scholarly journals Ferritin: An Inflammatory Player Keeping Iron at the Core of Pathogen-Host Interactions

2020 ◽  
Vol 8 (4) ◽  
pp. 589 ◽  
Author(s):  
Ana C. Moreira ◽  
Gonçalo Mesquita ◽  
Maria Salomé Gomes
Keyword(s):  
Inflammatory Diseases ◽  
Essential Element ◽  
Basic Research ◽  
Cell Types ◽  
Acid Synthesis ◽  
Organ Damage ◽  
Iron Storage ◽  
Host Interactions ◽  
Cellular Iron ◽  
Iron Storage Protein

Iron is an essential element for virtually all cell types due to its role in energy metabolism, nucleic acid synthesis and cell proliferation. Nevertheless, if free, iron induces cellular and organ damage through the formation of free radicals. Thus, iron levels must be firmly controlled. During infection, both host and microbe need to access iron and avoid its toxicity. Alterations in serum and cellular iron have been reported as important markers of pathology. In this regard, ferritin, first discovered as an iron storage protein, has emerged as a biomarker not only in iron-related disorders but also in inflammatory diseases, or diseases in which inflammation has a central role such as cancer, neurodegeneration or infection. The basic research on ferritin identification and functions, as well as its role in diseases with an inflammatory component and its potential as a target in host-directed therapies, are the main considerations of this review.

scholarly journals Physical phenotype of blood cells is altered in COVID-19

2021 ◽  
Author(s):  
Markéta Kubánková ◽  
Bettina Hohberger ◽  
Jakob Hoffmanns ◽  
Julia Fürst ◽  
Martin Herrmann ◽  
...  
Keyword(s):  
Blood Cells ◽  
Inflammatory Diseases ◽  
Vascular Occlusion ◽  
Cell Types ◽  
Organ Damage ◽  
Clinical Syndrome ◽  
The Body ◽  
Physical Parameters ◽  
Physical Changes

Clinical syndrome coronavirus disease 2019 (COVID-19) induced by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is characterized by rapid spreading and high mortality worldwide. While the pathology is not yet fully understood, hyper-inflammatory response and coagulation disorders leading to congestions of microvessels are considered to be key drivers of the still increasing death toll. Until now, physical changes of blood cells have not been considered to play a role in COVID-19 related vascular occlusion and organ damage. Here we report an evaluation of multiple physical parameters including the mechanical features of five frequent blood cell types, namely erythrocytes, lymphocytes, monocytes, neutrophils, and eosinophils. More than 4 million blood cells of 17 COVID-19 patients at different levels of severity, 24 volunteers free from infectious or inflammatory diseases, and 14 recovered COVID-19 patients were analyzed. We found significant changes in erythrocyte deformability, lymphocyte stiffness, monocyte size, and neutrophil size and deformability. While some of these changes recovered to normal values after hospitalization, others persisted for months after hospital discharge, evidencing the long-term imprint of COVID-19 on the body.

scholarly journals Mobilization of Iron Stored in Bacterioferritin Is Required for Metabolic Homeostasis in Pseudomonas aeruginosa

Pathogens ◽  
2020 ◽  
Vol 9 (12) ◽  
pp. 980
Author(s):  
Achala N. D. Punchi Hewage ◽  
Leo Fontenot ◽  
Jessie Guidry ◽  
Thomas Weldeghiorghis ◽  
Anil K. Mehta ◽  
...  
Keyword(s):  
Iron Homeostasis ◽  
Culture Media ◽  
Acid Synthesis ◽  
Iron Limitation ◽  
Metabolic Homeostasis ◽  
Intracellular Iron ◽  
Amino Acid Synthesis ◽  
Iron Storage ◽  
Low Levels ◽  
Iron Storage Protein

Iron homeostasis offers a significant bacterial vulnerability because pathogens obtain essential iron from their mammalian hosts, but host-defenses maintain vanishingly low levels of free iron. Although pathogens have evolved mechanisms to procure host-iron, these depend on well-regulated iron homeostasis. To disrupt iron homeostasis, our work has targeted iron mobilization from the iron storage protein bacterioferritin (BfrB) by blocking a required interaction with its cognate ferredoxin partner (Bfd). The blockade of the BfrB–Bfd complex by deletion of the bfd gene (Δbfd) causes iron to irreversibly accumulate in BfrB. In this study we used mass spectrometry and NMR spectroscopy to compare the proteomic response and the levels of key intracellular metabolites between wild type (wt) and isogenic ΔbfdP. aeruginosa strains. We find that the irreversible accumulation of unusable iron in BfrB leads to acute intracellular iron limitation, even if the culture media is iron-sufficient. Importantly, the iron limitation and concomitant iron metabolism dysregulation trigger a cascade of events that lead to broader metabolic homeostasis disruption, which includes sulfur limitation, phenazine-mediated oxidative stress, suboptimal amino acid synthesis and altered carbon metabolism.

