The Role of Iron Regulation in Immunometabolism and Immune-Related Disease

Cronin, Shane J. F.; Woolf, Clifford J.; Weiss, Guenter; Penninger, Josef

doi:10.3389/fmolb.2019.00116

Cited by 197 publications

(182 citation statements)

References 204 publications

(230 reference statements)

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“…For example, secretion of GM-CSF by tumor cells stimulates secretion of Tf by neutrophils and drives tumor growth and metastasis (156). In the early stages of tumorigenesis pro-inflammatory cytokines prompt M 1 -like macrophages to sequester iron and produce ROS as an anti-tumor defense mechanism, but chronic inflammation and immune tolerance can lead to M 2 -like TAMs releasing iron to support tumor progression (157). Interestingly, iron chelation can shift TAMs from the iron-donor to iron sequestration phenotype (158).…”

Section: Modifying the Local Tumor Microenvironmentmentioning

confidence: 99%

Altered Iron Metabolism and Impact in Cancer Biology, Metastasis, and Immunology

et al. 2020

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Iron is an essential nutrient that plays a complex role in cancer biology. Iron metabolism must be tightly controlled within cells. Whilst fundamental to many cellular processes and required for cell survival, excess labile iron is toxic to cells. Increased iron metabolism is associated with malignant transformation, cancer progression, drug resistance and immune evasion. Depleting intracellular iron stores, either with the use of iron chelating agents or mimicking endogenous regulation mechanisms, such as microRNAs, present attractive therapeutic opportunities, some of which are currently under clinical investigation. Alternatively, iron overload can result in a form of regulated cell death, ferroptosis, which can be activated in cancer cells presenting an alternative anti-cancer strategy. This review focuses on alterations in iron metabolism that enable cancer cells to meet metabolic demands required during different stages of tumorigenesis in relation to metastasis and immune response. The strength of current evidence is considered, gaps in knowledge are highlighted and controversies relating to the role of iron and therapeutic targeting potential are discussed. The key question we address within this review is whether iron modulation represents a useful approach for treating metastatic disease and whether it could be employed in combination with existing targeted drugs and immune-based therapies to enhance their efficacy.

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Section: Modifying the Local Tumor Microenvironmentmentioning

confidence: 99%

Altered Iron Metabolism and Impact in Cancer Biology, Metastasis, and Immunology

et al. 2020

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“…More specifically, the Fe-S clusters are necessary for the efficient function of Complexes I-III of the ETC. 73 However, a recent study of hemoglobin-haptoglobin-treated monocytes shows that glucose transporters, fatty aldehyde dehydrogenase, and glucose-6-phosphate-1 dehydrogenase are also within the top 50 upregulated proteins. 74 More work will need to be done to determine how these genes and their associated pathways influence cellular iron uptake and cycling.…”

Section: Lipid Bufferingmentioning

confidence: 99%

Adipose tissue macrophages: Unique polarization and bioenergetics in obesity

Caslin

Bhanot

Bolus

et al. 2020

Immunological Reviews

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Macrophages comprise a majority of the resident immune cells in adipose tissue (AT) and regulate both tissue homeostasis in the lean state and metabolic dysregulation in obesity. Since the AT environment rapidly changes based upon systemic energy status, AT macrophages (ATMs) must adapt phenotypically and metabolically. There is a distinct dichotomy in the polarization and bioenergetics of in vitro models, with M2 macrophages utilizing oxidative phosphorylation (OX PHOS) and M1 macrophages utilizing glycolysis. Early studies suggested differential polarization of ATMs, with M2‐like macrophages predominant in lean AT and M1‐like macrophages in obese AT. However, recent studies show that the phenotypic plasticity of ATMs is far more complicated, which is also reflected in their bioenergetics. Multiple ATM populations exist along the M2 to M1 continuum and appear to utilize both glycolysis and OX PHOS in obesity. The significance of the dual fuel bioenergetics is unclear and may be related to an intermediate polarization, their buffering capacity, or the result of a mixed population of distinct polarized ATMs. Recent evidence also suggests that ATMs of lean mice serve as a substrate buffer or reservoir to modulate lipid, catecholamine, and iron availability. Furthermore, recent models of weight loss and weight cycling reveal additional roles for ATMs in systemic metabolism. Evaluating ATM phenotype and intracellular metabolism together may more accurately illuminate the consequences of ATM accumulation in obese AT, lending further insight into obesity‐related comorbidities in humans.

