Ironing Out the Wrinkles in Host Defense: Interactions between Iron Homeostasis and Innate Immunity

Wang, Lijian; Cherayil, Bobby J.

doi:10.1159/000210016

Cited by 57 publications

(58 citation statements)

References 163 publications

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“…Similarly, the other interferon-stimulated proteins we found to be regulated could exert various cellular roles. Accessibility of extracellular iron is another key strategy to limiting pathogens (92) and is indicated by our data to be important for multipotent LS ϩ K cells. Interestingly, the iron transport proteins lipocalin-2 and lactotransferrin are also shown to serve other functionalities, like the sensing of bacterial carbohydrates (56,57).…”

Section: Distinct Self-protective Signatures In Multipotent Ls ϩ K Anmentioning

confidence: 81%

Proteomic Cornerstones of Hematopoietic Stem Cell Differentiation: Distinct Signatures of Multipotent Progenitors and Myeloid Committed Cells

Klimmeck

Hansson

Raffel

et al. 2012

Molecular & Cellular Proteomics

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Section: Distinct Self-protective Signatures In Multipotent Ls ϩ K Anmentioning

confidence: 81%

Proteomic Cornerstones of Hematopoietic Stem Cell Differentiation: Distinct Signatures of Multipotent Progenitors and Myeloid Committed Cells

Klimmeck

Hansson

Raffel

et al. 2012

Molecular & Cellular Proteomics

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“…Changes in iron availability can influence microbial growth and affect the function of macrophages and other innate immune cells (23,24). Furthermore, iron redistribution via modulation of hepcidin-ferroportin expression is a well-established antimicrobial strategy in mammals.…”

Section: Figurementioning

confidence: 99%

Intra-graft expression of genes involved in iron homeostasis predicts the development of operational tolerance in human liver transplantation

Bohne

Martínez‐Llordella²,

Lozano³

et al. 2012

J. Clin. Invest.

191

209

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Following organ transplantation, lifelong immunosuppressive therapy is required to prevent the host immune system from destroying the allograft. This can cause severe side effects and increased recipient morbidity and mortality. Complete cessation of immunosuppressive drugs has been successfully accomplished in selected transplant recipients, providing proof of principle that operational allograft tolerance is attainable in clinical transplantation. The intra-graft molecular pathways associated with successful drug withdrawal, however, are not well defined. In this study, we analyzed sequential blood and liver tissue samples collected from liver transplant recipients enrolled in a prospective multicenter immunosuppressive drug withdrawal clinical trial. Before initiation of drug withdrawal, operationally tolerant and non-tolerant recipients differed in the intragraft expression of genes involved in the regulation of iron homeostasis. Furthermore, as compared with nontolerant recipients, operationally tolerant patients exhibited higher serum levels of hepcidin and ferritin and increased hepatocyte iron deposition. Finally, liver tissue gene expression measurements accurately predicted the outcome of immunosuppressive withdrawal in an independent set of patients. These results point to a critical role for iron metabolism in the regulation of intra-graft alloimmune responses in humans and provide a set of biomarkers to conduct drug-weaning trials in liver transplantation.

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“…These findings would complement other known iron sequestration mechanisms through posttranslational down-regulation of FPN1, mediated by the increased circulating levels of hepcidin associated with infection, 31 and mechanisms mediated by Nramp1, lactoferrin, and siderocalin, which have well-described functions in innate immunity. [32][33][34][35] With regards to the second question, we hypothesized that depletion of Steap3 might cause abnormal inflammatory responses in macrophages. To confirm this, we used LPS to treat BMDM.…”

confidence: 99%

Metalloreductase Steap3 coordinates the regulation of iron homeostasis and inflammatory responses

et al. 2012

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The online version of this article has a Supplementary Appendix. BackgroundIron and its homeostasis are intimately related to inflammatory responses, but the underlying molecular mechanisms are poorly understood. We investigated the role of Steap3 in regulating iron homeostasis in macrophages, and the effects of Steap3 depletion on host inflammatory responses. Design and MethodsWe analyzed bone marrow-derived macrophages and primary cultured hepatocytes from Steap3 -/-mouse models to investigate the roles of Steap3 in coordinately regulating iron homeostasis and inflammatory responses. First, we examined iron distribution and iron status in cells deficient in Steap3, as well as the requirement for the Steap3 gene during inflammatory responses. Secondly, we analyzed the regulation of Steap3 expression by inflammatory stimuli and thus, the influence of these stimuli on iron distribution and homeostasis. ResultsWe found that Steap3 mRNA was expressed at high levels in macrophages and hepatocytes. Steap3 deficiency led to impaired iron homeostasis, causing abnormal iron distribution and a decreased availability of cytosolic iron in macrophages. Among STEAP family members, Steap3 mRNA was uniquely down-regulated in macrophages stimulated by lipopolysaccharides. To determine whether Steap3 regulated iron homeostasis during inflammatory stress, we treated Steap3 -/-mice with lipopolysaccharide, which produced greater iron accumulation in the vital tissues of these mice compared to in the tissues of wild-type controls. Furthermore, Steap3 depletion led to impaired induction of interferon-b, monocyte chemoattractant protein-5, and interferon induced protein-10 in macrophages via the TLR4-mediated signaling pathway. ConclusionsSteap3 is important in regulating both iron homeostasis and TLR4-mediated inflammatory responses in macrophages. Steap3 deficiency causes abnormal iron status and homeostasis, which leads to impaired TLR4-mediated inflammatory responses in macrophages. Following inflammatory stimuli, Steap3 depletion causes dysregulated iron sequestration and distribution. Our results provide important insights into the function of Steap3 as a coordinate regulator of both iron homeostasis and innate immunity. Haematologica 2012;97(12):1826-1835. doi:10.3324/haematol.2012 This is an open-access paper. Metalloreductase Steap3 coordinates the regulation of iron homeostasis and inflammatory responses ABSTRACT© F e r r a t a S t o r t i F o u n d a t i o n

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Ironing Out the Wrinkles in Host Defense: Interactions between Iron Homeostasis and Innate Immunity

Cited by 57 publications

References 163 publications

Proteomic Cornerstones of Hematopoietic Stem Cell Differentiation: Distinct Signatures of Multipotent Progenitors and Myeloid Committed Cells

Proteomic Cornerstones of Hematopoietic Stem Cell Differentiation: Distinct Signatures of Multipotent Progenitors and Myeloid Committed Cells

Intra-graft expression of genes involved in iron homeostasis predicts the development of operational tolerance in human liver transplantation

Metalloreductase Steap3 coordinates the regulation of iron homeostasis and inflammatory responses

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