|
1
|
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.
Collapse
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
| |
Collapse
|
|
2
|
Zhang H, Lv B, Liu K, Du J, Jin H, Huang Y. Sulfur dioxide controls M1 macrophage polarization by sulphenylation of prolyl hydroxylase 2 at cysteine 260. Free Radic Biol Med 2025; 230:33-47. [PMID: 39892500 DOI: 10.1016/j.freeradbiomed.2025.01.054] [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: 10/25/2024] [Revised: 01/28/2025] [Accepted: 01/29/2025] [Indexed: 02/03/2025]
Abstract
M1 macrophage polarization plays a pivotal role in inflammation-related diseases. However, the endogenous regulatory factors and mechanisms underlying M1 macrophage polarization have not been entirely clarified. This study aimed to explore whether endogenous sulfur dioxide (SO2) is involved in M1 macrophage polarization and its mechanism. In the study, we found that the endogenous SO2/aspartate aminotransferase1 (AAT1) pathway was downregulated during M1 polarization of macrophages induced by lipopolysaccharide (LPS) stimulation, and supplementation with SO2 donors or AAT1 overexpression restored SO2 content, suppressed protein expression of inducible nitric oxide synthase, restrained mRNA level of M1 phenotype-related genes tumor necrosis factor α, interleukin-1β and interleukin-12β and decreased the CD86 expression. In addition, AAT1-knockdowned macrophages exhibited reduced level of hypoxia-inducible factor-1α (HIF-1α) hydroxylation, elevated HIF-1α protein level, and polarization into M1-type, while supplementation with SO2 reversed the above effects. Mechanistically, SO2 maintained prolyl hydroxylase (PHD) activity in a thiol-dependent manner. SO2 maintained PHD2 activity by sulphenylating PHD2 at Cys260, thereby reducing HIF-1α protein levels and subsequently inhibiting M1 macrophage polarization. Besides, SO2 enhanced PHD2 sulphenylation, inhibited M1 macrophage polarization, and alleviated lung damage in a mouse model of LPS-induced acute lung injury. These results suggested that downregulation of the endogenous SO2/AAT1 pathway was a pivotal mechanism for M1 macrophage polarization. SO2 maintained PHD2 activity via sulphenylation of Cys260, and promoted HIF-1α hydroxylation and degradation, thereby impeding M1 macrophage polarization.
Collapse
Affiliation(s)
- Han Zhang
- Department of Pediatrics, Children's Medical Center, Peking University First Hospital, 100034, Beijing, China
| | - Boyang Lv
- Department of Pediatrics, Children's Medical Center, Peking University First Hospital, 100034, Beijing, China
| | - Keyu Liu
- Department of Pediatrics, Children's Medical Center, Peking University First Hospital, 100034, Beijing, China
| | - Junbao Du
- Department of Pediatrics, Children's Medical Center, Peking University First Hospital, 100034, Beijing, China
| | - Hongfang Jin
- Department of Pediatrics, Children's Medical Center, Peking University First Hospital, 100034, Beijing, China; State Key Laboratory of Vascular Homeostasis and Remodeling, 100191, Peking University, Beijing, China.
| | - Yaqian Huang
- Department of Pediatrics, Children's Medical Center, Peking University First Hospital, 100034, Beijing, China; State Key Laboratory of Vascular Homeostasis and Remodeling, 100191, Peking University, Beijing, China.
| |
Collapse
|
|
3
|
Dwyer KD, Snyder CA, Coulombe KLK. Cardiomyocytes in Hypoxia: Cellular Responses and Implications for Cell-Based Cardiac Regenerative Therapies. Bioengineering (Basel) 2025; 12:154. [PMID: 40001674 PMCID: PMC11851968 DOI: 10.3390/bioengineering12020154] [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: 01/04/2025] [Revised: 01/28/2025] [Accepted: 02/02/2025] [Indexed: 02/27/2025] Open
Abstract
Myocardial infarction (MI) is a severe hypoxic event, resulting in the loss of up to one billion cardiomyocytes (CMs). Due to the limited intrinsic regenerative capacity of the heart, cell-based regenerative therapies, which feature the implantation of stem cell-derived cardiomyocytes (SC-CMs) into the infarcted myocardium, are being developed with the goal of restoring lost muscle mass, re-engineering cardiac contractility, and preventing the progression of MI into heart failure (HF). However, such cell-based therapies are challenged by their susceptibility to oxidative stress in the ischemic environment of the infarcted heart. To maximize the therapeutic benefits of cell-based approaches, a better understanding of the heart environment at the cellular, tissue, and organ level throughout MI is imperative. This review provides a comprehensive summary of the cardiac pathophysiology occurring during and after MI, as well as how these changes define the cardiac environment to which cell-based cardiac regenerative therapies are delivered. This understanding is then leveraged to frame how cell culture treatments may be employed to enhance SC-CMs' hypoxia resistance. In this way, we synthesize both the complex experience of SC-CMs upon implantation and the engineering techniques that can be utilized to develop robust SC-CMs for the clinical translation of cell-based cardiac therapies.
Collapse
Affiliation(s)
| | | | - Kareen L. K. Coulombe
- Institute for Biology, Engineering, and Medicine, School of Engineering, Brown University, Providence, RI 02912, USA; (K.D.D.); (C.A.S.)
| |
Collapse
|
|
4
|
Stefanache A, Lungu II, Butnariu IA, Calin G, Gutu C, Marcu C, Grierosu C, Bogdan Goroftei ER, Duceac LD, Dabija MG, Popa F, Damir D. Understanding How Minerals Contribute to Optimal Immune Function. J Immunol Res 2023; 2023:3355733. [PMID: 37946846 PMCID: PMC10632063 DOI: 10.1155/2023/3355733] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2023] [Revised: 08/16/2023] [Accepted: 09/09/2023] [Indexed: 11/12/2023] Open
Abstract
Sufficient mineral supply is vital not only for the innate immune system but also for the components of the adaptive immune defense, which encompass defense mechanisms against pathogens and the delicate balance of pro- and anti-inflammatory regulation in the long term. Generally, a well-balanced diet is capable of providing the necessary minerals to support the immune system. Nevertheless, specific vulnerable populations should be cautious about obtaining adequate amounts of minerals such as magnesium, zinc, copper, iron, and selenium. Inadequate levels of these minerals can temporarily impair immune competence and disrupt the long-term regulation of systemic inflammation. Therefore, comprehending the mechanisms and sources of these minerals is crucial. In exceptional circumstances, mineral deficiencies may necessitate supplementation; however, excessive intake of supplements can have adverse effects on the immune system and should be avoided. Consequently, any supplementation should be approved by medical professionals and administered in recommended doses. This review emphasizes the crucial significance of minerals in promoting optimal functioning of the immune system. It investigates the indispensable minerals required for immune system function and the regulation of inflammation. Moreover, it delves into the significance of maintaining an optimized intake of minerals from a nutritional standpoint.
Collapse
Affiliation(s)
- Alina Stefanache
- “Grigore T. Popa” University of Medicine and Pharmacy, Iasi 700115, Romania
| | - Ionut-Iulian Lungu
- “Grigore T. Popa” University of Medicine and Pharmacy, Iasi 700115, Romania
| | | | - Gabriela Calin
- Faculty of Dental Medicine, “Apollonia” University of Iasi, 11 Pacurari Street, Iasi 700511, Romania
| | - Cristian Gutu
- Faculty of Medicine and Pharmacy, University Dunarea de Jos, 47 Domneasca Street, Galati 800008, Romania
| | - Constantin Marcu
- Faculty of Medicine and Pharmacy, University Dunarea de Jos, 47 Domneasca Street, Galati 800008, Romania
| | - Carmen Grierosu
- Faculty of Dental Medicine, “Apollonia” University of Iasi, 11 Pacurari Street, Iasi 700511, Romania
| | | | - Letitia-Doina Duceac
- Faculty of Medicine and Pharmacy, University Dunarea de Jos, 47 Domneasca Street, Galati 800008, Romania
| | | | - Florina Popa
- Faculty of Medicine and Pharmacy, University Dunarea de Jos, 47 Domneasca Street, Galati 800008, Romania
| | - Daniela Damir
- “Grigore T. Popa” University of Medicine and Pharmacy, Iasi 700115, Romania
| |
Collapse
|
|
5
|
Tam FF, Ning KL, Lee M, Dumlao JM, Choy JC. Cytokine induction of HIF-1α during normoxia in A549 human lung carcinoma cells is regulated by STAT1 and JNK signalling pathways. Mol Immunol 2023; 160:12-19. [PMID: 37295053 DOI: 10.1016/j.molimm.2023.06.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2023] [Revised: 05/30/2023] [Accepted: 06/02/2023] [Indexed: 06/12/2023]
Abstract
Hypoxia inducible factor-1ɑ (HIF-1ɑ) is the regulatory subunit of the HIF-1 transcription factor that is a regulator of cell physiological responses to hypoxia. However, the biological function and regulatory mechanisms controlling HIF-1α in normoxia are poorly understood. Here, we first examined the role of HIF-1α in the inflammatory activation of A549 human lung carcinoma cells in normoxia. Inactivation of the HIF-1α gene by CRISPR/Cas9 reduced the secretion of CXCL8 induced by stimulation with a cytokine mixture (CM) consisting of IL-1, TNFα and IFNγ. We next determined that cytokines act co-operatively to induce expression and nuclear accumulation of HIF-1α. To investigate the signalling mechanisms by which cytokines induce HIF-1α in normoxia, pharmacological inhibitors against the Jak/STAT, PI3K, NFκB, MEK/ERK, and JNK pathways were used. Inhibition of the Jak/STAT and JNK pathways inhibited the induction and nuclear accumulation of HIF-1ɑ by cytokines. Furthermore, siRNA knockdown of STAT1 and JNK also reduced the induction of HIF-1α by cytokines. Finally, pharmacological inhibition of these two pathways also blocked the trans-activation of HIF-1. These findings have implications for understanding the role and regulatory mechanisms of HIF-1ɑ in inflammation and cell biology.
Collapse
Affiliation(s)
- Franklin F Tam
- Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, British Columbia, Canada
| | - Kevin Luong Ning
- Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, British Columbia, Canada
| | - Martin Lee
- Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, British Columbia, Canada
| | - Jenice M Dumlao
- Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, British Columbia, Canada
| | - Jonathan C Choy
- Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, British Columbia, Canada.
| |
Collapse
|
|
6
|
Iacobini C, Vitale M, Haxhi J, Pesce C, Pugliese G, Menini S. Mutual Regulation between Redox and Hypoxia-Inducible Factors in Cardiovascular and Renal Complications of Diabetes. Antioxidants (Basel) 2022; 11:2183. [PMID: 36358555 PMCID: PMC9686572 DOI: 10.3390/antiox11112183] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2022] [Revised: 10/31/2022] [Accepted: 11/02/2022] [Indexed: 08/30/2023] Open
Abstract
Oxidative stress and hypoxia-inducible factors (HIFs) have been implicated in the pathogenesis of diabetic cardiovascular and renal diseases. Reactive oxygen species (ROS) mediate physiological and pathophysiological processes, being involved in the modulation of cell signaling, differentiation, and survival, but also in cyto- and genotoxic damage. As master regulators of glycolytic metabolism and oxygen homeostasis, HIFs have been largely studied for their role in cell survival in hypoxic conditions. However, in addition to hypoxia, other stimuli can regulate HIFs stability and transcriptional activity, even in normoxic conditions. Among these, a regulatory role of ROS and their byproducts on HIFs, particularly the HIF-1α isoform, has received growing attention in recent years. On the other hand, HIF-1α and HIF-2α exert mutually antagonistic effects on oxidative damage. In diabetes, redox-mediated HIF-1α deregulation contributes to the onset and progression of cardiovascular and renal complications, and recent findings suggest that deranged HIF signaling induced by hyperglycemia and other cellular stressors associated with metabolic disorders may cause mitochondrial dysfunction, oxidative stress, and inflammation. Understanding the mechanisms of mutual regulation between HIFs and redox factors and the specific contribution of the two main isoforms of HIF-α is fundamental to identify new therapeutic targets for vascular complications of diabetes.
Collapse
Affiliation(s)
- Carla Iacobini
- Department of Clinical and Molecular Medicine, “La Sapienza” University, 00189 Rome, Italy
| | - Martina Vitale
- Department of Clinical and Molecular Medicine, “La Sapienza” University, 00189 Rome, Italy
| | - Jonida Haxhi
- Department of Clinical and Molecular Medicine, “La Sapienza” University, 00189 Rome, Italy
| | - Carlo Pesce
- Department of Neurosciences, Rehabilitation, Ophthalmology, Genetic and Maternal Infantile Sciences (DINOGMI), Department of Excellence of MIUR, University of Genoa Medical School, 16132 Genoa, Italy
| | - Giuseppe Pugliese
- Department of Clinical and Molecular Medicine, “La Sapienza” University, 00189 Rome, Italy
| | - Stefano Menini
- Department of Clinical and Molecular Medicine, “La Sapienza” University, 00189 Rome, Italy
| |
Collapse
|
|
7
|
Lintel H, Abbas DB, Lavin CV, Griffin M, Guo JL, Guardino N, Churukian A, Gurtner GC, Momeni A, Longaker MT, Wan DC. Transdermal deferoxamine administration improves excisional wound healing in chronically irradiated murine skin. J Transl Med 2022; 20:274. [PMID: 35715816 PMCID: PMC9205074 DOI: 10.1186/s12967-022-03479-4] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2022] [Accepted: 06/11/2022] [Indexed: 01/13/2023] Open
Abstract
BACKGROUND Radiation-induced skin injury is a well-known risk factor for impaired wound healing. Over time, the deleterious effects of radiation on skin produce a fibrotic, hypovascular dermis poorly suited to wound healing. Despite increasing understanding of the underlying pathophysiology, therapeutic options remain elusive. Deferoxamine (DFO), an iron-chelating drug, has been shown in prior murine studies to ameliorate radiation-induced skin injury as well as improve wound healing outcomes in various pathologic conditions when administered transdermally. In this preclinical study, we evaluated the effects of deferoxamine on wound healing outcomes in chronically irradiated murine skin. METHODS Wild-type mice received 30 Gy of irradiation to their dorsal skin and were left to develop chronic fibrosis. Stented excisional wounds were created on their dorsal skin. Wound healing outcomes were compared across 4 experimental conditions: DFO patch treatment, vehicle-only patch treatment, untreated irradiated wound, and untreated nonirradiated wounds. Gross closure rate, wound perfusion, scar elasticity, histology, and nitric oxide assays were compared across the conditions. RESULTS Relative to vehicle and untreated irradiated wounds, DFO accelerated wound closure and reduced the frequency of healing failure in irradiated wounds. DFO augmented wound perfusion throughout healing and upregulated angiogenesis to levels observed in nonirradiated wounds. Histology revealed DFO increased wound thickness, collagen density, and improved collagen fiber organization to more closely resemble nonirradiated wounds, likely contributing to the observed improved scar elasticity. Lastly, DFO upregulated inducible nitric oxide synthase and increased nitric oxide production in early healing wounds. CONCLUSION Deferoxamine treatment presents a potential therapeutic avenue through which to target impaired wound healing in patients following radiotherapy.