scholarly journals Chemistry and Biology of Ferritin

Metallomics ◽  
2021 ◽  
Author(s):  
Marina Plays ◽  
Sebastian Müller ◽  
Raphaël Rodriguez
Keyword(s):  
Iron Homeostasis ◽  
Cell Metabolism ◽  
Essential Element ◽  
Biological Functions ◽  
Iron Storage ◽  
Potential Biomarker ◽  
Specific Manner ◽  
Cellular Compartments ◽  
Structure And Activity ◽  
Iron Storage Protein

Abstract Iron is an essential element required by cells and has been described as a key player in ferroptosis. Ferritin operates as a fundamental iron storage protein in cells forming multimeric assemblies with crystalline iron cores. We discuss the latest findings on ferritin structure and activity and its link to cell metabolism and ferroptosis. The chemistry of iron, including its oxidations states, is important for its biological functions, its reactivity and the biology of ferritin. Ferritin can be localized in different cellular compartments and secreted by cells with a variety of functions depending on its spatial context. Here, we discuss how cellular ferritin localization is tightly linked to its function in a tissue-specific manner, and how impairment of iron homeostasis is implicated in diseases including cancer and COVID-19. Ferritin is a potential biomarker and we discuss latest research where it has been employed for imaging purposes and drug delivery.

scholarly journals CD63 is Regulated by Iron via the IRE-IRP System and is Important for Ferritin Secretion by Extracellular Vesicles

Blood ◽  
2021 ◽  
Author(s):  
Izumi Yanatori ◽  
Des R Richardson ◽  
Herschel Shrikant Dhekne ◽  
Shinya Toyokuni ◽  
Fumio Kishi
Keyword(s):  
Extracellular Vesicles ◽  
Storage Protein ◽  
Regulatory Protein ◽  
Iron Loading ◽  
Nuclear Receptor Coactivator ◽  
Iron Storage ◽  
Cellular Iron ◽  
Associated Proteins ◽  
Responsive Element ◽  
Iron Storage Protein

Extracellular vesicles (EVs) transfer functional molecules between cells. CD63 is a widely recognized EV marker that contributes to EV secretion from cells. However, the regulation of its expression remains largely unknown. Ferritin is a cellular iron storage protein that can be also secreted by the exosome pathway (Truman-Rosentsvit M. et al. BLOOD 131 (2018) 342-352), with serum ferritin levels classically reflecting body iron stores. Iron metabolism-associated proteins, such as ferritin, are intricately regulated by cellular iron levels via the iron responsive element (IRE)-iron regulatory protein (IRP) system. Herein, we present a novel mechanism demonstrating that the expression of the EV-associated protein, CD63, is under the regulation of the IRE-IRP system. We discovered a canonical IRE in the 5'-untranslated region (UTR) of CD63 mRNA responsible for regulating its expression in response to increased iron. Cellular iron-loading caused a marked increase in CD63 expression and the secretion from cells of CD63 positive (i.e., CD63(+)) EVs, which were shown to contain ferritin-H (FtH) and -L (FtL). Our results demonstrate that under iron-loading, intracellular ferritin is transferred via nuclear receptor coactivator 4 (NCOA4) to CD63(+) EVs that are then secreted. Such iron-regulated secretion of the major iron storage protein ferritin via CD63(+) EVs, poses significant impact for understanding the local cell-to-cell exchange of ferritin and iron.

Polygonal profiles of ferritin molecules

1983 ◽  
Vol 41 ◽  
pp. 600-601
Author(s):  
William H. Massover
Keyword(s):  
Axial Ratio ◽  
X Ray Diffraction ◽  
Rhombic Dodecahedron ◽  
Apparent Contradiction ◽  
Iron Storage ◽  
X Ray ◽  
Hexagonal Shape ◽  
Axes Of Symmetry ◽  
Apparent Conflict ◽  
Iron Storage Protein

