scholarly journals New Insights into the Pivotal Role of Iron/Heme Metabolism in TLR4/NF-κB Signaling-Mediated Inflammatory Responses in Human Monocytes

Cells ◽  
2021 ◽  
Vol 10 (10) ◽  
pp. 2549
Author(s):  
Dong Young Kang ◽  
Nipin Sp ◽  
Eun Seong Jo ◽  
Jin-Moo Lee ◽  
Kyoung-Jin Jang
Keyword(s):  
Iron Metabolism ◽  
High Glucose ◽  
Aminolevulinic Acid ◽  
Inflammatory Responses ◽  
Heme Biosynthesis ◽  
Heme Synthesis ◽  
Heme Metabolism ◽  
Inflammatory Conditions ◽  
Iron Heme

Iron metabolism and heme biosynthesis are essential processes in cells during the energy cycle. Alteration in these processes could create an inflammatory condition, which results in tumorigenesis. Studies are conducted on the exact role of iron/heme metabolism in induced inflammatory conditions. This study used lipopolysaccharide (LPS)- or high-glucose-induced inflammation conditions in THP-1 cells to study how iron/heme metabolism participates in inflammatory responses. Here, we used iron and heme assays for measuring total iron and heme. We also used flow cytometry and Western blotting to analyze molecular responses. Our results demonstrated that adding LPS or high-glucose induced iron formation and heme synthesis and elevated the expression levels of proteins responsible for iron metabolism and heme synthesis. We then found that further addition of heme or 5-aminolevulinic acid (ALA) increased heme biosynthesis and promoted inflammatory responses by upregulating TLR4/NF-κB and inflammatory cytokine expressions. We also demonstrated the inhibition of heme synthesis using succinylacetone (SA). Moreover, N-MMP inhibited LPS- or high-glucose-induced inflammatory responses by inhibiting TLR4/NF-κB signaling. Hence, iron/heme metabolism checkpoints could be considered a target for treating inflammatory conditions.

Remodeling the regulation of iron metabolism during erythroid differentiation to ensure efficient heme biosynthesis

Blood ◽  
2006 ◽  
Vol 107 (10) ◽  
pp. 4159-4167 ◽  
Author(s):  
Matthias Schranzhofer ◽  
Manfred Schifrer ◽  
Javier Antonio Cabrera ◽  
Stephan Kopp ◽  
Peter Chiba ◽  
...  
Keyword(s):  
Iron Metabolism ◽  
Aminolevulinic Acid ◽  
Fetal Liver ◽  
Mrna Translation ◽  
Erythroid Differentiation ◽  
Heme Biosynthesis ◽  
Iron Storage ◽  
Iron Regulatory Proteins ◽  
Heme Synthesis ◽  
Mrna Binding

Terminal erythropoiesis is accompanied by extreme demand for iron to ensure proper hemoglobinization. Thus, erythroblasts must modify the “standard” post-transcriptional feedback regulation, balancing expression of ferritin (Fer; iron storage) versus transferrin receptor (TfR1; iron uptake) via specific mRNA binding of iron regulatory proteins (IRPs). Although erythroid differentiation involves high levels of incoming iron, TfR1 mRNA stability must be sustained and Fer mRNA translation must not be activated because iron storage would counteract hemoglobinization. Furthermore, translation of the erythroid-specific form of aminolevulinic acid synthase (ALAS-E) mRNA, catalyzing the first step of heme biosynthesis and regulated similarly as Fer mRNA by IRPs, must be ensured. We addressed these questions using mass cultures of primary murine erythroid progenitors from fetal liver, either undergoing sustained proliferation or highly synchronous differentiation. We indeed observed strong inhibition of Fer mRNA translation and efficient ALAS-E mRNA translation in differentiating erythroblasts. Moreover, in contrast to self-renewing cells, TfR1 stability and IRP mRNA binding were no longer modulated by iron supply. These and additional data stemming from inhibition of heme synthesis with succinylacetone or from iron overload suggest that highly efficient utilization of iron in mitochondrial heme synthesis during normal erythropoiesis alters the regulation of iron metabolism via the IRE/IRP system.