Collapse
Affiliation(s)
- Hendrik Lintel
- Hagey Laboratory for Pediatric Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, USA
| | - Darren B Abbas
- Hagey Laboratory for Pediatric Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, USA
| | - Christopher V Lavin
- Hagey Laboratory for Pediatric Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, USA
| | - Michelle Griffin
- Hagey Laboratory for Pediatric Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, USA
| | - Jason L Guo
- Hagey Laboratory for Pediatric Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, USA
| | - Nicholas Guardino
- Hagey Laboratory for Pediatric Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, USA
| | - Andrew Churukian
- Hagey Laboratory for Pediatric Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, USA
| | | | - Arash Momeni
- Hagey Laboratory for Pediatric Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, USA
| | - Michael T Longaker
- Hagey Laboratory for Pediatric Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, USA
- Institute for Stem Cell Biology and Regenerative Medicine, Stanford University Medical Center, Stanford, CA, USA
| | - Derrick C Wan
- Hagey Laboratory for Pediatric Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, USA.
- Department of Surgery, Hagey Family Faculty Scholar in Pediatric Regenerative Medicine, Stanford University School of Medicine, 257 Campus Drive West, Stanford, CA, 94305, USA.
| |
Collapse
|
|
8
|
de Oliveira J, Denadai MB, Costa DL. Crosstalk between Heme Oxygenase-1 and Iron Metabolism in Macrophages: Implications for the Modulation of Inflammation and Immunity. Antioxidants (Basel) 2022; 11:861. [PMID: 35624725 PMCID: PMC9137896 DOI: 10.3390/antiox11050861] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2022] [Revised: 04/21/2022] [Accepted: 04/22/2022] [Indexed: 12/16/2022] Open
Abstract
Heme oxygenase-1 (HO-1) is an enzyme that catalyzes the degradation of heme, releasing equimolar amounts of carbon monoxide (CO), biliverdin (BV), and iron. The anti-inflammatory and antioxidant properties of HO-1 activity are conferred in part by the release of CO and BV and are extensively characterized. However, iron constitutes an important product of HO-1 activity involved in the regulation of several cellular biological processes. The macrophage-mediated recycling of heme molecules, in particular those contained in hemoglobin, constitutes the major mechanism through which living organisms acquire iron. This process is finely regulated by the activities of HO-1 and of the iron exporter protein ferroportin. The expression of both proteins can be induced or suppressed in response to pro- and anti-inflammatory stimuli in macrophages from different tissues, which alters the intracellular iron concentrations of these cells. As we discuss in this review article, changes in intracellular iron levels play important roles in the regulation of cellular oxidation reactions as well as in the transcriptional and translational regulation of the expression of proteins related to inflammation and immune responses, and therefore, iron metabolism represents a potential target for the development of novel therapeutic strategies focused on the modulation of immunity and inflammation.
Collapse
Affiliation(s)
- Joseana de Oliveira
- Departamento de Bioquímica e Imunologia, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirao Preto 14049-900, Brazil; (J.d.O.); (M.B.D.)
- Programa de Pós-Graduação em Imunologia Básica e Aplicada, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirao Preto 14049-900, Brazil
| | - Marina B. Denadai
- Departamento de Bioquímica e Imunologia, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirao Preto 14049-900, Brazil; (J.d.O.); (M.B.D.)
- Programa de Pós-Graduação em Imunologia Básica e Aplicada, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirao Preto 14049-900, Brazil
| | - Diego L. Costa
- Departamento de Bioquímica e Imunologia, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirao Preto 14049-900, Brazil; (J.d.O.); (M.B.D.)
- Programa de Pós-Graduação em Imunologia Básica e Aplicada, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirao Preto 14049-900, Brazil
| |
Collapse
|
|
9
|
Yoshida T, Okumura T, Matsuo Y, Okuyama T, Michiura T, Kaibori M, Umezaki N, Bono H, Hirota K, Sekimoto M. Activation of transcription factor HIF inhibits IL-1β-induced NO production in primary cultured rat hepatocytes. Nitric Oxide 2022; 124:1-14. [PMID: 35460897 DOI: 10.1016/j.niox.2022.04.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2021] [Revised: 04/07/2022] [Accepted: 04/08/2022] [Indexed: 10/18/2022]
Abstract
Roxadustat and other hypoxia-inducible factor-prolyl hydroxylase inhibitors (HIF-PHIs) have recently been approved for the treatment of chronic renal anemia. In macrophages and monocytes, the activation of HIF-1 by pro-inflammatory cytokines induces iNOS expression and activity through the NF-κB pathway to produce nitric oxide (NO), which causes liver injury when excessively produced. Few studies have reported a relationship between HIF activity and iNOS induction in hepatocytes. We investigated the effect of drug- and hypoxia-induced HIF activations on NO production in primary cultured rat hepatocytes. Roxadustat treatment and hypoxic conditions activated HIF. Contrary to expectations, HIF-PHI treatment and hypoxia inhibited IL-1β-induced NO production. RNA-Seq analysis of mRNA expression in rat hepatocytes showed that roxadustat treatment decreased the expression of genes related to inflammation, and genes in the NF-κB signaling pathway were induced by IL-1β. Moreover, roxadustat suppressed IL-1β-activated signaling pathways in an HIF-dependent manner. GalN/LPS-treated rats were used as in vivo models of hepatic injury, and roxadustat treatment showed a tendency to suppress the death of rats. Therefore, exogenous HIF-1 activation, including HIF-PHI and hypoxia exposures, suppressed IL-1β-induced iNOS mRNA expression and subsequent NO production in hepatocytes, by suppressing the NF-κB signaling pathway. Roxadustat treatment suppresses the expression of pro-inflammatory genes by activating HIF, and thus may exhibit hepatoprotective effects.
Collapse
Affiliation(s)
- Terufumi Yoshida
- Department of Surgery, Kansai Medical University, 2-5-1 Shinmachi, Hirakata, Osaka, 573-1010, Japan.
| | - Tadayoshi Okumura
- Department of Surgery, Kansai Medical University, 2-5-1 Shinmachi, Hirakata, Osaka, 573-1010, Japan; Research Organization of Science and Technology, Ritsumeikan University, 1-1 Noji-higashi, Kusatsu, Shiga, 525-8577, Japan.
| | - Yoshiyuki Matsuo
- Department of Human Stress Response Science, Institute of Biomedical Science, Kansai Medical University, 2-5-1 Shinmachi, Hirakata, Osaka, 573-1010, Japan.
| | - Tetsuya Okuyama
- Department of Surgery, Kansai Medical University, 2-5-1 Shinmachi, Hirakata, Osaka, 573-1010, Japan; Research Organization of Science and Technology, Ritsumeikan University, 1-1 Noji-higashi, Kusatsu, Shiga, 525-8577, Japan.
| | - Taku Michiura
- Department of Surgery, Kansai Medical University, 2-5-1 Shinmachi, Hirakata, Osaka, 573-1010, Japan.
| | - Masaki Kaibori
- Department of Surgery, Kansai Medical University, 2-5-1 Shinmachi, Hirakata, Osaka, 573-1010, Japan.
| | - Nodoka Umezaki
- Department of Surgery, Kansai Medical University, 2-5-1 Shinmachi, Hirakata, Osaka, 573-1010, Japan.
| | - Hidemasa Bono
- Program of Biomedical Science, Graduate School of Integrated Sciences for Life, Hiroshima University, 3-10-23 Kagamiyama, Higashi-Hiroshima, Hiroshima, 739-0046, Japan.
| | - Kiichi Hirota
- Department of Human Stress Response Science, Institute of Biomedical Science, Kansai Medical University, 2-5-1 Shinmachi, Hirakata, Osaka, 573-1010, Japan.
| | - Mitsugu Sekimoto
- Department of Surgery, Kansai Medical University, 2-5-1 Shinmachi, Hirakata, Osaka, 573-1010, Japan.
| |
Collapse
|
|
10
|
Alves Mota C, Stéfanie Sara Lopes Lera-Nonose D, Ávila Brustolin A, Chiqueto Duarte G, Carolina Mota Dos Santos M, Valdrinez Campana Lonardoni M, Gomes Verzignassi Silveira T. Low expression of hypoxia-inducible factor-1α and differential expression of immune mediators during experimental infection with Leishmania (Viannia) spp. Cytokine 2022; 153:155833. [PMID: 35247649 DOI: 10.1016/j.cyto.2022.155833] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2021] [Revised: 02/04/2022] [Accepted: 02/11/2022] [Indexed: 11/27/2022]
Abstract
Leishmania (Viannia) species are the major agents of cutaneous leishmaniasis (CL) in the Americas. Ulcerative stigmatizing skin lesions generally characterize CL. The microenvironment during Leishmania infection is rich in inflammatory cells and molecules, which contrasts with low oxygen levels. The hypoxia-inducible factor (HIF)-1α activates several genes in response to hypoxia and inflammatory reactions, but its role in the CL course is poorly understood. We investigated the expression pattern of the genes HIF-1α, arginase, inducible NO synthase (iNOS), interferon (IFN)-γ, interleukin (IL)-12, and IL-10 in skin lesions and lymph nodes of golden hamsters infected with L. braziliensis, L. lainsoni, and L. naiffi. The animals were infected and followed for 105 days, with paw volume measurements and photos taken weekly. Euthanasia was performed at 0, 15, 56, and 105 days post-infection. The parasite load of paw and lymph node tissues were measured through absolute quantification at real-time PCR (qPCR), and reverse transcription qPCR (RT-qPCR) was applied to demonstrate the relative mRNA expression of the target genes. Among groups, animals infected with L. braziliensis had the highest parasite load in paws and lymph nodes. HIF-1α mRNA was down-regulated during chronic Leishmania (Viannia) infection but demonstrated less inhibition in hamsters infected with L. lainsoni and L. naiffi. Arginase was the most detectable gene in animals infected by L. braziliensis; IFN-γ and IL-10 genes were the most detectable in L. lainsoni and L. naiffi-infected animals. HIF-1α gene transcription seemed to be down-modulated byL. (Viannia)infection and was less inhibited by L. lainsoni and L. naiffi when compared toL. braziliensis. Animals with L. lainsoni and L. naiffi showed better control of the disease. Further studies are necessary to evaluate the mechanism influencing HIF-1α expression and its role on CL protection; such research could elucidate potential use of HIF-1α as a therapeutic target.
Collapse
Affiliation(s)
- Camila Alves Mota
- Programa de Pós-Graduação em Ciências da Saúde, Universidade Estadual de Maringá, Maringá, Paraná, Brasil.
| | | | - Aline Ávila Brustolin
- Programa de Pós-Graduação em Ciências da Saúde, Universidade Estadual de Maringá, Maringá, Paraná, Brasil
| | | | | | - Maria Valdrinez Campana Lonardoni
- Laboratório de Leishmanioses, Departamento de Análises Clínicas e Biomedicina, Universidade Estadual de Maringá, Maringá, Paraná, Brasil
| | - Thaís Gomes Verzignassi Silveira
- Laboratório de Leishmanioses, Departamento de Análises Clínicas e Biomedicina, Universidade Estadual de Maringá, Maringá, Paraná, Brasil
| |
Collapse
|
|
11
|
Ono K, Sumiya M, Yoshinobu N, Dode T, Katayama T, Ueda N, Nagahama K. Angiogenesis Promotion by Combined Administration of DFO and Vein Endothelial Cells Using Injectable, Biodegradable, Nanocomposite Hydrogel Scaffolds. ACS APPLIED BIO MATERIALS 2022; 5:471-482. [PMID: 35045699 DOI: 10.1021/acsabm.1c00870] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Desferrioxamine (DFO) upregulates HIF-1α and stimulates expression of vascular endothelial growth factor (VEGF), thereby accelerating neovascularization. As DFO acts primarily upon surrounding vein endothelial cells to stimulate angiogenesis, the angiogenic efficacy of DFO could be reduced in severely injured tissues lacking a sufficient number of vein endothelial cells. We hypothesized that combined administration of DFO and vein endothelial cells is a promising tissue engineering approach for promoting neovascularization. In this study, we evaluated the applicability of this approach using injectable, biocompatible, biodegradable nanocomposite gels consisting of poly(dl-lactide-co-glycolide)-b-polyethylene glycol-b-poly(dl-lactide-co-glycolide) (PLGA-PEG-PLGA) copolymers and clay nanoparticle LAPONITE. The nanocomposites exhibited irreversible thermo-gelation in the presence of DFO, and the mechanical strength was strongly affected by the amount of DFO. The storage moduli of the gels increased with increasing amount of DFO. These results indicate that the interaction between DFO and LAPONITE works as physical cross-linking points and facilitates the formation of the gel network. The nanocomposite gels achieved sustained slow release of DFO due to interactions between DFO and LAPONITE. Human umbilical vein endothelial cells (HUVECs) cultured on DFO-loaded nanocomposite gels exhibited a higher degree of vascular tube formation than cells cultured on nanocomposite gels without DFO. Moreover, the number of branching points and the diameter of the blood vessels regenerated in the gels significantly increased with increasing DFO amount, indicating that DFO released from the gels facilitates vascular tube-forming capacity. As a proof of concept, we demonstrate that the combined administration of DFO and vein endothelial cells using nanocomposite gels promotes greater angiogenesis than DFO administration alone using the same gels by in vivo experiments, confirming the validity of our hypothesis. Considering the multiple advantages of nanocomposite gels with regard to potential vascularization capacity, certain biocompatibility, biodegradability, and injectable cell- and drug-delivery capacity, we concluded that the nanocomposite gels have potential utility as scaffolding biomaterials for vascularization in tissue engineering applications.