The molecular structure of the iron-storage protein, ferritin, is becoming known in ever finer detail. The 24 apoferritin subunits (MW ca. 20,000) have a 2:1 axial ratio and are polymerized with 4:3:2 symmetry to form an outer shell surrounding a variable amount of microcrystalline iron, Recent x-ray diffraction results indicate that the projected outline of the native molecule has a quasi-hexagonal shape when viewed down the 3-fold axes of symmetry, and a quasi-square shape when looking down the 4-fold axes. To date, no electron microscope study has reported observing anything other than circular profiles, which would indicate that ferritin is strictly spherical. The apparent conflict between the "hollow sphere" of electron microscopy (E.M.) and the "truncated rhombic dodecahedron" of x-ray diffraction could reflect the poorer effective resolution of E.M. coming from radiation damage, staining, drying, etc. The present study investigates the detailed shape of individual ferritin molecules in order to search for the predicted aspherical profiles and to interpret the nature of this apparent contradiction.

scholarly journals Heme Oxygenase-1 Deficiency and Oxidative Stress: A Review of 9 Independent Human Cases and Animal Models

2021 ◽  
Vol 22 (4) ◽  
pp. 1514 ◽  
Author(s):  
Akihiro Yachie
Keyword(s):  
Oxidative Stress ◽  
Animal Models ◽  
Heme Oxygenase ◽  
Inflammatory Diseases ◽  
Cell Types ◽  
Pharmacological Intervention ◽  
Heme Oxygenase 1 ◽  
Inflammatory Reactions

Since Yachie et al. reported the first description of human heme oxygenase (HO)-1 deficiency more than 20 years ago, few additional human cases have been reported in the literature. A detailed analysis of the first human case of HO-1 deficiency revealed that HO-1 is involved in the protection of multiple tissues and organs from oxidative stress and excessive inflammatory reactions, through the release of multiple molecules with anti-oxidative stress and anti-inflammatory functions. HO-1 production is induced in vivo within selected cell types, including renal tubular epithelium, hepatic Kupffer cells, vascular endothelium, and monocytes/macrophages, suggesting that HO-1 plays critical roles in these cells. In vivo and in vitro studies have indicated that impaired HO-1 production results in progressive monocyte dysfunction, unregulated macrophage activation and endothelial cell dysfunction, leading to catastrophic systemic inflammatory response syndrome. Data from reported human cases of HO-1 deficiency and numerous studies using animal models suggest that HO-1 plays critical roles in various clinical settings involving excessive oxidative stress and inflammation. In this regard, therapy to induce HO-1 production by pharmacological intervention represents a promising novel strategy to control inflammatory diseases.

scholarly journals Organoids to Dissect Gastrointestinal Virus–Host Interactions: What Have We Learned?

Viruses ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 999
Author(s):  
Sue E. Crawford ◽  
Sasirekha Ramani ◽  
Sarah E. Blutt ◽  
Mary K. Estes
Keyword(s):  
Cell Types ◽  
Human Infection ◽  
Viral Pathogens ◽  
Host Interactions ◽  
Complex Interactions ◽  
Microbe Interactions ◽  
Host Microbe Interactions ◽  
Human Intestinal Epithelium ◽  
Human Viruses ◽  
Human Infections

Historically, knowledge of human host–enteric pathogen interactions has been elucidated from studies using cancer cells, animal models, clinical data, and occasionally, controlled human infection models. Although much has been learned from these studies, an understanding of the complex interactions between human viruses and the human intestinal epithelium was initially limited by the lack of nontransformed culture systems, which recapitulate the relevant heterogenous cell types that comprise the intestinal villus epithelium. New investigations using multicellular, physiologically active, organotypic cultures produced from intestinal stem cells isolated from biopsies or surgical specimens provide an exciting new avenue for understanding human specific pathogens and revealing previously unknown host–microbe interactions that affect replication and outcomes of human infections. Here, we summarize recent biologic discoveries using human intestinal organoids and human enteric viral pathogens.

scholarly journals Glucocorticoid Receptor β (GRβ): Beyond Its Dominant-Negative Function

2021 ◽  
Vol 22 (7) ◽  
pp. 3649
Author(s):  
Patricia Ramos-Ramírez ◽  
Omar Tliba
Keyword(s):  
Current Knowledge ◽  
Inflammatory Diseases ◽  
Cell Communication ◽  
Cell Types ◽  
The Body ◽  
Dominant Negative ◽  
Negative Effects ◽  
Independent Manner ◽  
Distinct Cell ◽  
Induced Apoptosis

Glucocorticoids (GCs) act via the GC receptor (GR), a receptor ubiquitously expressed in the body where it drives a broad spectrum of responses within distinct cell types and tissues, which vary in strength and specificity. The variability of GR-mediated cell responses is further extended by the existence of GR isoforms, such as GRα and GRβ, generated through alternative splicing mechanisms. While GRα is the classic receptor responsible for GC actions, GRβ has been implicated in the impairment of GRα-mediated activities. Interestingly, in contrast to the popular belief that GRβ actions are restricted to its dominant-negative effects on GRα-mediated responses, GRβ has been shown to have intrinsic activities and “directly” regulates a plethora of genes related to inflammatory process, cell communication, migration, and malignancy, each in a GRα-independent manner. Furthermore, GRβ has been associated with increased cell migration, growth, and reduced sensitivity to GC-induced apoptosis. We will summarize the current knowledge of GRβ-mediated responses, with a focus on the GRα-independent/intrinsic effects of GRβ and the associated non-canonical signaling pathways. Where appropriate, potential links to airway inflammatory diseases will be highlighted.

