic lymphohistiocytosis (HLH), and available evidence also points to a role in other conditions, including aplastic anemia (AA) and graft failure following allogeneic hematopoietic stem cell transplantation. Recently, the therapeutic potential of IFN-γ inhibition has been documented; emapalumab, an anti-IFN-γ monoclonal antibody, has been approved in the United States for treatment of primary HLH that is refractory, recurrent or progressive, or in patients with intolerance to conventional therapy. Moreover, ruxolitinib, an inhibitor of JAK/STAT intracellular signaling, is currently being investigated for treating HLH. In AA, IFN-γ inhibits hematopoiesis by disrupting the interaction between thrombopoietin and its receptor, c-MPL. Eltrombopag, a small-molecule agonist of c-MPL, acts at a different binding site to IFN-γ and is thus able to circumvent its inhibitory effects. Ongoing trials will elucidate the role of IFN-γ neutralization in secondary HLH and future studies could explore this strategy in controlling hyperinflammation due to CAR T cells.
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Affiliation(s)
- Pietro Merli
- Department of Pediatric Hematology and Oncology, Cell and Gene Therapy, IRCCS Bambino Gesù Children's Hospital, Rome, Italy
| | - Concetta Quintarelli
- Department of Pediatric Hematology and Oncology, Cell and Gene Therapy, IRCCS Bambino Gesù Children's Hospital, Rome, Italy.,Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy
| | - Luisa Strocchio
- Department of Pediatric Hematology and Oncology, Cell and Gene Therapy, IRCCS Bambino Gesù Children's Hospital, Rome, Italy
| | - Franco Locatelli
- Department of Pediatric Hematology and Oncology, Cell and Gene Therapy, IRCCS Bambino Gesù Children's Hospital, Rome, Italy.,Sapienza, University of Rome, Rome, Italy
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Keiner M, Fuchs J, Bauer N, Moritz A. Evaluation of reticulocyte hemoglobin content (RETIC-HGB) for the diagnosis of iron-limited erythropoiesis in cats. Vet Clin Pathol 2021; 49:557-566. [PMID: 33617045 DOI: 10.1111/vcp.12925] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2019] [Revised: 04/20/2020] [Accepted: 04/27/2020] [Indexed: 11/28/2022]
Abstract
BACKGROUND Decreased reticulocyte hemoglobin content (CHr) (Siemens ADVIA 2120) reflects iron-limited erythropoiesis (ILE). RETIC-HGB (IDEXX ProCyte Dx) is a novel marker of ILE for veterinary use. OBJECTIVES We aimed to evaluate reference intervals (RIs) and the utility of RETIC-HGB and CHr in the diagnosis of feline ILE. MATERIALS AND METHODS RIs were established in 59 healthy cats. Intra-assay coefficients of variation (CVs) and correlations between RETIC-HGB and CHr were assessed. Two hundred and seventy-five cats were classified as having ILE or not based on low plasma iron or low transferrin saturation along with anemia and/or altered RBC indices. CHr, RETIC-HGB, and serum amyloid A (SAA) were compared between the groups. The sensitivity and specificity of RETIC-HGB and CHr to diagnose ILE were analyzed to determine the RI lower limits. RESULTS RIs for RETIC-HGB and CHr were 12.5-18.0 and 14.0-19.9 pg, respectively. The CV was 3% for both variables. RETIC-HGB and CHr were moderately correlated (rs = 0.59) with a bias of -1.2 picograms (pgs). Twenty of the 275 cats were classified as having ILE. Compared with non-ILE cats, ILE cats had significantly lower median RETIC-HGB (14.3 vs 15.2 pg, P = .0046) and mean CHr (14.7 vs 16.5 pg, P < .0001) values and significantly increased median SAA (44.6 vs 2.3 µg/dl, P < .0001) values. Using the lower RI limits resulted in a low sensitivity and relatively high specificity to diagnose ILE in cats. CONCLUSIONS ILE was characterized by decreased CHr and RETIC-HGB; however, sensitivity was low. The moderate correlation between RETIC-HGB and CHr is likely due to species differences and different methodology.
