Hamp Type-1 Promotes Antimicrobial Defense via Direct Microbial Killing and Regulating Iron Metabolism in Grass Carp (Ctenopharyngodon idella)

Hepcidin is an antimicrobial peptide and regulator of iron homeostasis which has two isoforms in most fishes and some mammals. Previous studies have reported that the two hepcidin isoforms have different roles. Hamp type-1 plays a regulatory role in iron metabolism and hamp type-2 mostly performs an antimicrobial role. In this study, we found that Ctenopharyngodon idella (C. idella) have only one hepcidin isoform (hamp type-1), which showed both broad-spectrum antibacterial and iron regulatory functions. C. idella hepcidin mature peptide (hepcidin-25) and truncated peptide (hepcidin-20) exhibited bactericidal activities against both Gram-positive and Gram-negative bacteria in a dose-dependent manner in part through membrane rupture and binding to bacterial genomic DNA. The data from challenge tests demonstrated that the administration of hepcidin-25 significantly reduced mortality rates of C. idella by A. hydrophila infection, probably due to direct bactericidal activities of the peptide and a reduction of iron content in the fish serum. In addition, a comparison between hepcidin-20 and -25 suggests that the N terminal 5 amino acids play a critical role in reducing iron content in fish serum. Our findings revealed an important role of hamp type-1 in maintaining iron homeostasis and fighting against bacterial infections, suggesting the hepcidin has implications for the prevention and control of bacterial infection in aquaculture.

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Distinct Cytokine Profiles of Neonatal Natural Killer T Cells after Expansion with Subsets of Dendritic Cells

Journal of Experimental Medicine ◽

10.1084/jem.193.10.1221 ◽

2001 ◽

Vol 193 (10) ◽

pp. 1221-1226 ◽

Cited By ~ 118

Author(s):

Norimitsu Kadowaki ◽

Svetlana Antonenko ◽

Stephen Ho ◽

Marie-Clotilde Rissoan ◽

Vassili Soumelis ◽

...

Keyword(s):

T Cells ◽

Dendritic Cells ◽

Natural Killer ◽

Critical Role ◽

Nkt Cells ◽

Dependent Manner ◽

Helper Cell Type ◽

Ifn Γ ◽

Natural Killer T

Natural killer T (NKT) cells are a highly conserved subset of T cells that have been shown to play a critical role in suppressing T helper cell type 1–mediated autoimmune diseases and graft versus host disease in an interleukin (IL)-4–dependent manner. Thus, it is important to understand how the development of IL-4– versus interferon (IFN)-γ–producing NKT cells is regulated. Here, we show that NKT cells from adult blood and those from cord blood undergo massive expansion in cell numbers (500–70,000-fold) during a 4-wk culture with IL-2, IL-7, phytohemagglutinin, anti-CD3, and anti-CD28 mAbs. Unlike adult NKT cells that preferentially produce both IL-4 and IFN-γ, neonatal NKT cells preferentially produce IL-4 after polyclonal activation. Addition of type 2 dendritic cells (DC2) enhances the development of neonatal NKT cells into IL-4+IFN-γ− NKT2 cells, whereas addition of type 1 dendritic cells (DC1) induces polarization towards IL-4−IFN-γ+ NKT1 cells. Adult NKT cells display limited plasticity for polarization induced by DC1 or DC2. Thus, newly generated NKT cells may possess the potent ability to develop into IL-4+IFN-γ− NKT2 cells in response to appropriate stimuli and may thereafter acquire the tendency to produce both IL-4 and IFN-γ.

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Angiotensin II plays a critical role in diabetic pulmonary fibrosis most likely via activation of NADPH oxidase-mediated nitrosative damage

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00629.2010 ◽

2011 ◽

Vol 301 (1) ◽

pp. E132-E144 ◽

Cited By ~ 34

Author(s):

Junling Yang ◽

Yi Tan ◽

Fenglian Zhao ◽

Zhongsen Ma ◽

Yuehui Wang ◽

...