Collapse
Affiliation(s)
- Kimika Ono
- Department of Nanobiochemistry, Frontiers of Innovative Research in Science and Technology (FIRST), Konan University, 7-1-20 Minatojima-minamimachi, Chuo-Ku, Kobe 650-0047, Japan
| | - Manami Sumiya
- Department of Nanobiochemistry, Frontiers of Innovative Research in Science and Technology (FIRST), Konan University, 7-1-20 Minatojima-minamimachi, Chuo-Ku, Kobe 650-0047, Japan
| | - Naohiro Yoshinobu
- Department of Nanobiochemistry, Frontiers of Innovative Research in Science and Technology (FIRST), Konan University, 7-1-20 Minatojima-minamimachi, Chuo-Ku, Kobe 650-0047, Japan
| | - Tatsuya Dode
- Department of Nanobiochemistry, Frontiers of Innovative Research in Science and Technology (FIRST), Konan University, 7-1-20 Minatojima-minamimachi, Chuo-Ku, Kobe 650-0047, Japan
| | - Tokitaka Katayama
- Department of Nanobiochemistry, Frontiers of Innovative Research in Science and Technology (FIRST), Konan University, 7-1-20 Minatojima-minamimachi, Chuo-Ku, Kobe 650-0047, Japan
| | - Natsumi Ueda
- Department of Nanobiochemistry, Frontiers of Innovative Research in Science and Technology (FIRST), Konan University, 7-1-20 Minatojima-minamimachi, Chuo-Ku, Kobe 650-0047, Japan
| | - Koji Nagahama
- Department of Nanobiochemistry, Frontiers of Innovative Research in Science and Technology (FIRST), Konan University, 7-1-20 Minatojima-minamimachi, Chuo-Ku, Kobe 650-0047, Japan
| |
Collapse
|
|
12
|
Monteith AJ, Skaar EP. The impact of metal availability on immune function during infection. Trends Endocrinol Metab 2021; 32:916-928. [PMID: 34483037 PMCID: PMC8516721 DOI: 10.1016/j.tem.2021.08.004] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/15/2021] [Revised: 08/12/2021] [Accepted: 08/13/2021] [Indexed: 12/16/2022]
Abstract
Nutrient transition metals are required cofactors for many proteins to perform functions necessary for life. As such, the concentration of nutrient metals is carefully maintained to retain critical biological processes while limiting toxicity. During infection, invading bacterial pathogens must acquire essential metals, such as zinc, manganese, iron, and copper, from the host to colonize and cause disease. To combat this, the host exploits the essentiality and toxicity of nutrient metals by producing factors that limit metal availability, thereby starving pathogens or accumulating metals in excess to intoxicate the pathogen in a process termed 'nutritional immunity'. As a result of inflammation, a heterogeneous environment containing both metal-replete and -deplete niches is created, in which nutrient metal availability may have an underappreciated role in regulating immune cell function during infection. How the host manipulates nutrient metal availability during infection, and the downstream effects that nutrient metals and metal-sequestering proteins have on immune cell function, are discussed in this review.
Collapse
Affiliation(s)
- Andrew J Monteith
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Eric P Skaar
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA; Vanderbilt Institute for Infection, Immunology, & Inflammation, Vanderbilt University Medical Center, Nashville, TN, USA.
| |
Collapse
|
|
13
|
DeRosa A, Leftin A. The Iron Curtain: Macrophages at the Interface of Systemic and Microenvironmental Iron Metabolism and Immune Response in Cancer. Front Immunol 2021; 12:614294. [PMID: 33986740 PMCID: PMC8110925 DOI: 10.3389/fimmu.2021.614294] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2020] [Accepted: 03/29/2021] [Indexed: 12/13/2022] Open
Abstract
Macrophages fulfill central functions in systemic iron metabolism and immune response. Infiltration and polarization of macrophages in the tumor microenvironment is associated with differential cancer prognosis. Distinct metabolic iron and immune phenotypes in tumor associated macrophages have been observed in most cancers. While this prompts the hypothesis that macroenvironmental manifestations of dysfunctional iron metabolism have direct associations with microenvironmental tumor immune response, these functional connections are still emerging. We review our current understanding of the role of macrophages in systemic and microenvironmental immune response and iron metabolism and discuss these functions in the context of cancer and immunometabolic precision therapy approaches. Accumulation of tumor associated macrophages with distinct iron pathologies at the invasive tumor front suggests an "Iron Curtain" presenting as an innate functional interface between systemic and microenvironmental iron metabolism and immune response that can be harnessed therapeutically to further our goal of treating and eliminating cancer.
Collapse
Affiliation(s)
- Angela DeRosa
- Department of Pharmacological Sciences, Stony Brook University School of Medicine, Stony Brook, NY, United States
| | - Avigdor Leftin
- Department of Pharmacological Sciences, Stony Brook University School of Medicine, Stony Brook, NY, United States
- Department of Radiology, Stony Brook University School of Medicine, Stony Brook, NY, United States
| |
Collapse
|
|
14
|
Weiler S, Nairz M. TAM-ing the CIA-Tumor-Associated Macrophages and Their Potential Role in Unintended Side Effects of Therapeutics for Cancer-Induced Anemia. Front Oncol 2021; 11:627223. [PMID: 33842333 PMCID: PMC8027083 DOI: 10.3389/fonc.2021.627223] [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: 11/08/2020] [Accepted: 03/01/2021] [Indexed: 12/21/2022] Open
Abstract
Cancer-induced anemia (CIA) is a common consequence of neoplasia and has a multifactorial pathophysiology. The immune response and tumor treatment, both intended to primarily target malignant cells, also affect erythropoiesis in the bone marrow. In parallel, immune activation inevitably induces the iron-regulatory hormone hepcidin to direct iron fluxes away from erythroid progenitors and into compartments of the mononuclear phagocyte system. Moreover, many inflammatory mediators inhibit the synthesis of erythropoietin, which is essential for stimulation and differentiation of erythroid progenitor cells to mature cells ready for release into the blood stream. These pathophysiological hallmarks of CIA imply that the bone marrow is not only deprived of iron as nutrient but also of erythropoietin as central growth factor for erythropoiesis. Tumor-associated macrophages (TAM) are present in the tumor microenvironment and display altered immune and iron phenotypes. On the one hand, their functions are altered by adjacent tumor cells so that they promote rather than inhibit the growth of malignant cells. As consequences, TAM may deliver iron to tumor cells and produce reduced amounts of cytotoxic mediators. Furthermore, their ability to stimulate adaptive anti-tumor immune responses is severely compromised. On the other hand, TAM are potential off-targets of therapeutic interventions against CIA. Red blood cell transfusions, intravenous iron preparations, erythropoiesis-stimulating agents and novel treatment options for CIA may interfere with TAM function and thus exhibit secondary effects on the underlying malignancy. In this Hypothesis and Theory, we summarize the pathophysiological hallmarks, clinical implications and treatment strategies for CIA. Focusing on TAM, we speculate on the potential intended and unintended effects that therapeutic options for CIA may have on the innate immune response and, consequently, on the course of the underlying malignancy.
Collapse
Affiliation(s)
- Stefan Weiler
- National Poisons Information Centre, Tox Info Suisse, Associated Institute of the University of Zurich, Zurich, Switzerland.,Department of Chemistry and Applied Biosciences, Institute of Pharmaceutical Sciences, Eidgenossische Technische Hochschule Zurich, Zurich, Switzerland
| | - Manfred Nairz
- Department of Internal Medicine II, Infectious Diseases, Immunology, Rheumatology, Pneumology, Medical University of Innsbruck, Innsbruck, Austria
| |
Collapse
|
|
15
|
Tran CW, Gold MJ, Garcia-Batres C, Tai K, Elford AR, Himmel ME, Elia AJ, Ohashi PS. Hypoxia-inducible factor 1 alpha limits dendritic cell stimulation of CD8 T cell immunity. PLoS One 2020; 15:e0244366. [PMID: 33382742 PMCID: PMC7775062 DOI: 10.1371/journal.pone.0244366] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2020] [Accepted: 12/08/2020] [Indexed: 12/31/2022] Open
Abstract
Dendritic cells are sentinels of the immune system and represent a key cell in the activation of the adaptive immune response. Hypoxia-inducible factor 1 alpha (HIF-1α)–a crucial oxygen sensor stabilized during hypoxic conditions–has been shown to have both activating and inhibitory effects in immune cells in a context- and cell-dependent manner. Previous studies have demonstrated that in some immune cell types, HIF-1α serves a pro-inflammatory role. Genetic deletion of HIF-1α in macrophages has been reported to reduce their pro-inflammatory function. In contrast, loss of HIF-1α enhanced the pro-inflammatory activity of dendritic cells in a bacterial infection model. In this study, we aimed to further clarify the effects of HIF-1α in dendritic cells. Constitutive expression of HIF-1α resulted in diminished immunostimulatory capacity of dendritic cells in vivo, while conditional deletion of HIF-1α in dendritic cells enhanced their ability to induce a cytotoxic T cell response. HIF-1α-expressing dendritic cells demonstrated increased production of inhibitory mediators including IL-10, iNOS and VEGF, which correlated with their reduced capacity to drive effector CD8+ T cell function. Altogether, these data reveal that HIF-1α can promote the anti-inflammatory functions of dendritic cells and provides insight into dysfunctional immune responses in the context of HIF-1α activation.
Collapse
Affiliation(s)
- Charles W. Tran
- Princess Margaret Cancer Centre, Toronto, Ontario, Canada
- Department of Immunology, University of Toronto, Toronto, Ontario, Canada
| | | | | | - Kelly Tai
- Princess Margaret Cancer Centre, Toronto, Ontario, Canada
- Department of Immunology, University of Toronto, Toronto, Ontario, Canada
| | | | | | - Andrew J. Elia
- Princess Margaret Cancer Centre, Toronto, Ontario, Canada
| | - Pamela S. Ohashi
- Princess Margaret Cancer Centre, Toronto, Ontario, Canada
- Department of Immunology, University of Toronto, Toronto, Ontario, Canada
- * E-mail:
| |
Collapse
|
|
16
|
Behmoaras J. The versatile biochemistry of iron in macrophage effector functions. FEBS J 2020; 288:6972-6989. [PMID: 33354925 DOI: 10.1111/febs.15682] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2020] [Revised: 12/16/2020] [Accepted: 12/21/2020] [Indexed: 01/01/2023]
Abstract
Macrophages are mononuclear phagocytes with remarkable polarization ability that allow them to have tissue-specific functions during development, homeostasis, inflammatory and infectious disease. One particular trophic factor in the tissue environment is iron, which is intimately linked to macrophage effector functions. Macrophages have a well-described role in the control of systemic iron levels, but their activation state is also depending on iron-containing proteins/enzymes. Haemoproteins, dioxygenases and iron-sulphur (Fe-S) enzymes are iron-binding proteins that have bactericidal, metabolic and epigenetic-related functions, essential to shape the context-dependent macrophage polarization. In this review, I describe mainly pro-inflammatory macrophage polarization focussing on the role of iron biochemistry in selected haemoproteins and Fe-S enzymes. I show how iron, as part of haem or Fe-S clusters, participates in the cellular control of pro-inflammatory redox reactions in parallel with its role as enzymatic cofactor. I highlight a possible coordinated regulation of haemoproteins and Fe-S enzymes during classical macrophage activation. Finally, I describe tryptophan and α-ketoglutarate metabolism as two essential effector pathways in macrophages that use diverse iron biochemistry at different enzymatic steps. Through these pathways, I show how iron participates in the regulation of essential metabolites that shape macrophage function.
Collapse
|
|
17
|
Valente de Souza L, Hoffmann A, Weiss G. Impact of bacterial infections on erythropoiesis. Expert Rev Anti Infect Ther 2020; 19:619-633. [PMID: 33092423 DOI: 10.1080/14787210.2021.1841636] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
INTRODUCTION The importance of iron is highlighted by the many complex metabolic pathways in which it is involved. A sufficient supply is essential for the effective production of 200 billion erythrocytes daily, a process called erythropoiesis. AREAS COVERED During infection, the human body can withhold iron from pathogens, mechanism termed nutritional immunity. The subsequent disturbances in iron homeostasis not only impact on immune function and infection control, but also negatively affect erythropoiesis. The complex interplay between iron, immunity, erythropoiesis and infection control on the molecular and clinical level are highlighted in this review. Diagnostic algorithms for correct interpretation and diagnosis of the iron status in the setting of infection are presented. Therapeutic concepts are discussed regarding effects on anemia correction, but also toward their role on the course of infection. EXPERT OPINION In the setting of infection, anemia is often neglected and its impact on the course of diseases is incompletely understood. Clinical expertise can be improved in correct diagnosing of anemia and disturbances of iron homeostasis. Systemic studies are needed to evaluate the impact of specific therapeutic interventions on anemia correction on the course of infection, but also on patients' cardiovascular performance and quality of life.
Collapse
Affiliation(s)
- Lara Valente de Souza
- Department of Internal Medicine II, Infectious Diseases, Immunology, Rheumatology, Medical University ofI nnsbruck, Innsbruck, Austria.,Christian Doppler Laboratory for Iron Metabolism and Anemia Research, Medical University of Innsbruck, Innsbruck, Austria
| | - Alexander Hoffmann
- Department of Internal Medicine II, Infectious Diseases, Immunology, Rheumatology, Medical University ofI nnsbruck, Innsbruck, Austria.,Christian Doppler Laboratory for Iron Metabolism and Anemia Research, Medical University of Innsbruck, Innsbruck, Austria
| | - Günter Weiss
- Department of Internal Medicine II, Infectious Diseases, Immunology, Rheumatology, Medical University ofI nnsbruck, Innsbruck, Austria.,Christian Doppler Laboratory for Iron Metabolism and Anemia Research, Medical University of Innsbruck, Innsbruck, Austria
| |
Collapse
|
|
18
|
Yang X, Liu H, Ye T, Duan C, Lv P, Wu X, Liu J, Jiang K, Lu H, Yang H, Xia D, Peng E, Chen Z, Tang K, Ye Z. AhR activation attenuates calcium oxalate nephrocalcinosis by diminishing M1 macrophage polarization and promoting M2 macrophage polarization. Am J Cancer Res 2020; 10:12011-12025. [PMID: 33204326 PMCID: PMC7667681 DOI: 10.7150/thno.51144] [Citation(s) in RCA: 63] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2020] [Accepted: 10/04/2020] [Indexed: 02/06/2023] Open
Abstract
Calcium oxalate (CaOx) crystal can trigger kidney injury, which contributes to the pathogenesis of nephrocalcinosis. The phenotypes of infiltrating macrophage may impact CaOx-mediated kidney inflammatory injury as well as crystal deposition. How aryl hydrocarbon receptor (AhR) regulates inflammation and macrophage polarization is well understood; however, how it modulates CaOx nephrocalcinosis remains unclear. Methods: Mice were intraperitoneally injected with glyoxylate to establish CaOx nephrocalcinosis model with or without the treatment of AhR activator 6-formylindolo(3,2-b)carbazole (FICZ). Positron emission tomography computed tomography (PET-CT) imaging, Periodic acid-Schiff (PAS) staining, and polarized light optical microscopy were used to evaluate kidney injury and crystal deposition in mice kidney. Western blotting, immunofluorescence, chromatin immunoprecipitation, microRNA-fluorescence in situ hybridization, and luciferase reporter assays were applied to analyze polarization state and regulation mechanism of macrophage. Results: AhR expression was significantly upregulated and negatively correlated with interferon-regulatory factor 1 (IRF1) and hypoxia inducible factor 1-alpha (HIF-1α) levels in a murine CaOx nephrocalcinosis model following administration of FICZ. Moreover, AhR activation suppressed IRF1 and HIF-1α levels and decreased M1 macrophage polarization in vitro. In terms of the mechanism, bioinformatics analysis and chromatin immunoprecipitation assay confirmed that AhR could bind to miR-142a promoter to transcriptionally activate miR-142a. In addition, luciferase reporter assays validated that miR-142a inhibited IRF1 and HIF-1α expression by directly targeting their 3'-untranslated regions. Conclusions: Our results indicated that AhR activation could diminish M1 macrophage polarization and promote M2 macrophage polarization to suppress CaOx nephrocalcinosis via the AhR-miR-142a-IRF1/HIF-1α pathway.
