IL-6 Regulates Hepcidin Expression Via the BMP/SMAD Pathway by Altering BMP6, TMPRSS6 and TfR2 Expressions at Normal and Inflammatory Conditions in BV2 Microglia

Varga, Edit; Pap, Ramóna; Jánosa, Gergely; Sipos, Katalin; Pandur, Edina

doi:10.1007/s11064-021-03322-0

Cited by 25 publications

(14 citation statements)

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“…Neuron-microglia communication is involved not only in the energy balance and inflammation but also in the regulation of iron homeostasis via the FKN/CX3CR1 axis [ 7 , 17 ]. FKN and pro-inflammatory cytokines such as IL-6, increase cellular iron retention by elevating HAMP expression and triggering FP internalisation contributing to iron-mediated toxicity and neuronal cell death [ 17 , 65 , 66 ]. Our observations correlate with our previous results that the mRNA level of HAMP significantly increased, and FP was eliminated from the plasma membrane in the STZ-treated hypothalamus suggesting iron accumulation.…”

Section: Discussionmentioning

confidence: 99%

Alterations of the expression levels of glucose, inflammation, and iron metabolism related miRNAs and their target genes in the hypothalamus of STZ-induced rat diabetes model

Pandur

Szabó

Hormay

et al. 2022

Diabetol Metab Syndr

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Background The hypothalamus of the central nervous system is implicated in the development of diabetes due to its glucose-sensing function. Dysregulation of the hypothalamic glucose-sensing neurons leads to abnormal glucose metabolism. It has been described that fractalkine (FKN) is involved in the development of hypothalamic inflammation, which may be one of the underlying causes of a diabetic condition. Moreover, iron may play a role in the pathogenesis of diabetes via the regulation of hepcidin, the iron regulatory hormone synthesis. MicroRNAs (miRNAs) are short non-coding molecules working as key regulators of gene expression, usually by inhibiting translation. Hypothalamic miRNAs are supposed to have a role in the control of energy balance by acting as regulators of hypothalamic glucose metabolism via influencing translation. Methods Using a miRNA array, we analysed the expression of diabetes, inflammation, and iron metabolism related miRNAs in the hypothalamus of a streptozotocin-induced rat type 1 diabetes model. Determination of the effect of miRNAs altered by STZ treatment on the target genes was carried out at protein level. Results We found 18 miRNAs with altered expression levels in the hypothalamus of the STZ-treated animals, which act as the regulators of mRNAs involved in glucose metabolism, pro-inflammatory cytokine synthesis, and iron homeostasis suggesting a link between these processes in diabetes. The alterations in the expression level of these miRNAs could modify hypothalamic glucose sensing, tolerance, uptake, and phosphorylation by affecting the stability of hexokinase-2, insulin receptor, leptin receptor, glucokinase, GLUT4, insulin-like growth factor receptor 1, and phosphoenolpyruvate carboxykinase mRNA molecules. Additional miRNAs were found to be altered resulting in the elevation of FKN protein. The miRNA, mRNA, and protein analyses of the diabetic hypothalamus revealed that the iron import, export, and iron storage were all influenced by miRNAs suggesting the disturbance of hypothalamic iron homeostasis. Conclusion It can be supposed that glucose metabolism, inflammation, and iron homeostasis of the hypothalamus are linked via the altered expression of common miRNAs as well as the increased expression of FKN, which contribute to the imbalance of energy homeostasis, the synthesis of pro-inflammatory cytokines, and the iron accumulation of the hypothalamus. The results raise the possibility that FKN could be a potential target of new therapies targeting both inflammation and iron disturbances in diabetic conditions. Graphical Abstract

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Section: Discussionmentioning

confidence: 99%

Alterations of the expression levels of glucose, inflammation, and iron metabolism related miRNAs and their target genes in the hypothalamus of STZ-induced rat diabetes model

Pandur

Szabó

Hormay

et al. 2022

Diabetol Metab Syndr

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“…IL-6 affect iron levels in cells by controlling the transcription of hepcidin which is a short cysteine-rich peptide hormone that can influence intestinal absorption and the release of iron in macrophages Fe stores. The transcription of hepcidin is mediated by IL-6 via the activation of JAK-STAT3 pathway [ 43 , 44 ], and the expression of hepcidin is found to be activated by BMP/SMAD pathway [ 45 ]. Hepcidin first binds to ferroportin (FPN) and cause internalization of hepcidin-FPN that is soon degraded into lysosomes [ 46 ].…”