Keyword(s):

Angiotensin Ii ◽

Nadph Oxidase ◽

Lung Fibrosis ◽

Critical Role ◽

Receptor Expression ◽

Lung Fibroblasts ◽

Dependent Manner ◽

Ang Ii ◽

Diabetic Mice

Diabetic patients have a high risk of pulmonary disorders that are usually associated with restrictive impairment of lung function, suggesting a fibrotic process (van den Borst B, Gosker HR, Zeegers MP, Schols AM. Chest 138: 393–406, 2010; Ehrlich SF, Quesenberry CP Jr, Van Den Eeden SK, Shan J, Ferrara A. Diabetes Care 33: 55–60, 2010). The present study was undertaken to define whether and how diabetes causes lung fibrosis. Lung samples from streptozotocin-induced type 1 diabetic mice, spontaneously developed type 1 diabetic OVE26 mice, and their age-matched controls were investigated with histopathological and biochemical analysis. Signaling mechanism was investigated with cultured normal human lung fibroblasts in vitro. In both diabetes models, histological examination with Sirius red and hemotoxylin and eosin stains showed fibrosis along with massive inflammatory cell infiltration. The fibrotic and inflammatory processes were confirmed by real-time PCR and Western blotting assays for the increased fibronectin, CTGF, PAI-1, and TNFα mRNA and protein expressions. Diabetes also significantly increased NADPH oxidase (NOX) expression and protein nitration along with upregulation of angiotensin II (Ang II) and its receptor expression. In cell culture, exposure of lung fibroblasts to Ang II increased CTGF expression in a dose- and time-dependent manner, which could be abolished by inhibition of superoxide, NO, and peroxynitrite accumulation. Furthermore, chronic infusion of Ang II to normal mice at a subpressor dose induced diabetes-like lung fibrosis, and Ang II receptor AT1 blocker (losartan) abolished the lung fibrotic and inflammatory responses in diabetic mice. These results suggest that Ang II plays a critical role in diabetic lung fibrosis, which is most likely caused by NOX activation-mediated nitrosative damage.

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Iron homeostasis and plant immune responses: Recent insights and translational implications

Journal of Biological Chemistry ◽

10.1074/jbc.rev120.010856 ◽

2020 ◽

Vol 295 (39) ◽

pp. 13444-13457 ◽

Cited By ~ 1

Author(s):

John H. Herlihy ◽

Terri A. Long ◽

John M. McDowell

Keyword(s):

Iron Deficiency ◽

Iron Metabolism ◽

Iron Homeostasis ◽

Iron Acquisition ◽

Plant Immunity ◽

Critical Role ◽

Critical Factor ◽

Hormone Signaling ◽

Natural Ecosystems ◽

Oxygen Intermediates

Iron metabolism and the plant immune system are both critical for plant vigor in natural ecosystems and for reliable agricultural productivity. Mechanistic studies of plant iron home-ostasis and plant immunity have traditionally been carried out in isolation from each other; however, our growing understanding of both processes has uncovered significant connections. For example, iron plays a critical role in the generation of reactive oxygen intermediates during immunity and has been recently implicated as a critical factor for immune-initiated cell death via ferroptosis. Moreover, plant iron stress triggers immune activation, suggesting that sensing of iron depletion is a mechanism by which plants recognize a pathogen threat. The iron deficiency response engages hormone signaling sectors that are also utilized for plant immune signaling, providing a probable explanation for iron-immunity cross-talk. Finally, interference with iron acquisition by pathogens might be a critical component of the immune response. Efforts to address the global burden of iron deficiency–related anemia have focused on classical breeding and transgenic approaches to develop crops biofortified for iron content. However, our improved mechanistic understanding of plant iron metabolism suggests that such alterations could promote or impede plant immunity, depending on the nature of the alteration and the virulence strategy of the pathogen. Effects of iron biofortification on disease resistance should be evaluated while developing plants for iron biofortification.

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Mechanism Underlying the Iron-dependent Nuclear Export of the Iron-responsive Transcription Factor Aft1p in Saccharomyces cerevisiae

Molecular Biology of the Cell ◽

10.1091/mbc.e06-11-1054 ◽

2007 ◽

Vol 18 (8) ◽

pp. 2980-2990 ◽

Cited By ~ 71

Author(s):

Ryo Ueta ◽

Naoko Fujiwara ◽

Kazuhiro Iwai ◽

Yuko Yamaguchi-Iwai

Keyword(s):