Collapse
|
|
19
|
Nairz M, Weiss G. Iron in infection and immunity. Mol Aspects Med 2020; 75:100864. [PMID: 32461004 DOI: 10.1016/j.mam.2020.100864] [Citation(s) in RCA: 199] [Impact Index Per Article: 39.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2020] [Revised: 04/25/2020] [Accepted: 05/05/2020] [Indexed: 12/12/2022]
Abstract
Iron is an essential micronutrient for virtually all living cells. In infectious diseases, both invading pathogens and mammalian cells including those of the immune system require iron to sustain their function, metabolism and proliferation. On the one hand, microbial iron uptake is linked to the virulence of most human pathogens. On the other hand, the sequestration of iron from bacteria and other microorganisms is an efficient strategy of host defense in line with the principles of 'nutritional immunity'. In an acute infection, host-driven iron withdrawal inhibits the growth of pathogens. Chronic immune activation due to persistent infection, autoimmune disease or malignancy however, sequesters iron not only from infectious agents, autoreactive lymphocytes and neoplastic cells but also from erythroid progenitors. This is one of the key mechanisms which collectively result in the anemia of chronic inflammation. In this review, we highlight the most important interconnections between iron metabolism and immunity, focusing on host defense against relevant infections and on the clinical consequences of anemia of inflammation.
Collapse
Affiliation(s)
- Manfred Nairz
- Department of Internal Medicine II, Infectious Diseases, Immunology, Rheumatology, Pneumology, Medical University of Innsbruck, Austria
| | - Günter Weiss
- Department of Internal Medicine II, Infectious Diseases, Immunology, Rheumatology, Pneumology, Medical University of Innsbruck, Austria; Christian Doppler Laboratory for Iron Metabolism and Anemia Research, Medical University of Innsbruck, Austria.
| |
Collapse
|
|
20
|
How Severe Anaemia Might Influence the Risk of Invasive Bacterial Infections in African Children. Int J Mol Sci 2020; 21:ijms21186976. [PMID: 32972031 PMCID: PMC7555399 DOI: 10.3390/ijms21186976] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2020] [Revised: 09/04/2020] [Accepted: 09/15/2020] [Indexed: 12/21/2022] Open
Abstract
Severe anaemia and invasive bacterial infections are common causes of childhood sickness and death in sub-Saharan Africa. Accumulating evidence suggests that severely anaemic African children may have a higher risk of invasive bacterial infections. However, the mechanisms underlying this association remain poorly described. Severe anaemia is characterized by increased haemolysis, erythropoietic drive, gut permeability, and disruption of immune regulatory systems. These pathways are associated with dysregulation of iron homeostasis, including the downregulation of the hepatic hormone hepcidin. Increased haemolysis and low hepcidin levels potentially increase plasma, tissue and intracellular iron levels. Pathogenic bacteria require iron and/or haem to proliferate and have evolved numerous strategies to acquire labile and protein-bound iron/haem. In this review, we discuss how severe anaemia may mediate the risk of invasive bacterial infections through dysregulation of hepcidin and/or iron homeostasis, and potential studies that could be conducted to test this hypothesis.
Collapse
|
|
21
|
McCarty MF, Lerner A. Nutraceuticals Targeting Generation and Oxidant Activity of Peroxynitrite May Aid Prevention and Control of Parkinson's Disease. Int J Mol Sci 2020; 21:3624. [PMID: 32455532 PMCID: PMC7279222 DOI: 10.3390/ijms21103624] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2020] [Revised: 04/29/2020] [Accepted: 05/18/2020] [Indexed: 12/14/2022] Open
Abstract
Parkinson's disease (PD) is a chronic low-grade inflammatory process in which activated microglia generate cytotoxic factors-most prominently peroxynitrite-which induce the death and dysfunction of neighboring dopaminergic neurons. Dying neurons then release damage-associated molecular pattern proteins such as high mobility group box 1 which act on microglia via a range of receptors to amplify microglial activation. Since peroxynitrite is a key mediator in this process, it is proposed that nutraceutical measures which either suppress microglial production of peroxynitrite, or which promote the scavenging of peroxynitrite-derived oxidants, should have value for the prevention and control of PD. Peroxynitrite production can be quelled by suppressing activation of microglial NADPH oxidase-the source of its precursor superoxide-or by down-regulating the signaling pathways that promote microglial expression of inducible nitric oxide synthase (iNOS). Phycocyanobilin of spirulina, ferulic acid, long-chain omega-3 fatty acids, good vitamin D status, promotion of hydrogen sulfide production with taurine and N-acetylcysteine, caffeine, epigallocatechin-gallate, butyrogenic dietary fiber, and probiotics may have potential for blunting microglial iNOS induction. Scavenging of peroxynitrite-derived radicals may be amplified with supplemental zinc or inosine. Astaxanthin has potential for protecting the mitochondrial respiratory chain from peroxynitrite and environmental mitochondrial toxins. Healthful programs of nutraceutical supplementation may prove to be useful and feasible in the primary prevention or slow progression of pre-existing PD. Since damage to the mitochondria in dopaminergic neurons by environmental toxins is suspected to play a role in triggering the self-sustaining inflammation that drives PD pathogenesis, there is also reason to suspect that plant-based diets of modest protein content, and possibly a corn-rich diet high in spermidine, might provide protection from PD by boosting protective mitophagy and thereby aiding efficient mitochondrial function. Low-protein diets can also promote a more even response to levodopa therapy.
Collapse
Affiliation(s)
| | - Aaron Lerner
- B. Rappaport School of Medicine, Technion-Israel Institute of Technology, Haifa 3525422, Israel
| |
Collapse
|
|
22
|
Kiefer MC, Motyka NI, Clements JD, Bitoun JP. Enterotoxigenic Escherichia coli Heat-Stable Toxin Increases the Rate of Zinc Release from Metallothionein and Is a Zinc- and Iron-Binding Peptide. mSphere 2020; 5:e00146-20. [PMID: 32238569 PMCID: PMC7113584 DOI: 10.1128/msphere.00146-20] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2020] [Accepted: 03/12/2020] [Indexed: 12/16/2022] Open
Abstract
Enterotoxigenic Escherichia coli (ETEC) is a major diarrheal pathogen in children in low- to middle-income countries. Previous studies have identified heat-stable enterotoxin (ST)-producing ETEC as one of the major diarrhea-causing pathogens in children younger than five years. In this study, we examined iron and zinc binding by both human and porcine ST variants and determined how host metallothionein could detoxify ST. We found that ST purified from ETEC culture supernatants eluted as a doublet during C18 reverse-phase chromatography. Leading edge fractions of the ST doublet were found to be devoid of iron, while trailing edge fractions of the ST doublet were found to contain measurable iron. Next, we found that purified ST could be reconstituted with iron under reducing and anaerobic conditions, and iron-bound ST attenuated the induction of cGMP in T84 epithelial cells. Moreover, we demonstrated that supernatants of ETEC 214-4 grown under increasing iron concentrations were only able to induce cGMP at iron concentrations greater than 5 μM. In vitro studies also demonstrated that ST binds zinc, and once bound, zinc removal from ST required denaturing conditions. Zinc-bound ST also failed to induce cGMP. We found that ST contributes disulfide bonds to the perceived oxidized glutathione pool, increases the rate of zinc release from metallothionein, and can be detoxified by metallothionein. Lastly, we showed ST induces transcriptional changes in genes previously shown to be regulated by deferoxamine. These studies demonstrate ST ETEC pathogenesis may be tied intimately to host mucosal metal status.IMPORTANCE Enterotoxigenic Escherichia coli (ETEC) is a major diarrheal pathogen in children in low- to middle-income countries, deployed military personnel, and travelers to regions of endemicity. The heat-stable toxin (ST) is a small nonimmunogenic secreted peptide with 3 disulfide bonds. It has been appreciated that dietary disulfides modulate intestinal redox potential and that ST could be detoxified using exogenous reductants. Using biochemical and spectroscopic approaches, we demonstrated that ST can separately bind iron and zinc under reducing conditions, thereby reducing ST toxicity. Moreover, we demonstrated that ST modulates the glutathione (GSH)/oxidized glutathione (GSSG) ratio and that ST should be considered a toxin oxidant. ST can be detoxified by oxidizing zinc-loaded metallothionine, causing free zinc to be released. These studies help lay a foundation to understand how diarrheal pathogens modulate intestinal redox potential and may impact how we design therapeutics and/or vaccines for the pathogens that produce them.
Collapse
Affiliation(s)
- Mallory C Kiefer
- Department of Microbiology and Immunology, Tulane University School of Medicine, New Orleans, Louisiana, USA
| | - Natalya I Motyka
- Department of Microbiology and Immunology, Tulane University School of Medicine, New Orleans, Louisiana, USA
| | - John D Clements
- Department of Microbiology and Immunology, Tulane University School of Medicine, New Orleans, Louisiana, USA
| | - Jacob P Bitoun
- Department of Microbiology and Immunology, Tulane University School of Medicine, New Orleans, Louisiana, USA
| |
Collapse
|
|
23
|
Schley G, Klanke B, Kalucka J, Schatz V, Daniel C, Mayer M, Goppelt-Struebe M, Herrmann M, Thorsteinsdottir M, Palsson R, Beneke A, Katschinski DM, Burzlaff N, Eckardt KU, Weidemann A, Jantsch J, Willam C. Mononuclear phagocytes orchestrate prolyl hydroxylase inhibition-mediated renoprotection in chronic tubulointerstitial nephritis. Kidney Int 2019; 96:378-396. [DOI: 10.1016/j.kint.2019.02.016] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2018] [Revised: 01/14/2019] [Accepted: 02/14/2019] [Indexed: 12/22/2022]
|
|
24
|
Lee M, Wang C, Jin SW, Labrecque MP, Beischlag TV, Brockman MA, Choy JC. Expression of human inducible nitric oxide synthase in response to cytokines is regulated by hypoxia-inducible factor-1. Free Radic Biol Med 2019; 130:278-287. [PMID: 30391674 DOI: 10.1016/j.freeradbiomed.2018.10.441] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/08/2018] [Revised: 09/19/2018] [Accepted: 10/24/2018] [Indexed: 02/06/2023]
Abstract
The production of nitric oxide (NO) by inducible NO synthase (iNOS) and the regulation of gene expression by hypoxia-inducible factors (HIFs) are important for many aspects of human cell biology. However, little is known about whether iNOS expression is controlled by HIFs in human cells. Stimulation of A549 human lung epithelial cells with cytokines (TNF, IL-1 and IFNγ) increased the nuclear accumulation of HIF-1 in normoxic conditions. Activation of HIF-1 by hypoxia or CoCl2 was not sufficient to induce iNOS expression. However, pharmacological inhibition of HIF-1 reduced the induction of iNOS expression in A549 cells and primary human astrocytes. Moreover, elimination of HIF-1α expression and activity by CRISPR/Cas9 gene editing significantly reduced the induction of human iNOS gene promoter, mRNA and protein expression by cytokine stimulation. Three putative hypoxia response elements (HRE) are present within the human iNOS gene promoter and elimination of an HRE at -4981 bp reduced the induction of human iNOS promoter activity in response to cytokine stimulation. These findings establish an important role for HIF-1α in the induction of human iNOS gene expression in response to cytokine stimulation.
Collapse
Affiliation(s)
- Martin Lee
- Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, British Columbia, Canada; Centre for Cell Biology, Development and Disease, Simon Fraser University, Burnaby, British Columbia, Canada
| | - Christine Wang
- Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, British Columbia, Canada; Centre for Cell Biology, Development and Disease, Simon Fraser University, Burnaby, British Columbia, Canada
| | - Steven W Jin
- Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, British Columbia, Canada; Faculty of Health Sciences, Simon Fraser University, Burnaby, British Columbia, Canada
| | - Mark P Labrecque
- Faculty of Health Sciences, Simon Fraser University, Burnaby, British Columbia, Canada
| | - Timothy V Beischlag
- Faculty of Health Sciences, Simon Fraser University, Burnaby, British Columbia, Canada; Centre for Cell Biology, Development and Disease, Simon Fraser University, Burnaby, British Columbia, Canada
| | - Mark A Brockman
- Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, British Columbia, Canada; Faculty of Health Sciences, Simon Fraser University, Burnaby, British Columbia, Canada
| | - Jonathan C Choy
- Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, British Columbia, Canada; Centre for Cell Biology, Development and Disease, Simon Fraser University, Burnaby, British Columbia, Canada.
| |
Collapse
|
|
25
|
Nairz M, Dichtl S, Schroll A, Haschka D, Tymoszuk P, Theurl I, Weiss G. Iron and innate antimicrobial immunity-Depriving the pathogen, defending the host. J Trace Elem Med Biol 2018; 48:118-133. [PMID: 29773170 DOI: 10.1016/j.jtemb.2018.03.007] [Citation(s) in RCA: 74] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/09/2018] [Revised: 02/25/2018] [Accepted: 03/06/2018] [Indexed: 02/08/2023]
Abstract
The acute-phase response is triggered by the presence of infectious agents and danger signals which indicate hazards for the integrity of the mammalian body. One central feature of this response is the sequestration of iron into storage compartments including macrophages. This limits the availability of this essential nutrient for circulating pathogens, a host defence strategy known as 'nutritional immunity'. Iron metabolism and the immune response are intimately linked. In infections, the availability of iron affects both the efficacy of antimicrobial immune pathways and pathogen proliferation. However, host strategies to withhold iron from microbes vary according to the localization of pathogens: Infections with extracellular bacteria such as Staphylococcus aureus, Streptococcus, Klebsiella or Yersinia stimulate the expression of the iron-regulatory hormone hepcidin which targets the cellular iron-exporter ferroportin-1 causing its internalization and blockade of iron egress from absorptive enterocytes in the duodenum and iron-recycling macrophages. This mechanism disrupts both routes of iron delivery to the circulation, contributes to iron sequestration in the mononuclear phagocyte system and mediates the hypoferraemia of the acute phase response subsequently resulting in the development of anaemia of inflammation. When intracellular microbes are present, other strategies of microbial iron withdrawal are needed. For instance, in macrophages harbouring intracellular pathogens such as Chlamydia, Mycobacterium tuberculosis, Listeria monocytogenes or Salmonella Typhimurium, ferroportin-1-mediated iron export is turned on for the removal of iron from infected cells. This also leads to reduced iron availability for intra-macrophage pathogens which inhibits their growth and in parallel strengthens anti-microbial effector pathways of macrophages including the formation of inducible nitric oxide synthase and tumour necrosis factor. Iron plays a key role in infectious diseases both as modulator of the innate immune response and as nutrient for microbes. We need to gain a more comprehensive understanding of how the body can differentially respond to infection by extra- or intracellular pathogens. This knowledge may allow us to modulate mammalian iron homeostasis pharmaceutically and to target iron-acquisition systems of pathogens, thus enabling us to treat infections with novel strategies that act independent of established antimicrobials.