Section: Interaction Between Ferroptosis and Macrophagesmentioning

confidence: 99%

Interaction between macrophages and ferroptosis

et al. 2022

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Ferroptosis, a newly discovered iron-dependent cell death pathway, is characterized by lipid peroxidation and GSH depletion mediated by iron metabolism and is morphologically, biologically and genetically different from other programmed cell deaths. Besides, ferroptosis is usually found accompanied by inflammatory reactions. So far, it has been found participating in the development of many kinds of diseases. Macrophages are a group of immune cells that widely exist in our body for host defense and play an important role in tissue homeostasis by mediating inflammation and regulating iron, lipid and amino acid metabolisms through their unique functions like phagocytosis and efferocytosis, cytokines secretion and ROS production under different polarization. According to these common points in ferroptosis characteristics and macrophages functions, it’s obvious that there must be relationship between macrophages and ferroptosis. Therefore, our review aims at revealing the interaction between macrophages and ferroptosis concerning three metabolisms and integrating the application of certain relationship in curing diseases, mostly cancer. Finally, we also provide inspirations for further studies in therapy for some diseases by targeting certain resident macrophages in distinct tissues to regulate ferroptosis. Facts Ferroptosis is considered as a newly discovered form characterized by its nonapoptotic and iron-dependent lipid hydroperoxide, concerning iron, lipid and amino acid metabolisms. Ferroptosis has been widely found playing a crucial part in various diseases, including hepatic diseases, neurological diseases, cancer, etc. Macrophages are phagocytic immune cells, widely existing and owning various functions such as phagocytosis and efferocytosis, cytokines secretion and ROS production. Macrophages are proved to participate in mediating metabolisms and initiating immune reactions to maintain balance in our body. Recent studies try to treat cancer by altering macrophages’ polarization which damages tumor microenvironment and induces ferroptosis of cancer cells. Open questions How do macrophages regulate ferroptosis of other tissue cells specifically? Can we use the interaction between macrophages and ferroptosis in treating diseases other than cancer? What can we do to treat diseases related to ferroptosis by targeting macrophages? Is the use of the relationship between macrophages and ferroptosis more effective than other therapies when treating diseases?

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“…HAMP gene expression is upregulated by iron overload, inflammation, and decreased iron‐deficient states, and hypoxia 26 . Iron affects gene expression via BMP/SMAD pathways, while inflammation and IL‐6 utilize the JAK/STAT pathway 27 . Iron is essential for high load viruses including SARS‐CoV‐2, which is inhibited by iron chelators in‐vitro 28 .…”

Section: Introductionmentioning

confidence: 99%

“… 26 Iron affects gene expression via BMP/SMAD pathways, while inflammation and IL‐6 utilize the JAK/STAT pathway. 27 Iron is essential for high load viruses including SARS‐CoV‐2, which is inhibited by iron chelators in‐vitro. 28 But excess intracellular iron accumulations lead to apoptosis (ferroptosis) as seen in COVID‐19 patient biopsies.…”

Section: Introductionmentioning

confidence: 99%

Iron dysregulation in COVID‐19 and reciprocal evolution of SARS‐CoV‐2: Natura nihil frustra facit

Gupta

Maciorowski

Medernach

et al. 2022

J of Cellular Biochemistry

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After more than a year of the COVID-19 pandemic, SARS-CoV-2 infection rates with newer variants continue to devastate much of the world. Global healthcare systems are overwhelmed with high positive patient numbers.Silent hypoxia accompanied by rapid deterioration and some cases with septic shock is responsible for COVID-19 mortality in many hospitalized patients.There is an urgent need to further understand the relationships and interplay with human host components during pathogenesis and immune evasion strategies. Currently, acquired immunity through vaccination or prior infection usually provides sufficient protection against the emerging variants of SARS-CoV-2 except Omicron variant requiring recent booster. New strains have shown higher viral loads and greater transmissibility with more severe disease presentations. Notably, COVID-19 has a peculiar prognosis in severe patients with iron dysregulation and hypoxia which is still poorly understood. Studies have shown abnormally low serum iron levels in severe infection but a high iron overload in lung fibrotic tissue. Data from our in-silico structural analysis of the spike protein sequence along with host proteolysis processing suggests that the viral spike protein fragment mimics Hepcidin and is resistant to the major human proteases. This functional spike-derived peptide dubbed "Covidin" thus may be intricately involved with host ferroportin binding and internalization leading to dysregulated host iron metabolism. Here, we propose the possible role of this potentially allogenic mimetic hormone corresponding to severe COVID-19 immunopathology and illustrate that this molecular mimicry is responsible for a major pathway associated with severe disease status. Furthermore, through 3D molecular modeling and docking followed by MD simulation validation, we have unraveled the likely role of Covidin in iron dysregulation in COVID-19 patients. Our meta-analysis suggests the Hepcidin mimetic mechanism is highly conserved among its host range as well as among all new variants to date including Omicron. Extensive analysis of current mutations revealed that new variants are becoming

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IL-6 Regulates Hepcidin Expression Via the BMP/SMAD Pathway by Altering BMP6, TMPRSS6 and TfR2 Expressions at Normal and Inflammatory Conditions in BV2 Microglia

Cited by 25 publications

References 82 publications

Alterations of the expression levels of glucose, inflammation, and iron metabolism related miRNAs and their target genes in the hypothalamus of STZ-induced rat diabetes model

Alterations of the expression levels of glucose, inflammation, and iron metabolism related miRNAs and their target genes in the hypothalamus of STZ-induced rat diabetes model

Interaction between macrophages and ferroptosis

Iron dysregulation in COVID‐19 and reciprocal evolution of SARS‐CoV‐2: Natura nihil frustra facit

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