Saccharomyces Cerevisiae ◽

Intermolecular Interaction ◽

Nuclear Import ◽

Nuclear Export ◽

Iron Homeostasis ◽

Target Genes ◽

Critical Role ◽

Dependent Manner ◽

Constitutive Activation ◽

Nuclear Export Receptor

Aft1p is an iron-responsive transcriptional activator that plays a central role in maintaining iron homeostasis in Saccharomyces cerevisiae. Aft1p is regulated primarily by iron-induced shuttling of the protein between the nucleus and cytoplasm, but its nuclear import is not regulated by iron. Here, we have shown that the nuclear export of Aft1p is promoted in the presence of iron and that Msn5p is the nuclear export receptor (exportin) for Aft1p. Msn5p recognizes Aft1p in the iron-replete condition. Phosphorylation of S210 and S224 in Aft1p, which is not iron dependent, and the iron-induced intermolecular interaction of Aft1p are both essential for its recognition by Msn5p. Mutation of Cys291 of Aft1p to Phe, which causes Aft1p to be retained in the nucleus and results in constitutive activation of Aft1-target genes, disrupts the intermolecular interaction of Aft1p. Collectively, these results suggest that iron induces a conformational change in Aft1p, in which Aft1p Cys291 plays a critical role, and that, in turn, Aft1p is recognized by Msn5p and exported into the cytoplasm in an iron-dependent manner.

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The mitochondrial ABC transporter Atm1 plays a role in iron metabolism and virulence in the human fungal pathogen Cryptococcus neoformans

Medical Mycology ◽

10.1093/mmy/myx073 ◽

2017 ◽

Vol 56 (4) ◽

pp. 458-468 ◽

Cited By ~ 11

Author(s):

Eunsoo Do ◽

Seho Park ◽

Ming-Hui Li ◽

Jia-Mei Wang ◽

Chen Ding ◽

...

Keyword(s):

Cryptococcus Neoformans ◽

Abc Transporter ◽

Iron Metabolism ◽

Fungal Pathogen ◽

Iron Homeostasis ◽

Critical Role ◽

Yeast Saccharomyces Cerevisiae ◽

Cellular Processes ◽

Human Fungal Pathogen ◽

Mitochondrial Functions

Abstract Iron–sulfur clusters (ISC) are indispensable cofactors for essential enzymes in various cellular processes. In the model yeast Saccharomyces cerevisiae, the precursor of ISCs is exported from mitochondria via a mitochondrial ABC transporter Atm1 and used for cytosolic and nuclear ISC protein assembly. Although iron homeostasis has been implicated in the virulence of the human fungal pathogen Cryptococcus neoformans, the key components of the ISC biosynthesis pathway need to be fully elucidated. In the current study, a homolog of S. cerevisiae Atm1 was identified in C. neoformans, and its function was characterized. We constructed C. neoformans mutants lacking ATM1 and found that deletion of ATM1 affected mitochondrial functions. Furthermore, we observed diminished activity of the cytosolic ISC-containing protein Leu1 and the heme-containing protein catalase in the atm1 mutant. These results suggested that Atm1 is required for the biosynthesis of ISCs in the cytoplasm as well as heme metabolism in C. neoformans. In addition, the atm1 mutants were avirulent in a murine model of cryptococcosis. Overall, our results demonstrated that Atm1 plays a critical role in iron metabolism and virulence for C. neoformans.

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Effects of phosphodiesterase inhibitors on cytokine production by microglia

Multiple Sclerosis Journal ◽

10.1177/135245859900500210 ◽

1999 ◽

Vol 5 (2) ◽

pp. 126-133 ◽

Cited By ~ 59

Author(s):

Minka Yoshikawa ◽

Akio Suzumura ◽

Tsukasa Tamaru ◽

Tetsuya Takayanagi ◽

Makato Sawada

Keyword(s):

Neurological Diseases ◽

Interleukin 1 ◽

Mrna Level ◽

Critical Role ◽

Phosphodiesterase Inhibitors ◽

Dependent Manner ◽

Tnf Α ◽

The Central Nervous System ◽

Pass Through

Type III and IV phosphodiesterase inhibitors (PDEIs) have recently been shown to suppress the production of TNF-α in several types of cells. In the present study, we have shown that all the types of PDEIs, from type 1- to V-specific and non-specific, suppress the production of TNF-α by mouse microglia stimulated with lipopolysaccharide (LPS) in a dose-dependent manner. Certain combinations of three different types of PDEIs synergistically suppressed TNF-α production by microglia at a very low concentration (1 μM). Since some PDEIs reportedly pass through the blood-brain barrier (BBB), the combination of three PDEIs may be worth trying in neurological diseases, such as multiple sclerosis and HIV-related neurological diseases in which TNF-α may play a critical role. Some PDEIs also suppressed interleukin-1 (IL-1) and IL-6 production by mouse microglia stimulated with LPS. In contrast, the production of IL-10, which is known to be an inhibitory cytokine, was upregulated by certain PDEIs. The suppression of TNF-α and induction of IL-10 were confirmed at the mRNA level by RT - PCR. PDEIs may be useful anti-inflammatory agents by downregulating inflammatory cytokines and upregulating inhibitory cytokines in the central nervous system. (CNS).