Collapse
Affiliation(s)
- Manfred Nairz
- Department of Internal Medicine II, Infectious Diseases, Immunology, Rheumatology, Pneumology, Medical University of Innsbruck, Austria.
| | - Stefanie Dichtl
- Department of Internal Medicine II, Infectious Diseases, Immunology, Rheumatology, Pneumology, Medical University of Innsbruck, Austria
| | - Andrea Schroll
- Department of Internal Medicine II, Infectious Diseases, Immunology, Rheumatology, Pneumology, Medical University of Innsbruck, Austria
| | - David Haschka
- Department of Internal Medicine II, Infectious Diseases, Immunology, Rheumatology, Pneumology, Medical University of Innsbruck, Austria
| | - Piotr Tymoszuk
- Department of Internal Medicine II, Infectious Diseases, Immunology, Rheumatology, Pneumology, Medical University of Innsbruck, Austria
| | - Igor Theurl
- Department of Internal Medicine II, Infectious Diseases, Immunology, Rheumatology, Pneumology, Medical University of Innsbruck, Austria
| | - Günter Weiss
- Department of Internal Medicine II, Infectious Diseases, Immunology, Rheumatology, Pneumology, Medical University of Innsbruck, Austria
| |
Collapse
|
|
26
|
Schatz V, Neubert P, Rieger F, Jantsch J. Hypoxia, Hypoxia-Inducible Factor-1α, and Innate Antileishmanial Immune Responses. Front Immunol 2018. [PMID: 29520262 PMCID: PMC5827161 DOI: 10.3389/fimmu.2018.00216] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
Low oxygen environments and accumulation of hypoxia-inducible factors (HIFs) are features of infected and inflamed tissues. Here, we summarize our current knowledge on oxygen levels found in Leishmania-infected tissues and discuss which mechanisms potentially contribute to local tissue oxygenation in leishmanial lesions. Moreover, we review the role of hypoxia and HIF-1 on innate antileishmanial immune responses.
Collapse
Affiliation(s)
- Valentin Schatz
- Institute of Clinical Microbiology and Hygiene, University Hospital of Regensburg, University of Regensburg, Regensburg, Germany
| | - Patrick Neubert
- Institute of Clinical Microbiology and Hygiene, University Hospital of Regensburg, University of Regensburg, Regensburg, Germany
| | - Franz Rieger
- Institute of Clinical Microbiology and Hygiene, University Hospital of Regensburg, University of Regensburg, Regensburg, Germany
| | - Jonathan Jantsch
- Institute of Clinical Microbiology and Hygiene, University Hospital of Regensburg, University of Regensburg, Regensburg, Germany
| |
Collapse
|
|
27
|
ω-Alkynyl arachidonic acid promotes anti-inflammatory macrophage M2 polarization against acute myocardial infarction via regulating the cross-talk between PKM2, HIF-1α and iNOS. Biochim Biophys Acta Mol Cell Biol Lipids 2017; 1862:1595-1605. [DOI: 10.1016/j.bbalip.2017.09.009] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2017] [Revised: 09/16/2017] [Accepted: 09/24/2017] [Indexed: 12/12/2022]
|
|
28
|
Nairz M, Theurl I, Swirski FK, Weiss G. "Pumping iron"-how macrophages handle iron at the systemic, microenvironmental, and cellular levels. Pflugers Arch 2017; 469:397-418. [PMID: 28251312 PMCID: PMC5362662 DOI: 10.1007/s00424-017-1944-8] [Citation(s) in RCA: 121] [Impact Index Per Article: 15.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2016] [Revised: 01/25/2017] [Accepted: 01/29/2017] [Indexed: 12/12/2022]
Abstract
Macrophages reside in virtually every organ. First arising during embryogenesis, macrophages replenish themselves in the adult through a combination of self-renewal and influx of bone marrow-derived monocytes. As large phagocytic cells, macrophages participate in innate immunity while contributing to tissue-specific homeostatic functions. Among the key metabolic tasks are senescent red blood cell recycling, free heme detoxification, and provision of iron for de novo hemoglobin synthesis. While this systemic mechanism involves the shuttling of iron between spleen, liver, and bone marrow through the concerted function of defined macrophage populations, similar circuits appear to exist within the microenvironment of other organs. The high turnover of iron is the prerequisite for continuous erythropoiesis and tissue integrity but challenges macrophages’ ability to maintain cellular iron homeostasis and immune function. This review provides a brief overview of systemic, microenvironmental, and cellular aspects of macrophage iron handling with a focus on exciting and unresolved questions in the field.
Collapse
Affiliation(s)
- Manfred Nairz
- Department of Internal Medicine VI, Infectious Diseases, Immunology, Rheumatology, Pneumology, Medical University of Innsbruck, Anichstr. 35, 6020, Innsbruck, Austria. .,Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. .,Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
| | - Igor Theurl
- Department of Internal Medicine VI, Infectious Diseases, Immunology, Rheumatology, Pneumology, Medical University of Innsbruck, Anichstr. 35, 6020, Innsbruck, Austria
| | - Filip K Swirski
- Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.,Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Guenter Weiss
- Department of Internal Medicine VI, Infectious Diseases, Immunology, Rheumatology, Pneumology, Medical University of Innsbruck, Anichstr. 35, 6020, Innsbruck, Austria.
| |
Collapse
|
|
29
|
Schatz V, Strüssmann Y, Mahnke A, Schley G, Waldner M, Ritter U, Wild J, Willam C, Dehne N, Brüne B, McNiff JM, Colegio OR, Bogdan C, Jantsch J. Myeloid Cell-Derived HIF-1α Promotes Control of Leishmania major. THE JOURNAL OF IMMUNOLOGY 2016; 197:4034-4041. [PMID: 27798163 DOI: 10.4049/jimmunol.1601080] [Citation(s) in RCA: 48] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/21/2016] [Accepted: 09/15/2016] [Indexed: 12/30/2022]
Abstract
Hypoxia-inducible factor-1α (HIF-1α), which accumulates in mammalian host organisms during infection, supports the defense against microbial pathogens. However, whether and to what extent HIF-1α expressed by myeloid cells contributes to the innate immune response against Leishmania major parasites is unknown. We observed that Leishmania-infected humans and L. major-infected C57BL/6 mice exhibited substantial amounts of HIF-1α in acute cutaneous lesions. In vitro, HIF-1α was required for leishmanicidal activity and high-level NO production by IFN-γ/LPS-activated macrophages. Mice deficient for HIF-1α in their myeloid cell compartment had a more severe clinical course of infection and increased parasite burden in the skin lesions compared with wild-type controls. These findings were paralleled by reduced expression of type 2 NO synthase by lesional CD11b+ cells. Together, these data illustrate that HIF-1α is required for optimal innate leishmanicidal immune responses and, thereby, contributes to the cure of cutaneous leishmaniasis.
Collapse
Affiliation(s)
- Valentin Schatz
- Institute of Clinical Microbiology and Hygiene, University Hospital of Regensburg, University of Regensburg, 93053 Regensburg, Germany
| | - Yannic Strüssmann
- Institute of Clinical Microbiology and Hygiene, University Hospital of Regensburg, University of Regensburg, 93053 Regensburg, Germany
| | - Alexander Mahnke
- Mikrobiologisches Institut, Klinische Mikrobiologie, Immunologie, und Hygiene, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany
| | - Gunnar Schley
- Medizinische Klinik 4, Nephrologie und Hypertensiologie, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany
| | - Maximilian Waldner
- Medizinische Klinik 1, Gastroenterologie, Pneumologie und Endokrinologie, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany
| | - Uwe Ritter
- Institute of Immunology, University of Regensburg, 93053 Regensburg, Germany
| | - Jens Wild
- Institute of Clinical Microbiology and Hygiene, University Hospital of Regensburg, University of Regensburg, 93053 Regensburg, Germany
| | - Carsten Willam
- Medizinische Klinik 4, Nephrologie und Hypertensiologie, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany
| | - Nathalie Dehne
- Institute of Biochemistry I, Goethe-University Frankfurt, 60590 Frankfurt, Germany; and
| | - Bernhard Brüne
- Institute of Biochemistry I, Goethe-University Frankfurt, 60590 Frankfurt, Germany; and
| | - Jennifer M McNiff
- Department of Dermatology, Yale University School of Medicine, New Haven, CT 06510
| | - Oscar R Colegio
- Department of Dermatology, Yale University School of Medicine, New Haven, CT 06510
| | - Christian Bogdan
- Mikrobiologisches Institut, Klinische Mikrobiologie, Immunologie, und Hygiene, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany
| | - Jonathan Jantsch
- Institute of Clinical Microbiology and Hygiene, University Hospital of Regensburg, University of Regensburg, 93053 Regensburg, Germany;
| |
Collapse
|
|
30
|
Manzari B, Kudlow JE, Fardin P, Merello E, Ottaviano C, Puppo M, Eva A, Varesio L. Induction of Macrophage Glutamine: Fructose-6-Phosphate Amidotransferase Expression by Hypoxia and by Picolinic Acid. Int J Immunopathol Pharmacol 2016; 20:47-58. [PMID: 17346427 DOI: 10.1177/039463200702000106] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023] Open
Abstract
We studied the expression of glutamine:fructose-6-phosphate amidotransferase (GFAT), the rate limiting enzyme in the hexosamine biosynthetic pathway controlling protein glycosylation. We obtained the first evidence that the GFAT mRNA and protein are constitutively expressed in murine mononuclear phagocytes (Mf) and inducible by picolinic acid (PA), a catabolite of tryptophan, hypoxia and desferrioxamine (DFX). These stimuli share the property to transactivate gene expression through the Hypoxia Responsive Element (HRE). The promoter of GFAT contains the consensus sequence of HRE in position −74/-65 (GFAT-HRE), and we studied the role of HRE on the activation of the promoter utilizing appropriate expression vectors. We found that GFAT-HRE is essential for the response to hypoxia, PA or DFX and that Hypoxia Inducible Factor-1α (HIF-1α) can augment this response. Finally, we demonstrate that iron chelation is part of the mechanism by which PA and DFX activate GFAT expression. Our results provide the first indication that hypoxia, PA or DFX induce the transcription of GFAT gene in murine Mf cell lines and that the HRE of the promoter is essential for this response.
Collapse
Affiliation(s)
- B Manzari
- Laboratory of Molecular Biology, Giannina Gaslini Institute, Genoa, Italy
| | | | | | | | | | | | | | | |
Collapse
|
|
31
|
Mitterstiller AM, Haschka D, Dichtl S, Nairz M, Demetz E, Talasz H, Soares MP, Einwallner E, Esterbauer H, Fang FC, Geley S, Weiss G. Heme oxygenase 1 controls early innate immune response of macrophages to Salmonella Typhimurium infection. Cell Microbiol 2016; 18:1374-89. [PMID: 26866925 DOI: 10.1111/cmi.12578] [Citation(s) in RCA: 55] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2015] [Revised: 01/19/2016] [Accepted: 02/09/2016] [Indexed: 12/26/2022]
Abstract
Macrophages are central for the immune control of intracellular microbes. Heme oxygenase 1 (HO-1, hmox) is the first and rate limiting enzyme in the breakdown of heme originating from degraded senescent erythrocytes and heme-proteins, yielding equal amounts of iron, carbon monoxide and biliverdin. HO-1 is strongly up-regulated in macrophages in response to inflammatory signals, including bacterial endotoxin. In view of the essential role of iron for the growth and proliferation of intracellular bacteria along with known effects of the metal on innate immune function, we examined whether HO-1 plays a role in the control of infection with the intracellular bacterium Salmonella Typhimurium. We studied the course of infection in stably-transfected murine macrophages (RAW264.7) bearing a tetracycline-inducible plasmid producing hmox shRNA and in primary HO-1 knockout macrophages. While uptake of bacteria into macrophages was not affected, a significantly reduced survival of intracellular Salmonella was observed upon hmox knockdown or pharmacological hmox inhibition, which was independent of Nramp1 functionality. This could be traced to limitation of iron availability for intramacrophage bacteria along with enhanced stimulation of innate immune effector pathways, including the formation of reactive oxygen and nitrogen species and increased TNF-α expression. Mechanistically, these latter effects result from intracellular iron limitation with subsequent activation of NF-κB and further inos, tnfa and p47phox transcription along with reduced formation of the anti-inflammatory and radical scavenging molecules, CO and biliverdin as a consequence of HO-1 silencing. Taken together our data provide novel evidence that the infection-driven induction of HO-1 exerts detrimental effects in the early control of Salmonella infection, whereas hmox inhibition can favourably modulate anti-bacterial immune effector pathways of macrophages and promote bacterial elimination.
Collapse
Affiliation(s)
- Anna-Maria Mitterstiller
- Department of Internal Medicine VI, Infectious Diseases, Immunology, Rheumatology, Pneumology, Medical University of Innsbruck, 6020, Innsbruck, Austria
| | - David Haschka
- Department of Internal Medicine VI, Infectious Diseases, Immunology, Rheumatology, Pneumology, Medical University of Innsbruck, 6020, Innsbruck, Austria
| | - Stefanie Dichtl
- Department of Internal Medicine VI, Infectious Diseases, Immunology, Rheumatology, Pneumology, Medical University of Innsbruck, 6020, Innsbruck, Austria
| | - Manfred Nairz
- Department of Internal Medicine VI, Infectious Diseases, Immunology, Rheumatology, Pneumology, Medical University of Innsbruck, 6020, Innsbruck, Austria
| | - Egon Demetz
- Department of Internal Medicine VI, Infectious Diseases, Immunology, Rheumatology, Pneumology, Medical University of Innsbruck, 6020, Innsbruck, Austria
| | - Heribert Talasz
- Division of Clinical Biochemistry, Medical University of Innsbruck, 6020, Innsbruck, Austria
| | | | - Elisa Einwallner
- Department of Laboratory Medicine, Medical University of Vienna, 1090, Vienna, Austria
| | - Harald Esterbauer
- Department of Laboratory Medicine, Medical University of Vienna, 1090, Vienna, Austria
| | - Ferric C Fang
- University of Washington School of Medicine, 1959 NE Pacific Street, Seattle, WA, 98195-7735, USA
| | - Stephan Geley
- Division of Molecular Pathophysiology, Medical University of Innsbruck, 6020, Innsbruck, Austria
| | - Guenter Weiss
- Department of Internal Medicine VI, Infectious Diseases, Immunology, Rheumatology, Pneumology, Medical University of Innsbruck, 6020, Innsbruck, Austria.
| |
Collapse
|
|
32
|
Iqbal S, Hayman EG, Hong C, Stokum JA, Kurland DB, Gerzanich V, Simard JM. Inducible nitric oxide synthase (NOS-2) in subarachnoid hemorrhage: Regulatory mechanisms and therapeutic implications. Brain Circ 2016; 2:8-19. [PMID: 27774520 PMCID: PMC5074544 DOI: 10.4103/2394-8108.178541] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
Aneurysmal subarachnoid hemorrhage (SAH) typically carries a poor prognosis. Growing evidence indicates that overabundant production of nitric oxide (NO) may be responsible for a large part of the secondary injury that follows SAH. Although SAH modulates the activity of all three isoforms of nitric oxide synthase (NOS), the inducible isoform, NOS-2, accounts for a majority of NO-mediated secondary injuries after SAH. Here, we review the indispensable physiological roles of NO that must be preserved, even while attempting to downmodulate the pathophysiologic effects of NO that are induced by SAH. We examine the effects of SAH on the function of the various NOS isoforms, with a particular focus on the pathological effects of NOS-2 and on the mechanisms responsible for its transcriptional upregulation. Finally, we review interventions to block NOS-2 upregulation or to counteract its effects, with an emphasis on the potential therapeutic strategies to improve outcomes in patients afflicted with SAH. There is still much to be learned regarding the apparently maladaptive response of NOS-2 and its harmful product NO in SAH. However, the available evidence points to crucial effects that, on balance, are adverse, making the NOS-2/NO/peroxynitrite axis an attractive therapeutic target in SAH.