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“…Both nutritional iron deficiency and genetic defects affecting cellular iron uptake cause immunodeficiency in humans. The role of iron in the immune system has been particularly strongly linked to lymphocyte proliferation in response to antigen (Kurz et al 2011;Yambire et al 2019;Weber et al 2020;Cronin et al 2019). Our data provide a novel insight into the unique regulation of iron uptake in proliferating GC B cells.…”

Section: Discussionmentioning

confidence: 77%

“…This interpretation comes from our observation that deletion of CCP components EPN1 or PICALM, which reduced TFRC endocytosis more strongly than deletion of endophilin A2 did not result in altered cell metabolism or growth. Given that iron homeostasis is crucial across all hematopoietic lineages (Cronin et al 2019), all of which express endophilin A2 as the only endophilin A family member, the selective defect caused by endophilin A2 deletion in GC B cells thus points to a specialized regulation of endocytosis and iron uptake at this stage of the immune response. Such regulation may use the signaling-dependency of endophilin A2's function to couple iron uptake to signals driving positive selection of GC B cells.…”

Section: Discussionmentioning

confidence: 99%

“…The transcriptional analysis also revealed significant enrichment (at FDR<25%) of several iron and other metal transport and homeostasis gene sets in Sh3gl1 -/cells. Given the importance of cellular iron homeostasis for mitochondrial respiration and lymphocyte proliferation (Seligman et al 1992;Cronin et al 2019), we endeavored to test whether iron uptake played a role in the metabolic and survival defects in the absence of endophilin A2. Iron supplementation using ferrous sulphate or hemin chloride in both Ramos and primary B cell cultures showed a consistent though incomplete rescue of cell growth over time (Fig 6J, L), with little effect on non-targeted or WT cells (Fig 6K, M).…”

Section: Contrastingly Ocr Of T Cells Isolated Frommentioning

confidence: 99%

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Endophilin A2 regulates B cell protein trafficking and humoral responses

Malinova

Wasim

Engels

et al. 2020

Preprint

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HIGHLIGHTS• Genome-wide CRISPR screens comprehensively identify genes regulating antigen uptake in B cells • B cell receptor-mediated antigen internalization is mediated by both epsin1-dependent clathrincoated pits and a novel fast endophilin A2-mediated endocytosis.• Endophilin A2 is required for peripheral B cell development, antigen-specific germinal center responses and high-affinity IgG production.• Endophilin A2 is broadly essential for B cell intracellular trafficking pathways providing metabolic support of germinal center B cell proliferation, in part through regulation of iron uptake. SUMMARYAntigen-specific B cell responses require endosomal trafficking to regulate antigen uptake and presentation to helper T cells, and to control expression and signaling of immune receptors. However, the molecular composition of B cell endosomal trafficking pathways and their specific roles in B cell responses have not been systematically investigated. Here we report high-throughput identification of genes regulating B cell receptor (BCR)-mediated antigen internalization using genome-wide functional screens. We show that antigen internalization depends both on clathrin-coated pits and on clathrinindependent endocytosis mediated by endophilin A2. Although endophilin A2 is dispensable for presentation of the endocytosed antigen, it is required for metabolic support of germinal center (GC) B cell proliferation, in part through regulation of iron uptake. Consequently, endophilin A2 deficient mice show selective defects in GC B cell responses and production of high-affinity IgG. The requirement for endophilin A2 highlights a unique importance of clathrin-independent intracellular trafficking in GC B cell clonal expansion and antibody responses.Endoplasmic reticulum

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The Role of Iron Regulation in Immunometabolism and Immune-Related Disease

Cited by 197 publications

References 204 publications

Altered Iron Metabolism and Impact in Cancer Biology, Metastasis, and Immunology

Altered Iron Metabolism and Impact in Cancer Biology, Metastasis, and Immunology

Adipose tissue macrophages: Unique polarization and bioenergetics in obesity

Endophilin A2 regulates B cell protein trafficking and humoral responses

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