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Diet-Induced Non-anemic Iron Deficiency Attenuates Adaptive Thermogenesis via Defective Iron Metabolism of Adipose Tissue in C57BL/6 Mice

Current Developments in Nutrition ◽

10.1093/cdn/nzab059_031 ◽

2021 ◽

Vol 5 (Supplement_2) ◽

pp. 1330-1330

Author(s):

Jin-Seon Yook ◽

Shalom Sara Thomas ◽

Soonkyu Chung

Keyword(s):

Adipose Tissue ◽

Iron Deficiency ◽

Heat Release ◽

Serum Ferritin ◽

Iron Metabolism ◽

Iron Content ◽

Critical Role ◽

Dietary Iron ◽

Adaptive Thermogenesis ◽

Tissue Browning

Abstract Objectives Iron deficiency is one of the most common nutrient deficiencies worldwide. Adaptive thermogenesis plays a critical role for maintaining energy homeostasis. Currently, the role of dietary iron deficiency on adaptive thermogenesis is unknown. We hypothesized that dietary iron deficiency attenuates adaptive thermogenesis via dysfunctional iron metabolism in adipose tissue. Methods C57BL/6 male mice were fed a diet containing either adequate-iron (Cont: 35ppm) or deficient-iron (ID: 3ppm) throughout for 14 weeks and the last 10 weeks were fed a high-fat diet to induce obesity. Systemic iron status was evaluated by measuring serum ferritin, hemoglobin (Hb), and hematocrit (HCt). The iron content of adipose tissue was determined by ICP-MS spectrometer. The protein and gene expressions related to iron-handling and thermogenesis were measured in adipose tissue by Western blot analysis and qPCR. To assess adaptive thermogenic function, mice were exposed to cold temperature acutely (3 hour) or administrated with β3-adrenoceptor agonist (CL) for 5 days. The core body temperature and thermogenesis were determined by a rectal thermometer and infrared camera, respectively. Results The ID mice displayed a non-anemic iron deficiency with reduced serum ferritin (p < 0.01), increased weight gain (p < 0.05) and decreased insulin sensitivity (p < 0.05) compared to Cont. The iron content was significantly reduced in the inguinal (iWAT, p < 0.05) of the ID mice, which was linked with reduced thermogenic heat release upon acute cold treatment. In addition, ID mice markedly reduced the adipose tissue browning and thermogenic heat release upon CL stimulation compared with Cont. In terms of iron metabolism, CL-induced coordinated iron uptake for mitochondrial biogenesis in the iWAT was impaired in the ID mice, which was comparable to inflammation-mediated defective adipose tissue browning and thermogenesis. Conclusions Iron deficiency induced visceral obesity and compromised thermogenic function due to defective iron metabolism in C57BL6 mice. Funding Sources National Institutes of Health Grant 1R21HD094273.

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Regular Physical Exercise Modulates Iron Homeostasis in the 5xFAD Mouse Model of Alzheimer’s Disease

International Journal of Molecular Sciences ◽

10.3390/ijms22168715 ◽

2021 ◽

Vol 22 (16) ◽

pp. 8715

Author(s):

Irina Belaya ◽

Nina Kucháriková ◽

Veronika Górová ◽

Kai Kysenius ◽

Dominic J. Hare ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Physical Exercise ◽