Collapse
Affiliation(s)
- Sana Iqbal
- Department of Neurosurgery, School of Medicine, University of Maryland, Baltimore, Maryland, USA
| | - Erik G Hayman
- Department of Neurosurgery, School of Medicine, University of Maryland, Baltimore, Maryland, USA
| | - Caron Hong
- Department of Anesthesiology, School of Medicine, University of Maryland, Baltimore, Maryland, USA
| | - Jesse A Stokum
- Department of Neurosurgery, School of Medicine, University of Maryland, Baltimore, Maryland, USA
| | - David B Kurland
- Department of Neurosurgery, School of Medicine, University of Maryland, Baltimore, Maryland, USA
| | - Volodymyr Gerzanich
- Department of Neurosurgery, School of Medicine, University of Maryland, Baltimore, Maryland, USA
| | - J Marc Simard
- Department of Neurosurgery, School of Medicine, University of Maryland, Baltimore, Maryland, USA; Department of Pathology, School of Medicine, University of Maryland, Baltimore, Maryland, USA; Department of Physiology, School of Medicine, University of Maryland, Baltimore, Maryland, USA
| |
Collapse
|
|
33
|
Ser HL, Ab Mutalib NS, Yin WF, Chan KG, Goh BH, Lee LH. Evaluation of Antioxidative and Cytotoxic Activities of Streptomyces pluripotens MUSC 137 Isolated from Mangrove Soil in Malaysia. Front Microbiol 2015; 6:1398. [PMID: 26733951 PMCID: PMC4679926 DOI: 10.3389/fmicb.2015.01398] [Citation(s) in RCA: 43] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2015] [Accepted: 11/24/2015] [Indexed: 12/30/2022] Open
Abstract
Streptomyces pluripotens MUSC 137 was isolated from mangrove soil obtained from Tanjung Lumpur, Pahang, Malaysia. We investigated the phylogenetic, genomic, biochemical, and phenotypic characteristics of this strain. Uniquely adapted microorganisms from mangrove habitats have previously yielded compounds of biopharmaceutical interest. In order to examine the bioactivities possessed by the strain, fermentation extract was prepared through solvent extraction method prior to bioactivities screenings. Antioxidant activity was examined via DPPH assay while the cytotoxic effect was assessed by means of examining the activity of the extract against selected human cancer cell lines, namely colon cancer cells (HCT-116, Caco-2, SW480, and HT-29), breast cancer cell (MCF-7), lung cancer cell (A549), prostate cancer cell (DU145), and cervical cancer cell (Ca Ski). The results revealed MUSC 137 possesses significant antioxidant activity and demonstrates cytotoxic effect against several cancer cell lines tested. The results indicated MCF-7 cells were most susceptible to the extract with the lowest IC50 (61.33 ± 17.10 μg/mL), followed by HCT-116 and A549. Additionally, selective index (SI) showed that MUSC 137 extract was less toxic against normal cell lines when compared to MCF-7 and HCT-116 cells. The extract was further subjected to chemical analysis using GC–MS and revealed the presence of deferoxamine and pyrrolizidines related compounds which may account for the antioxidant and cytotoxic properties observed.
Collapse
Affiliation(s)
- Hooi-Leng Ser
- Biomedical Research Laboratory, Jeffrey Cheah School of Medicine and Health Sciences, Monash University Malaysia Bandar Sunway, Malaysia
| | - Nurul-Syakima Ab Mutalib
- UKM Medical Molecular Biology Institute-UKM Medical Centre, Universiti Kebangsaan Malaysia Kuala Lumpur, Malaysia
| | - Wai-Fong Yin
- Division of Genetics and Molecular Biology, Institute of Biological Sciences, Faculty of Science, University of Malaya Kuala Lumpur, Malaysia
| | - Kok-Gan Chan
- Division of Genetics and Molecular Biology, Institute of Biological Sciences, Faculty of Science, University of Malaya Kuala Lumpur, Malaysia
| | - Bey-Hing Goh
- Biomedical Research Laboratory, Jeffrey Cheah School of Medicine and Health Sciences, Monash University Malaysia Bandar Sunway, Malaysia
| | - Learn-Han Lee
- Biomedical Research Laboratory, Jeffrey Cheah School of Medicine and Health Sciences, Monash University Malaysia Bandar Sunway, Malaysia
| |
Collapse
|
|
34
|
Soares MP, Weiss G. The Iron age of host-microbe interactions. EMBO Rep 2015; 16:1482-500. [PMID: 26474900 DOI: 10.15252/embr.201540558] [Citation(s) in RCA: 165] [Impact Index Per Article: 16.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2015] [Accepted: 09/23/2015] [Indexed: 12/25/2022] Open
Abstract
Microbes exert a major impact on human health and disease by either promoting or disrupting homeostasis, in the latter instance leading to the development of infectious diseases. Such disparate outcomes are driven by the ever-evolving genetic diversity of microbes and the countervailing host responses that minimize their pathogenic impact. Host defense strategies that limit microbial pathogenicity include resistance mechanisms that exert a negative impact on microbes, and disease tolerance mechanisms that sustain host homeostasis without interfering directly with microbes. While genetically distinct, these host defense strategies are functionally integrated, via mechanisms that remain incompletely defined. Here, we explore the general principles via which host adaptive responses regulating iron (Fe) metabolism impact on resistance and disease tolerance to infection.
Collapse
Affiliation(s)
| | - Günter Weiss
- Department of Internal Medicine VI, Infectious Diseases, Immunology, Rheumatology, Pneumology, Medical University, Innsbruck, Austria
| |
Collapse
|
|
35
|
Abstract
Macrophages and neutrophils play a decisive role in host responses to intracellular bacteria including the agent of tuberculosis (TB), Mycobacterium tuberculosis as they represent the forefront of innate immune defense against bacterial invaders. At the same time, these phagocytes are also primary targets of intracellular bacteria to be abused as host cells. Their efficacy to contain and eliminate intracellular M. tuberculosis decides whether a patient initially becomes infected or not. However, when the infection becomes chronic or even latent (as in the case of TB) despite development of specific immune activation, phagocytes have also important effector functions. Macrophages have evolved a myriad of defense strategies to combat infection with intracellular bacteria such as M. tuberculosis. These include induction of toxic anti-microbial effectors such as nitric oxide and reactive oxygen intermediates, the stimulation of microbe intoxication mechanisms via acidification or metal accumulation in the phagolysosome, the restriction of the microbe's access to essential nutrients such as iron, fatty acids, or amino acids, the production of anti-microbial peptides and cytokines, along with induction of autophagy and efferocytosis to eliminate the pathogen. On the other hand, M. tuberculosis, as a prime example of a well-adapted facultative intracellular bacterium, has learned during evolution to counter-balance the host's immune defense strategies to secure survival or multiplication within this otherwise hostile environment. This review provides an overview of innate immune defense of macrophages directed against intracellular bacteria with a focus on M. tuberculosis. Gaining more insights and knowledge into this complex network of host-pathogen interaction will identify novel target sites of intervention to successfully clear infection at a time of rapidly emerging multi-resistance of M. tuberculosis against conventional antibiotics.
Collapse
Affiliation(s)
- Günter Weiss
- Department of Internal Medicine VI, Infectious Disease, Immunology, Rheumatology, Pneumology, Medical University of InnsbruckInnsbruck, Austria
| | - Ulrich E Schaible
- Cellular Microbiology, Priority Area Infections, Research Center BorstelBorstel, Germany
- Department of Immunology, London School of Hygiene and Tropical MedicineLondon, UK
- German Centre of Infection Research, TTU-TBBorstel, Germany
| |
Collapse
|
|
36
|
Zhu L, Zhao Q, Yang T, Ding W, Zhao Y. Cellular metabolism and macrophage functional polarization. Int Rev Immunol 2014; 34:82-100. [PMID: 25340307 DOI: 10.3109/08830185.2014.969421] [Citation(s) in RCA: 302] [Impact Index Per Article: 27.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Macrophages are a functionally heterogeneous cell population that is mainly shaped by a variety of microenvironmental stimuli. Interferon γ (IFN-γ), interleukin-1β (IL-1β), and lipopolysaccharide (LPS) induce a classical activation of macrophages (M1), whereas IL-4 and IL-13 induce an alternative activation program in macrophages (M2). Reprogramming of intracellular metabolisms is required for the proper polarization and functions of activated macrophages. Similar to the Warburg effect observed in tumor cells, M1 macrophages increase glucose consumption and lactate release and decreased oxygen consumption rate. In comparison, M2 macrophages mainly employ oxidative glucose metabolism pathways. In addition, fatty acids, vitamins, and iron metabolisms are also related to macrophage polarization. However, detailed metabolic pathways involved in macrophages have remained elusive. Understanding the bidirectional interactions between cellular metabolism and macrophage functions in physiological and pathological situations and the regulatory pathways involved may offer novel therapies for macrophage-associated diseases.
Collapse
Affiliation(s)
- Linnan Zhu
- 1Transplantation Biology Research Division, State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China
| | | | | | | | | |
Collapse
|
|
37
|
Nairz M, Schroll A, Demetz E, Tancevski I, Theurl I, Weiss G. 'Ride on the ferrous wheel'--the cycle of iron in macrophages in health and disease. Immunobiology 2014; 220:280-94. [PMID: 25240631 DOI: 10.1016/j.imbio.2014.09.010] [Citation(s) in RCA: 55] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2014] [Revised: 08/20/2014] [Accepted: 09/05/2014] [Indexed: 12/16/2022]
Abstract
Iron homeostasis and macrophage biology are closely interconnected. On the one hand, iron exerts multiple effects on macrophage polarization and functionality. On the other hand, macrophages are central for mammalian iron homeostasis. The phagocytosis of senescent erythrocytes and their degradation by macrophages enable efficient recycling of iron and the maintenance of systemic iron balance. Macrophages express multiple molecules and proteins for the acquisition and utilization of iron and many of these pathways are affected by inflammatory signals. Of note, iron availability within macrophages has significant effects on immune effector functions and metabolic pathways within these cells. This review summarizes the physiological and pathophysiological aspects of macrophage iron metabolism and highlights its relevant consequences on immune function and in common diseases such as infection and atherosclerosis.
Collapse
Affiliation(s)
- Manfred Nairz
- Department of Internal Medicine VI, Infectious Diseases, Immunology, Rheumatology, Pneumology, Medical University of Innsbruck, Austria.
| | - Andrea Schroll
- Department of Internal Medicine VI, Infectious Diseases, Immunology, Rheumatology, Pneumology, Medical University of Innsbruck, Austria
| | - Egon Demetz
- Department of Internal Medicine VI, Infectious Diseases, Immunology, Rheumatology, Pneumology, Medical University of Innsbruck, Austria
| | - Ivan Tancevski
- Department of Internal Medicine VI, Infectious Diseases, Immunology, Rheumatology, Pneumology, Medical University of Innsbruck, Austria
| | - Igor Theurl
- Department of Internal Medicine VI, Infectious Diseases, Immunology, Rheumatology, Pneumology, Medical University of Innsbruck, Austria
| | - Günter Weiss
- Department of Internal Medicine VI, Infectious Diseases, Immunology, Rheumatology, Pneumology, Medical University of Innsbruck, Austria.
| |
Collapse
|
|
38
|
Jung M, Mertens C, Brüne B. Macrophage iron homeostasis and polarization in the context of cancer. Immunobiology 2014; 220:295-304. [PMID: 25260218 DOI: 10.1016/j.imbio.2014.09.011] [Citation(s) in RCA: 62] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2014] [Revised: 08/07/2014] [Accepted: 09/05/2014] [Indexed: 12/28/2022]
Abstract
Macrophages are central in regulating iron homeostasis, which is tightly linked to their versatile role during innate immunity. They sequester iron by phagocytosis of senescent erythrocytes and represent a major source of available iron in the body. Macrophage iron homeostasis is coupled to the functional heterogeneity and plasticity of these cells, with their extreme roles during inflammation, immune modulation, and resolution of inflammation. It is now appreciated that the macrophage polarization process dictates expression profiles of genes involved in iron metabolism. Therefore, macrophages have evolved a multitude of mechanisms to sequester, transport, store, and release iron. A new, enigmatic protein entering the iron scene and affecting the macrophage phenotype is lipocalin-2. Iron sequestration in macrophages depletes the microenvironment, thereby limiting extracellular pathogen or tumor growth, while fostering inflammation. In contrast, iron release from macrophages contributes to bystander cell proliferation, which is important for tissue regeneration and repair. This dichotomy is also reflected by the dual role of lipocalin-2 in macrophages. Unfortunately, the iron release macrophage phenotype is also a characteristic of tumor-associated macrophages and stimulates tumor cell survival and growth. Iron sequestration versus its release is now appreciated to be associated with the macrophage polarization program and can be used to explain a number of biological functions attributed to distinct macrophage phenotypes. Here we discuss macrophage iron homeostasis with a special focus on lipocalin-2 related to the formation and function of tumor-associated macrophages.