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Affiliation(s)
- Miriam Keiner
- Small Animal Clinic, Internal Medicine, Justus-Liebig-University, Giessen, Germany
| | - Jannika Fuchs
- Department of Veterinary Clinical Sciences, Clinical Pathology and Clinical Pathophysiology, Justus-Liebig-University, Giessen, Germany
| | - Natali Bauer
- Department of Veterinary Clinical Sciences, Clinical Pathology and Clinical Pathophysiology, Justus-Liebig-University, Giessen, Germany
| | - Andreas Moritz
- Small Animal Clinic, Internal Medicine, Justus-Liebig-University, Giessen, Germany.,Department of Veterinary Clinical Sciences, Clinical Pathology and Clinical Pathophysiology, Justus-Liebig-University, Giessen, Germany
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Han Y, Huang W, Meng H, Zhan Y, Hou J. Pro-inflammatory cytokine interleukin-6-induced hepcidin, a key mediator of periodontitis-related anemia of inflammation. J Periodontal Res 2021; 56:690-701. [PMID: 33656216 DOI: 10.1111/jre.12865] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2020] [Revised: 01/05/2021] [Accepted: 02/06/2021] [Indexed: 12/15/2022]
Abstract
OBJECTIVES To investigate whether anemia of inflammation (AI) occurs in periodontitis patients and to further explore underlying pathogenesis of periodontitis-related AI by an experimental periodontitis model. BACKGROUND Previous studies have reported periodontitis patients could show a tendency toward AI. However, the relationship between periodontitis and AI remains unclear, and the related pathological mechanisms have not been identified. MATERIALS AND METHODS Periodontal clinical parameters, inflammatory markers, and anemia-related indicators were compared between 98 aggressive periodontitis (AgP) patients and 103 healthy subjects. An experimental periodontitis model was induced by ligature placement in mice. The changes in mice inflammatory markers, anemia indicators, hepcidin mRNA expression, and serum hepcidin concentrations were measured. Human and mouse liver cells were treated with interleukin-6 (IL-6) for analyzing the changes in hepcidin expression based on mRNA and protein levels. RESULTS AgP patients exhibited higher white blood cell counts, IL-6, and C-reactive protein. Adjusted linear regression analyses showed correlations between AgP and decreased hemoglobin (HGB) and hematocrit (HCT). The ligature-induced periodontitis caused systemic inflammation and elevated IL-6 levels. Lower red blood cell counts, HGB, and HCT were detected, whereas the levels of hepcidin mRNA expression and serum hepcidin concentrations increased. The treatment of hepatocytes with IL-6 induced both hepcidin mRNA expression and hepcidin secretion. CONCLUSIONS Systemic inflammation induced by periodontitis leads to an increased risk for AI. IL-6-induced hepcidin could play a central mediator role and act as a key pathologic mechanism. Our results demonstrate periodontitis may be considered as an additional inflammatory disease contributing to the development of AI.
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Affiliation(s)
- Ye Han
- Department of Periodontology, Peking University School and Hospital of Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Laboratory for Digital and Material Technology of Stomatology & Beijing Key Laboratory of Digital Stomatology, Beijing, China
| | - Wenxue Huang
- Department of Periodontology, Peking University School and Hospital of Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Laboratory for Digital and Material Technology of Stomatology & Beijing Key Laboratory of Digital Stomatology, Beijing, China
| | - Huanxin Meng
- Department of Periodontology, Peking University School and Hospital of Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Laboratory for Digital and Material Technology of Stomatology & Beijing Key Laboratory of Digital Stomatology, Beijing, China
| | - Yalin Zhan
- First Clinical Division, Peking University School and Hospital of Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Laboratory for Digital and Material Technology of Stomatology & Beijing Key Laboratory of Digital Stomatology, Beijing, China
| | - Jianxia Hou
- Department of Periodontology, Peking University School and Hospital of Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Laboratory for Digital and Material Technology of Stomatology & Beijing Key Laboratory of Digital Stomatology, Beijing, China
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Liu Q, Wu J, Zhang X, Wu X, Zhao Y, Ren J. Iron homeostasis and disorders revisited in the sepsis. Free Radic Biol Med 2021; 165:1-13. [PMID: 33486088 DOI: 10.1016/j.freeradbiomed.2021.01.025] [Citation(s) in RCA: 59] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/20/2020] [Revised: 12/31/2020] [Accepted: 01/11/2021] [Indexed: 12/26/2022]
Abstract
Sepsis is a life-threatening condition caused by a dysregulated host-response to inflammation, although it currently lacks a fully elucidated pathobiology. Iron is a crucial trace element that is essential for fundamental processes in both humans and bacteria. During sepsis, iron metabolism is altered, including increased iron transport and uptake into cells and decreased iron export. The intracellular sequestration of iron limits its availability to circulating pathogens, which serves as a conservative strategy against the pathogens. Although iron retention has been showed to have protective protect effects, an increase in labile iron may cause oxidative injury and cell death (e.g., pyroptosis, ferroptosis) as the condition progresses. Moreover, iron disorders are substantial and correlate with the severity of sepsis. This also suggests that iron may be useful as a diagnostic marker for evaluating the severity and predicting the outcome of the disease. Further knowledge about these disorders could help in evaluating how drugs targeting iron homeostasis can be optimally applied to improve the treatment of patients with sepsis. Here, we present a comprehensive review of recent advances in the understanding of iron metabolism, focusing on the regulatory mechanisms and iron-mediated injury in sepsis.
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Affiliation(s)
- Qinjie Liu
- Research Institute of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, 210002, PR China.
| | - Jie Wu
- Department of General Surgery, BenQ Medical Center, The Affiliated BenQ Hospital of Nanjing Medical University, Nanjing, 210002, PR China.
| | - Xufei Zhang
- Research Institute of General Surgery, Jinling Hospital, Nanjing Medical University, Nanjing, 210002, PR China.
| | - Xiuwen Wu
- Research Institute of General Surgery, Jinling Hospital, Nanjing, 210002, PR China.
| | - Yun Zhao
- Department of General Surgery, BenQ Medical Center, The Affiliated BenQ Hospital of Nanjing Medical University, Nanjing, 210002, PR China.
| | - Jianan Ren
- Research Institute of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, 210002, PR China; Department of General Surgery, BenQ Medical Center, The Affiliated BenQ Hospital of Nanjing Medical University, Nanjing, 210002, PR China; Research Institute of General Surgery, Jinling Hospital, Nanjing Medical University, Nanjing, 210002, PR China.
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