Mouse Model ◽

Iron Metabolism ◽

Iron Content ◽

Iron Homeostasis ◽

Regular Exercise ◽

5Xfad Mouse ◽

The Brain ◽

Regular Physical Exercise

Dysregulation of brain iron metabolism is one of the pathological features of aging and Alzheimer’s disease (AD), a neurodegenerative disease characterized by progressive memory loss and cognitive impairment. While physical inactivity is one of the risk factors for AD and regular exercise improves cognitive function and reduces pathology associated with AD, the underlying mechanisms remain unclear. The purpose of the study is to explore the effect of regular physical exercise on modulation of iron homeostasis in the brain and periphery of the 5xFAD mouse model of AD. By using inductively coupled plasma mass spectrometry and a variety of biochemical techniques, we measured total iron content and level of proteins essential in iron homeostasis in the brain and skeletal muscles of sedentary and exercised mice. Long-term voluntary running induced redistribution of iron resulted in altered iron metabolism and trafficking in the brain and increased iron content in skeletal muscle. Exercise reduced levels of cortical hepcidin, a key regulator of iron homeostasis, coupled with interleukin-6 (IL-6) decrease in cortex and plasma. We propose that regular exercise induces a reduction of hepcidin in the brain, possibly via the IL-6/STAT3/JAK1 pathway. These findings indicate that regular exercise modulates iron homeostasis in both wild-type and AD mice.

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Sideroflexin 4 affects Fe-S cluster biogenesis, iron metabolism, mitochondrial respiration and heme biosynthetic enzymes

Scientific Reports ◽

10.1038/s41598-019-55907-z ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 5

Author(s):

Bibbin T. Paul ◽

Lia Tesfay ◽

C. R. Winkler ◽

Frank M. Torti ◽

Suzy V. Torti

Keyword(s):

Iron Metabolism ◽

Mitochondrial Respiration ◽

Iron Homeostasis ◽

Cluster Formation ◽

Critical Role ◽

Mitochondrial Respiratory Chain ◽

Phenotypic Characteristics ◽

Respiratory Chain Complexes ◽

Chain Complexes ◽

The Stability

AbstractSideroflexin4 (SFXN4) is a member of a family of nuclear-encoded mitochondrial proteins. Rare germline mutations in SFXN4 lead to phenotypic characteristics of mitochondrial disease including impaired mitochondrial respiration and hematopoetic abnormalities. We sought to explore the function of this protein. We show that knockout of SFXN4 has profound effects on Fe-S cluster formation. This in turn diminishes mitochondrial respiratory chain complexes and mitochondrial respiration and causes a shift to glycolytic metabolism. SFXN4 knockdown reduces the stability and activity of cellular Fe-S proteins, affects iron metabolism by influencing the cytosolic aconitase–IRP1 switch, redistributes iron from the cytosol to mitochondria, and impacts heme synthesis by reducing levels of ferrochelatase and inhibiting translation of ALAS2. We conclude that SFXN4 is essential for normal functioning of mitochondria, is necessary for Fe-S cluster biogenesis and iron homeostasis, and plays a critical role in mitochondrial respiration and synthesis of heme.

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Conventional type 1 dendritic cells protect against age-related adipose tissue dysfunction and obesity

Cellular and Molecular Immunology ◽

10.1038/s41423-021-00812-7 ◽

2022 ◽

Author(s):

Elena Hernández-García ◽

Francisco J. Cueto ◽

Emma C. L. Cook ◽

Ana Redondo-Urzainqui ◽

Sara Charro-Zanca ◽

...

Keyword(s):

Dendritic Cells ◽

Adipose Tissue ◽

Critical Role ◽

Liver Steatosis ◽

Dependent Manner ◽

Inkt Cells ◽

Immune Balance ◽

Age Related ◽

Conventional Type

AbstractConventional dendritic cells (cDCs) scan and integrate environmental cues in almost every tissue, including exogenous metabolic signals. While cDCs are critical in maintaining immune balance, their role in preserving energy homeostasis is unclear. Here, we showed that Batf3-deficient mice lacking conventional type 1 DCs (cDC1s) had increased body weight and adiposity during aging. This led to impaired energy expenditure and glucose tolerance, insulin resistance, dyslipidemia, and liver steatosis. cDC1 deficiency caused adipose tissue inflammation that was preceded by a paucity of NK1.1+ invariant NKT (iNKT) cells. Accordingly, among antigen-presenting cells, cDC1s exhibited notable induction of IFN-γ production by iNKT cells, which plays a metabolically protective role in lean adipose tissue. Flt3L treatment, which expands the dendritic cell (DC) compartment, mitigated diet-induced obesity and hyperlipidemia in a Batf3-dependent manner. This effect was partially mediated by NK1.1+ cells. These results reveal a new critical role for the cDC1-iNKT cell axis in the regulation of adipose tissue homeostasis.

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