Abstract 307: Role of Epsins in Regulating LPS-Induced Sepsis

2015 ◽  
Vol 35 (suppl_1) ◽  
Author(s):  
Satish Pasula ◽  
Megan L Brophy ◽  
Kandice L Tessneer ◽  
Scott Hahn ◽  
John McManus ◽  
...  
Keyword(s):  
Inflammatory Responses ◽  
Tissue Injury ◽  
Lethal Dose ◽  
Surface Protein ◽  
Inflammatory Conditions ◽  
Fundamental Information ◽  
Subsequent Degradation ◽  
Surface Protein Expression ◽  
Deficient Mice

Background: Sepsis is caused by a deleterious host response to infection, which is primarily responsible for further injury of host tissue and cause of organ dysfunction. However, the underlying regulatory mechanisms are still not fully understood. Our goal is to define the novel role of epsins in regulating sepsis. Methods and Results: We engineered global (iDKO) and endothelial cell-specific (EC-iDKO) epsin deficient mice. When treated with lethal dose of LPS, epsin deficient mice were completely protected from LPS-induced septic death. These mice also exhibited decreased expression of tissue damage biomarkers and recruitment of neutrophils and macrophages to lungs compared to wild type (WT) suggesting that epsin deficiency mitigates sepsis induced tissue injury. Epsin deficiency further reduced expression of proinflammatory cytokines and adhesion molecules in the lungs suggesting that loss of epsin attenuates LPS-induced inflammatory responses. TAT complex production was also decreased in iDKO mice compared to WT indicating diminished coagulation and thrombin production. Knocking down of epsins in HUVECs resulted in reduced cell surface Tissue Factor (TF) expression. Loss of epsin in mice protected against loss of Thrombomodulin (TM), which is downregulated by sepsis. Mechanistically, loss of epsin inhibited LPS-induced TM internalization, while LPS treatment induced the ubiquitination of TM. Furthermore, co-IP of full length epsin 1 or epsin 1 without the UIM domain and TM demonstrated that UIM is required for the interaction between epsin 1 and TM. Collectively, we show that epsin-deficiency upregulates TM surface protein expression by preventing its internalization and subsequent degradation and inhibits heightened TF expression and activation under chronic inflammatory conditions such as that induced by LPS exposure. Conclusions: Our findings demonstrate that epsins play a key role in regulating coagulation and provide fundamental information on the modulation of the ratio of TM/TF in various thrombotic diseases including sepsis. Furthermore, we demonstrate loss of epsin protects mice against LPS-induced sepsis, suggesting a crucial role for epsins in promoting the development of LPS-induced sepsis.

The Proprotein Convertase Furin inhibits IL-13 Induced Inflammation in Airway Smooth Muscle by Regulating Integrin Associated Signaling Complexes

2021 ◽  
Author(s):  
Yidi Wu ◽  
Youliang Huang ◽  
Wenwu Zhang ◽  
Susan J. Gunst
Keyword(s):  
Smooth Muscle ◽  
Airway Smooth Muscle ◽  
Inflammatory Responses ◽  
Therapeutic Potential ◽  
Proprotein Convertase ◽  
Akt Activation ◽  
Inflammatory Conditions ◽  
Muscle Tissues ◽  
Muscle Myosin

Furin is a proprotein convertase that regulates the activation and inactivation of multiple proteins including matrix metalloproteinases, integrins and cytokines. It is a serine endoprotease that localizes to the plasma membrane and can be secreted into the extracellular space. The role of furin in regulating inflammation in isolated canine airway smooth muscle tissues was investigated. The treatment of airway tissues with recombinant furin (rFurin) inhibited the activation of Akt and eotaxin secretion induced by IL-13, and it prevented the IL-13 induced suppression of smooth muscle myosin heavy chain expression. rFurin promoted a differentiated phenotype by activating β1 integrin proteins and stimulating the activation of the adhesome proteins vinculin and paxillin by talin. Activated paxillin induced the binding of Akt to β-parvin IPP (ILK, PINCH, parvin) complexes, which inhibits Akt activation. Treatment of tissues with a furin inhibitor or the depletion of endogenous furin using shRNA resulted in Akt activation and inflammatory responses similar to those induced by IL-13. Furin inactivation or IL-13 caused talin cleavage and integrin inactivation, resulting in the inactivation of vinculin and paxillin. Paxillin inactivation resulted in the coupling of Akt to α-parvin IPP complexes, which catalyze Akt activation and an inflammatory response. The results demonstrate that furin inhibits inflammation in airway smooth muscle induced by IL-13, and that the anti-inflammatory effects of furin are mediated by activating integrin proteins and integrin-associated signaling complexes that regulate Akt-mediated pathways to the nucleus. Furin may have therapeutic potential for the treatment of inflammatory conditions of the lungs and airways.

scholarly journals PILOT RESEARCH OF A GENETIC PREDISPOSITION FOR CLINICAL MANIFESTATIONS OF ACUTE INTERMITTENT PORPHYRIA