The Flavonols Quercetin, Myricetin, Kaempferol, and Galangin Inhibit the Net Oxygen Consumption by Immune Complex- Stimulated Human and Rabbit Neutrophils

2014 ◽  
Vol 69 (7-8) ◽  
pp. 346-356 ◽  
Author(s):  
Andréa S. G. Figueiredo-Rinhel ◽  
Everton O. L. Santos ◽  
Luciana M. Kabeya ◽  
Ana Elisa C. S. Azzolini ◽  
Livia M. C. Simões-Ambrosio ◽  
...  
Keyword(s):  
Oxygen Consumption ◽  
Immune Complex ◽  
Respiratory Burst ◽  
Human Neutrophil ◽  
Inflammatory Diseases ◽  
Cell Types ◽  
Oxygen Electrode ◽  
Experimental Models ◽  
Human Neutrophils ◽  
Experimental Conditions

Stimulated human neutrophils exhibit increased net oxygen consumption (NOC) due to the conversion of O2 into the superoxide anion by the NADPH oxidase enzymatic complex during the respiratory burst. In several inflammatory diseases, overproduction of these oxidants causes tissue damage. The present study aims to: (a) optimize the experimental conditions used to measure the NOC in serum-opsonized zymosan (OZ)-and insoluble immune complex (i-IC)-stimulated human and rabbit neutrophils; and (b) compare the effect of four flavonols (quercetin, myricetin, kaempferol, and galangin) on this activity. We used a Clark-type oxygen electrode to measure the NOC of stimulated neutrophils. Eliciting the neutrophil respiratory burst with OZ and i-IC yielded similar maximum O2 uptake levels within the same species, but the human neutrophil NOC was almost four times higher than the rabbit neutrophil NOC. The optimal experimental conditions established for both cell types were 4·106 neutrophils mL-1, 2 mg mL-1 OZ, and 240 µg mL-1 i-IC. Upon stimulation with OZ or i-IC, the tested flavonols reduced the human and rabbit neutrophil NOC in the same order of potency - quercetin and galangin were the most and the least potent, respectively. These compounds were around four times more effective in inhibiting the rabbit as compared to the human neutrophil NOC, respectively. The four flavonols were not toxic to human or rabbit neutrophils. The experimental conditions used are suitable for both the determination of human and rabbit neutrophil NOC and for the assessment of the modulatory effects of natural compounds on these activities. The relationship between the level of NOC and the inhibitory potency of the flavonols suggests that rabbit neutrophils can be useful experimental models to predict the effect of drugs on immune complexstimulated human neutrophils.

Nuclear receptor Nur77: its role in chronic inflammatory diseases

2021 ◽  
Author(s):  
Sanne C. Lith ◽  
Carlie J.M. de Vries
Keyword(s):  
Nuclear Receptor ◽  
Inflammatory Disease ◽  
Inflammatory Responses ◽  
Current Knowledge ◽  
Inflammatory Diseases ◽  
Cell Types ◽  
Experimental Models ◽  
Therapeutic Interventions ◽  
Alternative Mechanism ◽  
Signaling Complex

Abstract Nur77 is a nuclear receptor that has been implicated as a regulator of inflammatory disease. The expression of Nur77 increases upon stimulation of immune cells and is differentially expressed in chronically inflamed organs in human and experimental models. Furthermore, in a variety of animal models dedicated to study inflammatory diseases, changes in Nur77 expression alter disease outcome. The available studies comprise a wealth of information on the function of Nur77 in diverse cell types and tissues. Negative cross-talk of Nur77 with the NFκB signaling complex is an example of Nur77 effector function. An alternative mechanism of action has been established, involving Nur77-mediated modulation of metabolism in macrophages as well as in T cells. In this review, we summarize our current knowledge on the role of Nur77 in atherosclerosis, inflammatory bowel disease, multiple sclerosis, rheumatoid arthritis, and sepsis. Detailed insight in the control of inflammatory responses will be essential in order to advance Nur77-targeted therapeutic interventions in inflammatory disease.

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