Collapse
Affiliation(s)
- Michaela Jung
- Institute of Biochemistry I/ZAFES, Faculty of Medicine, Goethe-University Frankfurt, 60590 Frankfurt, Germany
| | - Christina Mertens
- Institute of Biochemistry I/ZAFES, Faculty of Medicine, Goethe-University Frankfurt, 60590 Frankfurt, Germany
| | - Bernhard Brüne
- Institute of Biochemistry I/ZAFES, Faculty of Medicine, Goethe-University Frankfurt, 60590 Frankfurt, Germany.
| |
Collapse
|
|
39
|
Nairz M, Haschka D, Demetz E, Weiss G. Iron at the interface of immunity and infection. Front Pharmacol 2014; 5:152. [PMID: 25076907 PMCID: PMC4100575 DOI: 10.3389/fphar.2014.00152] [Citation(s) in RCA: 221] [Impact Index Per Article: 20.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2014] [Accepted: 06/10/2014] [Indexed: 12/18/2022] Open
Abstract
Both, mammalian cells and microbes have an essential need for iron, which is required for many metabolic processes and for microbial pathogenicity. In addition, cross-regulatory interactions between iron homeostasis and immune function are evident. Cytokines and the acute phase protein hepcidin affect iron homeostasis leading to the retention of the metal within macrophages and hypoferremia. This is considered to result from a defense mechanism of the body to limit the availability of iron for extracellular pathogens while on the other hand the reduction of circulating iron results in the development of anemia of inflammation. Opposite, iron and the erythropoiesis inducing hormone erythropoietin affect innate immune responses by influencing interferon-gamma (IFN-γ) mediated (iron) or NF-kB inducible (erythropoietin) immune effector pathways in macrophages. Thus, macrophages loaded with iron lose their ability to kill intracellular pathogens via IFN-γ mediated effector pathways such as nitric oxide (NO) formation. Accordingly, macrophages invaded by the intracellular bacterium Salmonella enterica serovar Typhimurium increase the expression of the iron export protein ferroportin thereby reducing the availability of iron for intramacrophage bacteria while on the other side strengthening anti-microbial macrophage effector pathways via increased formation of NO or TNF-α. In addition, certain innate resistance genes such as natural resistance associated macrophage protein function (Nramp1) or lipocalin-2 exert part of their antimicrobial activity by controlling host and/or microbial iron homeostasis. Consequently, pharmacological or dietary modification of cellular iron trafficking enhances host resistance to intracellular pathogens but may increase susceptibility to microbes in the extracellular compartment and vice versa. Thus, the control over iron homeostasis is a central battlefield in host–pathogen interplay influencing the course of an infectious disease in favor of either the mammalian host or the pathogenic invader.
Collapse
Affiliation(s)
- Manfred Nairz
- Department of Internal Medicine VI-Infectious Diseases, Immunology, Rheumatology, Pneumology, Medical University of Innsbruck Innsbruck, Austria
| | - David Haschka
- Department of Internal Medicine VI-Infectious Diseases, Immunology, Rheumatology, Pneumology, Medical University of Innsbruck Innsbruck, Austria
| | - Egon Demetz
- Department of Internal Medicine VI-Infectious Diseases, Immunology, Rheumatology, Pneumology, Medical University of Innsbruck Innsbruck, Austria
| | - Günter Weiss
- Department of Internal Medicine VI-Infectious Diseases, Immunology, Rheumatology, Pneumology, Medical University of Innsbruck Innsbruck, Austria
| |
Collapse
|
|
40
|
Xie L, Zhang X, Qi D, Guo X, Pang B, Du Y, Zou X, Guo S, Zhao X. Inhibition of inducible nitric oxide synthase expression and nitric oxide production in plateau pika (Ochotona curzoniae) at high altitude on Qinghai-Tibet Plateau. Nitric Oxide 2014; 38:38-44. [DOI: 10.1016/j.niox.2014.02.009] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2013] [Revised: 02/19/2014] [Accepted: 02/27/2014] [Indexed: 12/28/2022]
|
|
41
|
Welsh DJ, Peacock AJ. Cellular responses to hypoxia in the pulmonary circulation. High Alt Med Biol 2014; 14:111-6. [PMID: 23795730 DOI: 10.1089/ham.2013.1016] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023] Open
Abstract
Hypoxia can be defined as a reduction in available oxygen, whether in a whole organism or in a tissue or cell. It is a real life cause of pulmonary hypertension in humans both in terms of patients with chronic hypoxic lung disease and people living at high altitude. The effect of hypoxia on the pulmonary vasculature can be described in two ways; Hypoxic pulmonary vasoconstriction (HPV) (resulting from smooth muscle cell contraction) and pulmonary vascular remodelling (PVR) (resulting from pulmonary vascular cell proliferation). The pulmonary artery is made up of three resident cell types, the endothelial (intima), smooth muscle (media) and fibroblast (adventitia) cells. This review will examine the effects of hypoxia on the cells of the pulmonary vasculature and give an insight into the possible underlying mechanisms.
Collapse
Affiliation(s)
- David J Welsh
- Scottish Pulmonary Vascular Unit, Regional Heart and Lung Center, Glasgow, United Kingdom
| | | |
Collapse
|
|
42
|
Koskenkorva-Frank TS, Weiss G, Koppenol WH, Burckhardt S. The complex interplay of iron metabolism, reactive oxygen species, and reactive nitrogen species: insights into the potential of various iron therapies to induce oxidative and nitrosative stress. Free Radic Biol Med 2013; 65:1174-1194. [PMID: 24036104 DOI: 10.1016/j.freeradbiomed.2013.09.001] [Citation(s) in RCA: 310] [Impact Index Per Article: 25.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/17/2013] [Revised: 09/05/2013] [Accepted: 09/05/2013] [Indexed: 02/07/2023]
Abstract
Production of minute concentrations of superoxide (O2(*-)) and nitrogen monoxide (nitric oxide, NO*) plays important roles in several aspects of cellular signaling and metabolic regulation. However, in an inflammatory environment, the concentrations of these radicals can drastically increase and the antioxidant defenses may become overwhelmed. Thus, biological damage may occur owing to redox imbalance-a condition called oxidative and/or nitrosative stress. A complex interplay exists between iron metabolism, O2(*-), hydrogen peroxide (H2O2), and NO*. Iron is involved in both the formation and the scavenging of these species. Iron deficiency (anemia) (ID(A)) is associated with oxidative stress, but its role in the induction of nitrosative stress is largely unclear. Moreover, oral as well as intravenous (iv) iron preparations used for the treatment of ID(A) may also induce oxidative and/or nitrosative stress. Oral administration of ferrous salts may lead to high transferrin saturation levels and, thus, formation of non-transferrin-bound iron, a potentially toxic form of iron with a propensity to induce oxidative stress. One of the factors that determine the likelihood of oxidative and nitrosative stress induced upon administration of an iv iron complex is the amount of labile (or weakly-bound) iron present in the complex. Stable dextran-based iron complexes used for iv therapy, although they contain only negligible amounts of labile iron, can induce oxidative and/or nitrosative stress through so far unknown mechanisms. In this review, after summarizing the main features of iron metabolism and its complex interplay with O2(*-), H2O2, NO*, and other more reactive compounds derived from these species, the potential of various iron therapies to induce oxidative and nitrosative stress is discussed and possible underlying mechanisms are proposed. Understanding the mechanisms, by which various iron formulations may induce oxidative and nitrosative stress, will help us develop better tolerated and more efficient therapies for various dysfunctions of iron metabolism.
Collapse
Affiliation(s)
- Taija S Koskenkorva-Frank
- Chemical and Preclinical Research and Development, Vifor (International) Ltd., CH-9001 St. Gallen, Switzerland
| | - Günter Weiss
- Department of Internal Medicine VI, Infectious Diseases, Immunology, Rheumatology, Pneumology, Medical University of Innsbruck, Innsbruck, Austria
| | - Willem H Koppenol
- Institute of Inorganic Chemistry, Department of Chemistry and Applied Biosciences, ETH Zurich, Zurich, Switzerland
| | - Susanna Burckhardt
- Chemical and Preclinical Research and Development, Vifor (International) Ltd., CH-9001 St. Gallen, Switzerland; Institute of Inorganic Chemistry, Department of Chemistry and Applied Biosciences, ETH Zurich, Zurich, Switzerland.
| |
Collapse
|
|
43
|
Raggi F, Blengio F, Eva A, Pende D, Varesio L, Bosco MC. Identification of CD300a as a new hypoxia-inducible gene and a regulator of CCL20 and VEGF production by human monocytes and macrophages. Innate Immun 2013; 20:721-34. [PMID: 24131792 DOI: 10.1177/1753425913507095] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
Peripheral blood monocytes are recruited to inflammatory and tumor lesions where they undergo terminal differentiation into macrophages. Monocytes/macrophages integrate stimulatory and inhibitory signals present in the pathologic microenvironment through a defined repertoire of cell surface receptors, and deregulated expression of these molecules may result in amplification of inflammation or establishment of immune escape mechanisms. Characterization of the expression and function of these receptors is required for a better understanding of the regulation of monocyte/macrophage activity at pathologic sites. Hypoxia is a common feature of many pathological situations and an important regulator of monocyte/macrophage pro-inflammatory responses. In this study, we identify the leukocyte membrane antigen, CD300a, a member of the CD300 superfamily of immunoregulatory receptors, as a new hypoxia-inducible gene in primary human monocytes and monocyte-derived macrophages. CD300a mRNA up-regulation by hypoxia was rapid and reversible, paralleled by increased surface protein expression, and mediated by hypoxia-inducible factor-1α. CD300a induction was also triggered by the hypoxia-mimetic agent, desferrioxamine. CD300a exhibited both activating and inhibitory potential, differentially regulating CCL20 and vascular endothelial growth factor pro-inflammatory cytokine production by monocytes/macrophages upon triggering by an agonist Ab. These results suggest that CD300a induction by the hypoxic environment represents a mechanism of regulation of monocyte/macrophage pro-inflammatory responses at pathologic sites.
Collapse
Affiliation(s)
- Federica Raggi
- Laboratory of Molecular Biology, Istituto Giannina Gaslini, Genova, Italy
| | - Fabiola Blengio
- Laboratory of Molecular Biology, Istituto Giannina Gaslini, Genova, Italy
| | - Alessandra Eva
- Laboratory of Molecular Biology, Istituto Giannina Gaslini, Genova, Italy
| | | | - Luigi Varesio
- Laboratory of Molecular Biology, Istituto Giannina Gaslini, Genova, Italy
| | - Maria Carla Bosco
- Laboratory of Molecular Biology, Istituto Giannina Gaslini, Genova, Italy
| |
Collapse
|
|
44
|
Park YJ, Yoon SJ, Suh HW, Kim DO, Park JR, Jung H, Kim TD, Yoon SR, Min JK, Na HJ, Lee SJ, Lee HG, Lee YH, Lee HB, Choi I. TXNIP deficiency exacerbates endotoxic shock via the induction of excessive nitric oxide synthesis. PLoS Pathog 2013; 9:e1003646. [PMID: 24098117 PMCID: PMC3789754 DOI: 10.1371/journal.ppat.1003646] [Citation(s) in RCA: 51] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2013] [Accepted: 08/05/2013] [Indexed: 12/11/2022] Open
Abstract
Thioredoxin-interacting protein (TXNIP) has multiple functions, including tumor suppression and involvement in cell proliferation and apoptosis. However, its role in the inflammatory process remains unclear. In this report, we demonstrate that Txnip−/− mice are significantly more susceptible to lipopolysaccharide (LPS)-induced endotoxic shock. In response to LPS, Txnip−/− macrophages produced significantly higher levels of nitric oxide (NO) and inducible nitric oxide synthase (iNOS), and an iNOS inhibitor rescued Txnip−/− mice from endotoxic shock-induced death, demonstrating that NO is a major factor in TXNIP-mediated endotoxic shock. This susceptibility phenotype of Txnip−/− mice occurred despite reduced IL-1β secretion due to increased S-nitrosylation of NLRP3 compared to wild-type controls. Taken together, these data demonstrate that TXNIP is a novel molecule that links NO synthesis and NLRP3 inflammasome activation during endotoxic shock. TXNIP has many biological functions, including the inhibition of tumor growth, suppression of hepatocarcinogenesis, and regulation of glucose metabolism and reactive oxygen species (ROS) generation in different cell types. However, little is known about its role in the inflammatory process. In this study, our results demonstrate that TXNIP plays a critical role in the control of lethal endotoxin-induced shock by controlling NO production in innate immune cells via the regulation of iNOS expression. This regulation is mediated through changes in the activation and translocation of NF-κB that affect the NF-κB/iNOS pathway. In addition, excessive NO reduces the production of IL-1β via S-nitrosylation of the NLRP3 inflammasome. Subsequently, the survival of Txnip−/− mice is significantly decreased due to hypothermia and hypoglycemia. Overall, these results suggest that TXNIP is a novel therapeutic target for the treatment of inflammatory diseases.