2019 ◽  
Vol 64 (2) ◽  
pp. 123-137
Author(s):  
O. S. Pshenichnikova ◽  
M. V. Goncharova ◽  
Y. S. Pustovoit ◽  
I. V. Karpova ◽  
V. L. Surin
Keyword(s):  
Aminolevulinic Acid ◽  
Clinical Manifestations ◽  
Acute Intermittent Porphyria ◽  
Severe Form ◽  
Heme Biosynthesis ◽  
Whole Exome ◽  
Number Of Patients ◽  
Detoxification Systems ◽  
Illumina Hiseq4000

Introduction. Acute intermittent porphyria (AIP) is the most common and severe form of acute hepatic porphyria. AIP is caused by a deficiency in the third enzyme of the heme biosynthesis system — hydroxymethylbilanine synthase (HMBS) — and has a dominant inheritance type. However, the probability of the clinical manifestation of this condition in carriers of the mutation in the HMBS gene constitutes only 10–20 %. Thi s suggests that the presence of such a mutation can be a necessary but not a sufficient condition for the development of the disease.Aim. To search for additional genetic factors, which determine the clinical penetrance of AIP using Whole-Exome Sequencing.Materials and methods. Sequencing of the whole exome was performed using a TruSeqExomeLibraryPrepkit (Illumina) kit by an Illumina HiSeq4000 instrument for 6 women with API with known mutations in the HMBS gene. All the patients suffered from a severe form of the disease. As a reference, a version of the hg19 human genome was used.Results. No common mutations were found in the examined patients. However, in each patient, functional variations were found in the genes related to detoxification systems, regulation of the heme biosynthesis cascade and expression of delta-aminolevulinic acid synthase (ALAS1) and in genes of proteins regulating nervous system. These variations require further study involving an extended number of patients with AIP manifestations and their relatives, who are asymptomatic carriers of disorders in the gene HMBS.Conclusions. The results obtained have allowed us to formulate a hypothesis about a possible role of genetic defects in the penetrance of AIP, which determine the development of other neurological pathologies. This is evidenced by the presence of gene pathogenic variations in 5 out of 6 examined patients, defects in which are associated with hereditary myasthenia and muscle atrophy.

Toll-Like Receptor 4 (TLR4) and AMPK Relevance in Cardiovascular Disease

2021 ◽  
Author(s):  
Haleh Vaez ◽  
Hamid Soraya ◽  
Alireza Garjani ◽  
Tooba Gholikhani
Keyword(s):  
Cardiovascular Diseases ◽  
Inflammatory Responses ◽  
Inflammatory Diseases ◽  
Critical Role ◽  
Adenosine Monophosphate ◽  
Ampk Signaling ◽  
Inflammatory Conditions ◽  
Immune Mediated ◽  
Energy Sensor

Toll-like receptors (TLRs) are essential receptors of the innate immune system, playing a significant role in cardiovascular diseases. TLR4, with the highest expression among TLRs in the heart, has been investigated extensively for its critical role in different myocardial inflammatory conditions. Studies suggest that inhibition of TLR4 signaling pathways reduces inflammatory responses and even prevents additional injuries to the already damaged myocardium. Recent research results have led to a hypothesis that there may be a relation between TLR4 expression and 5' adenosine monophosphate-activated protein kinase (AMPK) signaling in various inflammatory conditions, including cardiovascular diseases. AMPK, as a cellular energy sensor, has been reported to show anti-inflammatory effects in various models of inflammatory diseases. AMPK, in addition to its physiological acts in the heart, plays an essential role in myocardial ischemia and hypoxia by activating various energy production pathways. Herein we will discuss the role of TLR4 and AMPK in cardiovascular diseases and a possible relation between TLRs and AMPK as a novel therapeutic target. In our opinion, AMPK-related TLR modulators will find application in treating different immune-mediated inflammatory disorders, especially inflammatory cardiac diseases, and present an option that will be widely used in clinical practice in the future.

scholarly journals Role of copper in mitochondrial iron metabolism

Blood ◽  
1976 ◽  
Vol 48 (1) ◽  
pp. 77-85 ◽  
Author(s):  
DM Williams ◽  
D Loukopoulos ◽  
GR Lee ◽  
GE Cartwright
Keyword(s):  
Cytochrome Oxidase ◽  
Iron Metabolism ◽  
Oxidase Activity ◽  
Ferrous Iron ◽  
Iron Uptake ◽  
Ferric Iron ◽  
Intracellular Iron ◽  
Cytochrome Oxidase Activity ◽  
Heme Synthesis

