Irgm1 protects hematopoietic stem cells by negative regulation of IFN signaling

King, Katherine Y.; Baldridge, Megan T.; Weksberg, David C.; Chambers, Stuart M.; Lukov, Georgi L.; Wu, Shanshan; Boles, Nathan C.; Jung, Sung Yun; Qin, Jun; Liú, Dan; Songyang, Zhou; Eissa, N. Tony; Taylor, Gregory A.; Goodell, Margaret A.

doi:10.1182/blood-2011-01-328682

Cited by 73 publications

(81 citation statements)

References 43 publications

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“…It is important to note that the serum cytokine data indicated that IFN-␥ levels were elevated systemically in Irgm1-deficient mice (which is in agreement with a previous analysis of Irgm1-deficient mice (40)). Consequently, it is likely that macrophages in those mice are already primed with IFN-␥, and thus we chose to examine the responses of cultured macrophages primed with IFN-␥.…”

Section: Resultssupporting

confidence: 70%

Metabolic Alterations Contribute to Enhanced Inflammatory Cytokine Production in Irgm1-deficient Macrophages

Schmidt

Fee

Henry

et al. 2017

Journal of Biological Chemistry

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Edited by Luke O'NeillThe immunity-related GTPases (IRGs) are a family of proteins that are induced by interferon (IFN)-␥ and play pivotal roles in immune and inflammatory responses. IRGs ostensibly function as dynamin-like proteins that bind to intracellular membranes and promote remodeling and trafficking of those membranes. Prior studies have shown that loss of Irgm1 in mice leads to increased lethality to bacterial infections as well as enhanced inflammation to non-infectious stimuli; however, the mechanisms underlying these phenotypes are unclear. In the studies reported here, we found that uninfected Irgm1-deficient mice displayed high levels of serum cytokines typifying profound autoinflammation. Similar increases in cytokine production were also seen in cultured, IFN-␥-primed macrophages that lacked Irgm1. A series of metabolic studies indicated that the enhanced cytokine production was associated with marked metabolic changes in the Irgm1-deficient macrophages, including increased glycolysis and an accumulation of long chain acylcarnitines. Cells were exposed to the glycolytic inhibitor, 2-deoxyglucose, or fatty acid synthase inhibitors to perturb the metabolic alterations, which resulted in dampening of the excessive cytokine production. These results suggest that Irgm1 deficiency drives metabolic dysfunction in macrophages in a manner that is cell-autonomous and independent of infectious triggers. This may be a significant contributor to excessive inflammation seen in Irgm1-deficient mice in different contexts.

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Section: Resultssupporting

confidence: 70%

Metabolic Alterations Contribute to Enhanced Inflammatory Cytokine Production in Irgm1-deficient Macrophages

Schmidt

Fee

Henry

et al. 2017

Journal of Biological Chemistry

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“…This inflammatory phenotype and impaired erythropoiesis that develops in mice is consistent with the changes in the aging hematopoietic compartment described as "myeloid skewing". 48,49 We also found that IFNγ, which is known to have deleterious effects on hematopoietic stem cells, 50 increased with age. Though aged mice demonstrated the widest distribution of serum Epo concentrations, Epo was not significantly elevated in the majority of aged mice despite anemia.…”

Section: Discussionmentioning

confidence: 65%

Investigation of the role of interleukin-6 and hepcidin antimicrobial peptide in the development of anemia with age

et al. 2013

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Anemia is common in older adults and associated with adverse health outcomes in epidemiological studies. A thorough understanding of the complex pathophysiological mechanisms driving anemia in the elderly is lacking; but inflammation, iron restriction, and impaired erythroid maturation are thought to influence the phenotype. We hypothesized that interleukin-6 contributes to this anemia, given its pro-inflammatory activities, its ability to induce hepcidin antimicrobial peptide, and its negative impact on several tissues in older adults. We tested this hypothesis by comparing changes in indices of inflammation, iron metabolism and erythropoiesis in aged C57BL/6 mice to aged mice with targeted deletions of interleukin-6 or hepcidin antimicrobial peptide. Circulating neutrophil and monocyte numbers and inflammatory cytokines increased with age. Decline in hemoglobin concentration and red blood cell number indicated that C57BL/6, interleukin-6 knockout mice, and hepcidin antimicrobial peptide knockout mice all demonstrated impaired erythropoiesis by 24 months. However, the interleukin-6 knock out genotype and the hepcidin antimicrobial peptide knock out genotype resulted in improved erythropoiesis in aged mice. Increased erythropoietic activity in the spleen suggested that the erythroid compartment was stressed in aged C57BL/6 mice compared to aged interleukin-6 knockout mice. Our data suggest C57BL/6 mice are an appropriate mammalian model for the study of anemia with age. Furthermore, although interleukin-6 and hepcidin antimicrobial peptide are not required, they can participate in the development of anemia in aging mice, and could be targeted, pre-clinically, with existing interventions to determine the feasibility of such agents for the treatment of anemia in older adults. ABSTRACTsuch as IL-1α or β.33 Thus, IL-6 and Hepc may have inde

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“…3 This follows previous papers demonstrating that IFN-␣ stimulates normal hematopoietic stem cells from dormancy, [4][5][6] which may eventually lead to depletion of the hematopoietic stem cell pool. Whether this differential effect is more pronounced on normal stem cells or on stem cells dysregulated by somatic mutations (such as those in polycythemia vera), where a yet-to-be-defined single or several somatic mutations generate a clone 7,8 which is followed by a clonal evolution marked by JAK2V617F mutation (see figure panel A), remains to be shown.…”

mentioning

confidence: 82%

“…2 This work stems from the notion that in addition to recurrent structural chromosome and gene aberrations, epigenetic changes (those that alter gene transcription without changing DNA sequences) also occur in AML blasts. 3 DNA hypermethylation is one form of reversible epigenetic alteration that occurs through DNA methyltransferases (DNMTs) enzymatically adding a methyl (CH3) group to cytosine in the context of cytosine-guanine (CpG) dinucleotide sequences. In AML, hypermethylation of CpG islands, CpG-rich regions often associated with gene promoters, results in the silencing of tumor suppressor genes and other genes important for hematopoietic differentiation.…”

Section: Epigenetic Priming: the Target? ----------------------------mentioning

confidence: 99%

Interferon and PV stem cells

Prchal

2011

Blood

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Irgm1 protects hematopoietic stem cells by negative regulation of IFN signaling

Cited by 73 publications

References 43 publications

Metabolic Alterations Contribute to Enhanced Inflammatory Cytokine Production in Irgm1-deficient Macrophages

Metabolic Alterations Contribute to Enhanced Inflammatory Cytokine Production in Irgm1-deficient Macrophages

Investigation of the role of interleukin-6 and hepcidin antimicrobial peptide in the development of anemia with age

Interferon and PV stem cells

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