Collapse
Affiliation(s)
- Young-Jun Park
- Immunotherapy Research Center, Korea Research Institute of Bioscience and Biotechnology, Yuseong-gu, Daejeon, Republic of Korea
- Department of Functional Genomics, University of Science and Technology, Yuseong-gu, Daejeon, Republic of Korea
| | - Sung-Jin Yoon
- Immunotherapy Research Center, Korea Research Institute of Bioscience and Biotechnology, Yuseong-gu, Daejeon, Republic of Korea
- Department of Functional Genomics, University of Science and Technology, Yuseong-gu, Daejeon, Republic of Korea
| | - Hyun-Woo Suh
- Immunotherapy Research Center, Korea Research Institute of Bioscience and Biotechnology, Yuseong-gu, Daejeon, Republic of Korea
| | - Dong Oh Kim
- Immunotherapy Research Center, Korea Research Institute of Bioscience and Biotechnology, Yuseong-gu, Daejeon, Republic of Korea
- Department of Functional Genomics, University of Science and Technology, Yuseong-gu, Daejeon, Republic of Korea
| | - Jeong-Ran Park
- Immunotherapy Research Center, Korea Research Institute of Bioscience and Biotechnology, Yuseong-gu, Daejeon, Republic of Korea
| | - Haiyoung Jung
- Immunotherapy Research Center, Korea Research Institute of Bioscience and Biotechnology, Yuseong-gu, Daejeon, Republic of Korea
- Department of Functional Genomics, University of Science and Technology, Yuseong-gu, Daejeon, Republic of Korea
| | - Tae-Don Kim
- Immunotherapy Research Center, Korea Research Institute of Bioscience and Biotechnology, Yuseong-gu, Daejeon, Republic of Korea
- Department of Functional Genomics, University of Science and Technology, Yuseong-gu, Daejeon, Republic of Korea
| | - Suk Ran Yoon
- Immunotherapy Research Center, Korea Research Institute of Bioscience and Biotechnology, Yuseong-gu, Daejeon, Republic of Korea
- Department of Functional Genomics, University of Science and Technology, Yuseong-gu, Daejeon, Republic of Korea
| | - Jeong-Ki Min
- Immunotherapy Research Center, Korea Research Institute of Bioscience and Biotechnology, Yuseong-gu, Daejeon, Republic of Korea
- Department of Biomolecular Science, University of Science & Technology, Yuseong-gu, Daejeon, Republic of Korea
| | - Hee-Jun Na
- Regenerative Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology, Yuseong-gu, Daejeon, Republic of Korea
| | - Seon-Jin Lee
- Medical Genomics Research Center, Korea Research Institute of Bioscience and Biotechnology, Yuseong-gu, Daejeon, Republic of Korea
| | - Hee Gu Lee
- Medical Genomics Research Center, Korea Research Institute of Bioscience and Biotechnology, Yuseong-gu, Daejeon, Republic of Korea
| | - Young Ho Lee
- Department of Anatomy, School of Medicine, Chungnam National University, Chung-gu, Daejeon, Republic of Korea
| | - Hee-Bong Lee
- Department of Biochemistry, College of Natural Sciences, Kangwon National University, Chuncheon, Republic of Korea
| | - Inpyo Choi
- Immunotherapy Research Center, Korea Research Institute of Bioscience and Biotechnology, Yuseong-gu, Daejeon, Republic of Korea
- Department of Functional Genomics, University of Science and Technology, Yuseong-gu, Daejeon, Republic of Korea
- * E-mail:
| |
Collapse
|
|
45
|
Troxell B, Hassan HM. Transcriptional regulation by Ferric Uptake Regulator (Fur) in pathogenic bacteria. Front Cell Infect Microbiol 2013; 3:59. [PMID: 24106689 PMCID: PMC3788343 DOI: 10.3389/fcimb.2013.00059] [Citation(s) in RCA: 324] [Impact Index Per Article: 27.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2013] [Accepted: 09/18/2013] [Indexed: 12/16/2022] Open
Abstract
In the ancient anaerobic environment, ferrous iron (Fe2+) was one of the first metal cofactors. Oxygenation of the ancient world challenged bacteria to acquire the insoluble ferric iron (Fe3+) and later to defend against reactive oxygen species (ROS) generated by the Fenton chemistry. To acquire Fe3+, bacteria produce low-molecular weight compounds, known as siderophores, which have extremely high affinity for Fe3+. However, during infection the host restricts iron from pathogens by producing iron- and siderophore-chelating proteins, by exporting iron from intracellular pathogen-containing compartments, and by limiting absorption of dietary iron. Ferric Uptake Regulator (Fur) is a transcription factor which utilizes Fe2+ as a corepressor and represses siderophore synthesis in pathogens. Fur, directly or indirectly, controls expression of enzymes that protect against ROS damage. Thus, the challenges of iron homeostasis and defense against ROS are addressed via Fur. Although the role of Fur as a repressor is well-documented, emerging evidence demonstrates that Fur can function as an activator. Fur activation can occur through three distinct mechanisms (1) indirectly via small RNAs, (2) binding at cis regulatory elements that enhance recruitment of the RNA polymerase holoenzyme (RNAP), and (3) functioning as an antirepressor by removing or blocking DNA binding of a repressor of transcription. In addition, Fur homologs control defense against peroxide stress (PerR) and control uptake of other metals such as zinc (Zur) and manganese (Mur) in pathogenic bacteria. Fur family members are important for virulence within bacterial pathogens since mutants of fur, perR, or zur exhibit reduced virulence within numerous animal and plant models of infection. This review focuses on the breadth of Fur regulation in pathogenic bacteria.
Collapse
Affiliation(s)
- Bryan Troxell
- Department of Immunology and Microbiology, Indiana University School of Medicine Indianapolis, IN, USA
| | | |
Collapse
|
|
46
|
Wang F, Xu P, Xie KC, Chen XF, Li CY, Huang Q. Effects of tumor microenviromental factors on VEGF expression. Biomed Rep 2013; 1:539-544. [PMID: 24648982 DOI: 10.3892/br.2013.115] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2013] [Accepted: 05/02/2013] [Indexed: 01/21/2023] Open
Abstract
The expression of vascular endothelial growth factor (VEGF) is regulated by microenvironmental factors within the tumors, such as hypoxia, free radicals, pH imbalance and nutrient deficiency. The purpose of this study was to observe VEGF activity in tumor cells under different stress conditions. A plasmid was generated, consisting of green fluorescent protein (GFP) fused to a 1,217-bp sequence, which was located downstream and upstream of the transcriptional start site of VEGF, respectively. The plasmid was stably transfected into 4T1 mouse breast carcinoma cells. Cells were cultured in a medium with nitric oxide (NO) donor sodium nitroprusside (SNP), hypoxia-mimetic agent deferoxamine mesylate (DFX), H2O2, absence of serum and lowered or elevated pH, or were heat-shocked, followed by measurement of VEGF activity by reverse transcription polymerase chain reaction (RT-PCR) and ELISA. Hypoxia, SNP and H2O2 led to increments of VEGF mRNA and protein expression, as well as of GFP expression. The pH alterations, serum deprivation and heat shock reduced VEGF mRNA expression, but had little effect on GFP expression. The results demonstrated that VEGF expression may be influenced by a number of microenvironmental factors and these factors may play important roles in regulating VEGF expression during tumorigenesis.
Collapse
Affiliation(s)
- Feng Wang
- Experimental Research Center, The First People's Hospital, Shanghai Jiaotong University, Shanghai 200080, P.R. China
| | - Ping Xu
- Experimental Research Center, The First People's Hospital, Shanghai Jiaotong University, Shanghai 200080, P.R. China
| | - Kuang-Chen Xie
- Experimental Research Center, The First People's Hospital, Shanghai Jiaotong University, Shanghai 200080, P.R. China
| | - Xia-Fang Chen
- Experimental Research Center, The First People's Hospital, Shanghai Jiaotong University, Shanghai 200080, P.R. China
| | - Chuan-Yuan Li
- Department of Radiation Oncology, University of Colorado Health Sciences Center, Aurora, CO 80010, USA
| | - Qian Huang
- Experimental Research Center, The First People's Hospital, Shanghai Jiaotong University, Shanghai 200080, P.R. China
| |
Collapse
|
|
47
|
Nairz M, Schleicher U, Schroll A, Sonnweber T, Theurl I, Ludwiczek S, Talasz H, Brandacher G, Moser PL, Muckenthaler MU, Fang FC, Bogdan C, Weiss G. Nitric oxide-mediated regulation of ferroportin-1 controls macrophage iron homeostasis and immune function in Salmonella infection. ACTA ACUST UNITED AC 2013; 210:855-73. [PMID: 23630227 PMCID: PMC3646493 DOI: 10.1084/jem.20121946] [Citation(s) in RCA: 164] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
NOS2-derived nitric oxide drives ferroportin-1–mediated iron export in Salmonella-infected macrophages, thus limiting bacterial growth. Nitric oxide (NO) generated by inducible NO synthase 2 (NOS2) affects cellular iron homeostasis, but the underlying molecular mechanisms and implications for NOS2-dependent pathogen control are incompletely understood. In this study, we found that NO up-regulated the expression of ferroportin-1 (Fpn1), the major cellular iron exporter, in mouse and human cells. Nos2−/− macrophages displayed increased iron content due to reduced Fpn1 expression and allowed for an enhanced iron acquisition by the intracellular bacterium Salmonella typhimurium. Nos2 gene disruption or inhibition of NOS2 activity led to an accumulation of iron in the spleen and splenic macrophages. Lack of NO formation resulted in impaired nuclear factor erythroid 2-related factor-2 (Nrf2) expression, resulting in reduced Fpn1 transcription and diminished cellular iron egress. After infection of Nos2−/− macrophages or mice with S. typhimurium, the increased iron accumulation was paralleled by a reduced cytokine (TNF, IL-12, and IFN-γ) expression and impaired pathogen control, all of which were restored upon administration of the iron chelator deferasirox or hyperexpression of Fpn1 or Nrf2. Thus, the accumulation of iron in Nos2−/− macrophages counteracts a proinflammatory host immune response, and the protective effect of NO appears to partially result from its ability to prevent iron overload in macrophages
Collapse
Affiliation(s)
- Manfred Nairz
- Department of Internal Medicine VI, Medical University of Innsbruck, 6020 Innsbruck, Austria
| | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
48
|
Prostaglandins as negative regulators against lipopolysaccharide, lipoteichoic acid, and peptidoglycan-induced inducible nitric oxide synthase/nitric oxide production through reactive oxygen species-dependent heme oxygenase 1 expression in macrophages. Shock 2013; 38:549-58. [PMID: 23042187 DOI: 10.1097/shk.0b013e31826b2826] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
Although prostaglandins (PGs) were reported to exert proinflammatory and anti-inflammatory effects in macrophages, their action mechanisms remain unclear. The effects of PGs including PGJ2 (J2), Δ-PGJ2 (Δ), 15-deoxy-Δ PGJ2 (15d), PGE2 (E2), and PGF2α (F2α) on lipopolysaccharide (LPS)-, lipoteichoic acid (LTA)-, and peptidoglycan (PGN)-induced inducible nitric oxide (NO) synthase (iNOS)/NO production by RAW264.7 macrophages were investigated. First, we found that induction of cyclooxygenase 2 (COX-2) protein occurred at a time earlier than that of heme oxygenase 1 (HO-1) protein, and the addition of the COX-2 inhibitor NS398 reduced HO-1 protein expression in LPS-, LTA-, and PGN-treated RAW264.7 macrophages. Incubation of RAW264.7 macrophages with the indicated PGs showed that J2, Δ, and 15d significantly induced HO-1 protein expression; however, E2 and F2α did not. Heme oxygenase 1 protein induced by J2, Δ, and 15d was inhibited by the transcriptional inhibitor, actinomycin (Act) D; the translational inhibitor, cycloheximide; and the antioxidant, N-acetyl cysteine (NAC). Increases in intracellular peroxide levels by J2, Δ, and 15d were detected via a 2',7'™-dichlorofluorescein diacetate (DCFH-DA) analysis, and they were prevented by the addition of NAC. In addition, J2, Δ, and 15d produced significant inhibition of LPS-, LTA-, and PGN-induced iNOS protein and NO production by RAW264.7 cells, in accordance with increased HO-1 protein expression. Reductions of LPS-, LTA-, and PGN-induced phosphorylated c-Jun N-terminal kinase, c-Jun protein, and activator protein 1 luciferase activity by J2, Δ, and 15d were identified, and the addition of the HO-1 inhibitor, tin protoporphyrin, reversed the inhibitory effects of Δ and 15d on LPS- and LTA-induced iNOS/NO, phosphorylated c-Jun N-terminal kinase, and c-Jun protein expressions by macrophages. Knockdown of HO-1 protein expression by HO-1 small interfering RNA blocked Δ and 15d inhibition of LPS- and LTA-induced events. Moreover, the compound, cyclopentenone (CP), which mimics the CP moiety of 15d, and its analog cyclohexenone were used, and cyclohexenone showed more potent induction of the HO-1 protein with effective inhibition of LPS-, LTA-, and PGN-induced iNOS/NO production than CP in macrophages. Reactive oxygen species-dependent HO-1 protein expression by PGs, which inhibited LPS-, LTA-, and PGN-induced iNOS/NO production, was identified in macrophages.
Collapse
|
|
49
|
Colleoni F, Padmanabhan N, Yung HW, Watson ED, Cetin I, Tissot van Patot MC, Burton GJ, Murray AJ. Suppression of mitochondrial electron transport chain function in the hypoxic human placenta: a role for miRNA-210 and protein synthesis inhibition. PLoS One 2013; 8:e55194. [PMID: 23383105 PMCID: PMC3559344 DOI: 10.1371/journal.pone.0055194] [Citation(s) in RCA: 90] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2012] [Accepted: 12/19/2012] [Indexed: 01/18/2023] Open
Abstract
Fetal growth is critically dependent on energy metabolism in the placenta, which drives active exchange of nutrients. Placental oxygen levels are therefore vital, and chronic hypoxia during pregnancy impairs fetal growth. Here we tested the hypothesis that placental hypoxia alters mitochondrial electron transport chain (ETS) function, and sought to identify underlying mechanisms. We cultured human placental cells under different oxygen concentrations. Mitochondrial respiration was measured, alongside levels of ETS complexes. Additionally, we studied placentas from sea-level and high-altitude pregnancies. After 4 d at 1% O2 (1.01 KPa), complex I-supported respiration was 57% and 37% lower, in trophoblast-like JEG3 cells and fibroblasts, respectively, compared with controls cultured at 21% O2 (21.24 KPa); complex IV-supported respiration was 22% and 30% lower. Correspondingly, complex I levels were 45% lower in placentas from high-altitude pregnancies than those from sea-level pregnancies. Expression of HIF-responsive microRNA-210 was increased in hypoxic fibroblasts and high-altitude placentas, whilst expression of its targets, iron-sulfur cluster scaffold (ISCU) and cytochrome c oxidase assembly protein (COX10), decreased. Moreover, protein synthesis inhibition, a feature of the high-altitude placenta, also suppressed ETS complex protein levels. Our results demonstrate that mitochondrial function is altered in hypoxic human placentas, with specific suppression of complexes I and IV compromising energy metabolism and potentially contributing to impaired fetal growth.
Collapse
Affiliation(s)
- Francesca Colleoni
- Department of Physiology, Development & Neuroscience, and Centre for Trophoblast Research, University of Cambridge, Cambridge, United Kingdom.
| | | | | | | | | | | | | | | |
Collapse
|
|
50
|
Prabhakar NR, Semenza GL. Adaptive and maladaptive cardiorespiratory responses to continuous and intermittent hypoxia mediated by hypoxia-inducible factors 1 and 2. Physiol Rev 2012; 92:967-1003. [PMID: 22811423 DOI: 10.1152/physrev.00030.2011] [Citation(s) in RCA: 476] [Impact Index Per Article: 36.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Hypoxia is a fundamental stimulus that impacts cells, tissues, organs, and physiological systems. The discovery of hypoxia-inducible factor-1 (HIF-1) and subsequent identification of other members of the HIF family of transcriptional activators has provided insight into the molecular underpinnings of oxygen homeostasis. This review focuses on the mechanisms of HIF activation and their roles in physiological and pathophysiological responses to hypoxia, with an emphasis on the cardiorespiratory systems. HIFs are heterodimers comprised of an O(2)-regulated HIF-1α or HIF-2α subunit and a constitutively expressed HIF-1β subunit. Induction of HIF activity under conditions of reduced O(2) availability requires stabilization of HIF-1α and HIF-2α due to reduced prolyl hydroxylation, dimerization with HIF-1β, and interaction with coactivators due to decreased asparaginyl hydroxylation. Stimuli other than hypoxia, such as nitric oxide and reactive oxygen species, can also activate HIFs. HIF-1 and HIF-2 are essential for acute O(2) sensing by the carotid body, and their coordinated transcriptional activation is critical for physiological adaptations to chronic hypoxia including erythropoiesis, vascularization, metabolic reprogramming, and ventilatory acclimatization. In contrast, intermittent hypoxia, which occurs in association with sleep-disordered breathing, results in an imbalance between HIF-1α and HIF-2α that causes oxidative stress, leading to cardiorespiratory pathology.
Collapse
Affiliation(s)
- Nanduri R Prabhakar
- Institute for Integrative Physiology and Center for Systems Biology of O2 Sensing, Biological Sciences Division, University of Chicago, Chicago, Illinois, USA.
| | | |
Collapse
|