Abstract Heme synthesis by copper-deficient cells was investigated to elucidate the nature of the defect in intracellular iron metabolism. Iron uptake from transferrin by copper-deficient reticulocytes was 52% of normal, and the rate of heme synthesis was 33% of normal. Hepatic mitochondria isolated from copper-deficient animals were deficient in cytochrome oxidase activity and failed to synthesize heme from ferric iron (Fe III) and protoporphyrin at the normal rate. The rate of heme synthesis correlated with the cytochrome oxidase activity. Heme synthesis from Fe(III) and protoporphyrin by normal mitochondria was enhanced by succinate and inhibited by malonate, antimycin A, azide, and cyanide. It is proposed that an intact electron transport system is required for the reduction of Fe(III), thereby providing a pool of ferrous iron (Fe II) for protoheme and heme a synthesis.

scholarly journals The Role of Maresins in Inflammatory Pain: Function of Macrophages in Wound Regeneration

2019 ◽  
Vol 20 (23) ◽  
pp. 5849 ◽  
Author(s):  
Sung-Min Hwang ◽  
Gehoon Chung ◽  
Yong Ho Kim ◽  
Chul-Kyu Park
Keyword(s):  
Inflammatory Pain ◽  
Inflammatory Responses ◽  
M2 Macrophage ◽  
Macrophage Phenotype ◽  
New Class ◽  
Inflammatory Conditions ◽  
Signaling Mechanisms ◽  
Macrophage Phagocytosis ◽  
Anti Inflammatory

Although acute inflammatory responses are host-protective and generally self-limited, unresolved and delayed resolution of acute inflammation can lead to further tissue damage and chronic inflammation. The mechanism of pain induction under inflammatory conditions has been studied extensively; however, the mechanism of pain resolution is not fully understood. The resolution of inflammation is a biosynthetically active process, involving specialized pro-resolving mediators (SPMs). In particular, maresins (MaRs) are synthesized from docosahexaenoic acid (DHA) by macrophages and have anti-inflammatory and pro-resolving capacities as well as tissue regenerating and pain-relieving properties. A new class of macrophage-derived molecules—MaR conjugates in tissue regeneration (MCTRs)—has been reported to regulate phagocytosis and the repair and regeneration of damaged tissue. Macrophages not only participate in the biosynthesis of SPMs, but also play an important role in phagocytosis. They exhibit different phenotypes categorized as proinflammatory M1-like phenotypes and anti-inflammatory M2 phenotypes that mediate both harmful and protective functions, respectively. However, the signaling mechanisms underlying macrophage functions and phenotypic changes have not yet been fully established. Recent studies report that MaRs help resolve inflammatory pain by enhancing macrophage phagocytosis and shifting cytokine release to the anti-inflammatory M2 phenotypes. Consequently, this review elucidated the characteristics of MaRs and macrophages, focusing on the potent action of MaRs to enhance the M2 macrophage phenotype profiles that possess the ability to alleviate inflammatory pain.

scholarly journals IL-36 Cytokines: Regulators of Inflammatory Responses and Their Emerging Role in Immunology of Reproduction

2019 ◽  
Vol 20 (7) ◽  
pp. 1649 ◽  
Author(s):  
José Murrieta-Coxca ◽  
Sandra Rodríguez-Martínez ◽  
Mario Cancino-Diaz ◽  
Udo Markert ◽  
Rodolfo Favaro ◽  
...  
Keyword(s):  
Reproductive Tract ◽  
Inflammatory Responses ◽  
Current Knowledge ◽  
Female Reproductive Tract ◽  
Inflammatory Conditions ◽  
Immune Mediators ◽  
Dynamic Expression ◽  
Cellular Recruitment ◽  
Inflammatory Processes

The IL-36 subfamily of cytokines has been recently described as part of the IL-1 superfamily. It comprises three pro-inflammatory agonists (IL-36α, IL-36β, and IL-36γ), their receptor (IL-36R), and one antagonist (IL-36Ra). Although expressed in a variety of cells, the biological relevance of IL-36 cytokines is most evident in the communication between epithelial cells, dendritic cells, and neutrophils, which constitute the common triad responsible for the initiation, maintenance, and expansion of inflammation. The immunological role of IL-36 cytokines was initially described in studies of psoriasis, but novel evidence demonstrates their involvement in further immune and inflammatory processes in physiological and pathological situations. Preliminary studies have reported a dynamic expression of IL-36 cytokines in the female reproductive tract throughout the menstrual cycle, as well as their association with the production of immune mediators and cellular recruitment in the vaginal microenvironment contributing to host defense. In pregnancy, alteration of the placental IL-36 axis has been reported upon infection and pre-eclampsia suggesting its pivotal role in the regulation of maternal immune responses. In this review, we summarize current knowledge regarding the regulatory mechanisms and biological actions of IL-36 cytokines, their participation in different inflammatory conditions, and the emerging data on their potential role in normal and complicated pregnancies.

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