JNK facilitates IL-1β-induced hepcidin transcription via JunB activation

Kanamori, Yohei; Murakami, Masaru; Matsui, Tohru; Funaba, Masayuki

doi:10.1016/j.cyto.2018.09.014

Cited by 11 publications

(10 citation statements)

References 41 publications

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“…Previous studies showed that IL-1β upregulates CCAAT-enhancer binding protein (CEBP) δ through IL-6, which then stimulated hepcidin transcription via C/EBP-BS and CRE site B as well as STAT3-BS on the hepcidin promoter [43,44]. A novel regulation of hepcidin by IL-1β is revealed under low oxygen levels in hepatocytes.…”

Section: Discussionmentioning

confidence: 99%

IL-1 beta-mediated macrophage-hepatocyte crosstalk upregulates hepcidin under physiological low oxygen levels

et al. 2019

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In mammals, the iron masterswitch hepcidin efficiently controls iron recycling by the macrophage-liver axis but the exact interplay between macrophages and hepatocytes remains poorly understood. We here study hepcidin response during macrophage differentiation as well as the macrophage-hepatocyte crosstalk and its subsequent effects on hepatocyte hepcidin using an in vitro co-culture model that mimics the physiological liver microenvironment. We show that macrophage differentiation strongly induces hepcidin by 60-fold both in THP1 macrophages and primary isolated monocyte-derived macrophages. Removal of H 2 O 2 by catalase or inhibition of NOX2 efficiently blocked hepcidin induction. After differentiation, macrophage hepcidin accounted for 10% of total hepatocyte hepcidin and did not respond to low oxygen levels. In contrast, co-culture of differentiated macrophages with Huh7 cells significantly induced hepatocyte hepcidin, which was further potentiated under low oxygen levels. Hepatocyte hepcidin was also upregulated when Huh7 cells were solely exposed to macrophage-conditioned hypoxic medium. A cytokine screen identified macrophage secreted IL-1β as major inducer of hepcidin in hepatocytes. In confirmation, treatment of Huh7 cells with the IL-1 receptor antagonist (anakinra) completely blunted macrophage-mediated hepcidin transcription in hepatocytes. Finally, detailed analysis of potentially involved signaling pathways points toward STAT3 and CEBPδ-mediated hepcidin induction independent of IL-6. In conclusion, our study demonstrates a strong NOX2-mediated hepcidin induction during macrophage differentiation. These differentiated macrophages are able to efficiently induce hepatocyte hepcidin mainly through secretion of IL-1β. Our data highlight a hitherto unrecognized role of macrophage-hepatocyte crosstalk for a joint and oxygen-dependent hepcidin production through STAT3 and CEBPδ.

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Section: Discussionmentioning

confidence: 99%

IL-1 beta-mediated macrophage-hepatocyte crosstalk upregulates hepcidin under physiological low oxygen levels

et al. 2019

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“…Hepcidin is also induced during the acute phase response to inflammatory stimuli [54,55]. Upregulation is primarily mediated via the JAK–STAT3 (Janus Kinase—Signal Transducer and Activator of Transcription proteins 3) pathway, most notably by interleukin-6 (IL-6) [56,57,58], but probably also by other cytokines including IL-22, type I interferon, and IL-1beta [55,59,60,61]. Cross-talk with BMP6/SMAD signalling is also required for the normal response to inflammatory stimuli, since loss of HJV blunts the hepcidin response in this context [62].…”

Section: Regulation Of Iron Status During Early Childhoodmentioning

confidence: 99%

The Importance of Iron Status for Young Children in Low- and Middle-Income Countries: A Narrative Review

Armitage

Moretti

2019

Pharmaceuticals

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Early childhood is characterised by high physiological iron demand to support processes including blood volume expansion, brain development and tissue growth. Iron is also required for other essential functions including the generation of effective immune responses. Adequate iron status is therefore a prerequisite for optimal child development, yet nutritional iron deficiency and inflammation-related iron restriction are widespread amongst young children in low- and middle-income countries (LMICs), meaning iron demands are frequently not met. Consequently, therapeutic iron interventions are commonly recommended. However, iron also influences infection pathogenesis: iron deficiency reduces the risk of malaria, while therapeutic iron may increase susceptibility to malaria, respiratory and gastrointestinal infections, besides reshaping the intestinal microbiome. This means caution should be employed in administering iron interventions to young children in LMIC settings with high infection burdens. In this narrative review, we first examine demand and supply of iron during early childhood, in relation to the molecular understanding of systemic iron control. We then evaluate the importance of iron for distinct aspects of physiology and development, particularly focusing on young LMIC children. We finally discuss the implications and potential for interventions aimed at improving iron status whilst minimising infection-related risks in such settings. Optimal iron intervention strategies will likely need to be individually or setting-specifically adapted according to iron deficiency, inflammation status and infection risk, while maximising iron bioavailability and considering the trade-offs between benefits and risks for different aspects of physiology. The effectiveness of alternative approaches not centred around nutritional iron interventions for children should also be thoroughly evaluated: these include direct targeting of common causes of infection/inflammation, and maternal iron administration during pregnancy.

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“…As for IL-1β, studies show that it can increase the expression of FPN in glial cells through the activation of p38-MAPK pathway, which may cause the excessive iron efflux and deposition in nerve cells and the environment [ 47 ]. Besides, IL-1β secreted by macrophages is proved to upregulate the transcription of hepcidin via enhancing the expression of CCAAT enhancer-binding protein (C/EBP) [ 48 , 49 ] and the expression of hepcidin with the help of phosphorylated c-Jun N-terminal kinase and its substrates c-Jun and JunB [ 50 ], thus leading to FPN degradation and iron overload. In some aspects, IL-1β and IL-6 can cause the same effect in the activation of hepcidin but through different signaling ways [ 51 ].…”

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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JNK facilitates IL-1β-induced hepcidin transcription via JunB activation

Cited by 11 publications

References 41 publications

IL-1 beta-mediated macrophage-hepatocyte crosstalk upregulates hepcidin under physiological low oxygen levels

IL-1 beta-mediated macrophage-hepatocyte crosstalk upregulates hepcidin under physiological low oxygen levels

The Importance of Iron Status for Young Children in Low- and Middle-Income Countries: A Narrative Review

Interaction between macrophages and ferroptosis

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