Role of hypoxia inducible factor-1α for interferon synthesis in mouse dendritic cells

Wobben, Regina; Hüsecken, Yvonne; Lodewick, Claudia; Gibbert, Kathrin; Fandrey, Joachim; Winning, Sandra

doi:10.1515/hsz-2012-0320

Cited by 64 publications

(50 citation statements)

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“…51 One hypothesis is that this hypoxic environment and/or RBC enucleation are transiently pro-inflammatory, and the stabilization of hypoxia-inducible factor and activation of innate immunity may contribute to IFN-a production. [52][53][54] A similar mechanism may exist in the placenta and serve as a niche for the maturation of HSCs. 55 Distinct type I and II IFNs are used in different contexts for hematopoietic development.…”

Section: Discussionmentioning

confidence: 98%

Interferon-α signaling promotes embryonic HSC maturation

Kim

Canver

Rhee

et al. 2016

Blood

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In the developing mouse embryo, the first hematopoietic stem cells (HSCs) arise in the aorta-gonad-mesonephros (AGM) and mature as they transit through the fetal liver (FL). Compared with FL and adult HSCs, AGM HSCs have reduced repopulation potential in irradiated adult transplant recipients but mechanisms underlying this deficiency in AGM HSCs are poorly understood. By co-expression gene network analysis, we deduced that AGM HSCs show lower levels of interferon-a (IFN-a)/Jak-Stat1-associated gene expression than FL HSCs. Treatment of AGM HSCs with IFN-a enhanced long-term hematopoietic engraftment and donor chimerism. Conversely, IFN-a receptor-deficient AGMs (Ifnar1 2/2 ), had significantly reduced donor chimerism. We identify adenine-thymine-rich interactive domain-3a (Arid3a), a factor essential for FL and B lymphopoiesis, as a key transcriptional co-regulator of IFN-a/Stat1 signaling. Arid3a occupies the genomic loci of Stat1 as well as several IFN-a effector genes, acting to regulate their expression. Accordingly, Arid3a 2/2 AGM HSCs had significantly reduced transplant potential, which was rescued by IFN-a treatment. Our results implicate the inflammatory IFN-a/ Jak-Stat pathway in the developmental maturation of embryonic HSCs, whose manipulation may lead to increased potency of reprogrammed HSCs for transplantation. (Blood. 2016;128(2):204-216)

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Section: Discussionmentioning

confidence: 98%

Interferon-α signaling promotes embryonic HSC maturation

Kim

Canver

Rhee

et al. 2016

Blood

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“…Whether succinate is needed for the Th17 response has yet to be determined. Interestingly, HIF-1a-deficient DCs show impaired ability to activate T cells [26], suggesting that this transcription factor is important for T cell polarization and activation. HIF-1a therefore enhances inflammation by influencing both the innate and adaptive immune system and succinate may be crucial in both cases via its effect on HIF-1a stabilization.…”

Section: Succinate and Hif-1a In Inflammationmentioning

confidence: 99%

Succinate: a metabolic signal in inflammation

Mills

O’Neill

2014

Trends in Cell Biology

514

409

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Succinate is an intermediate of the tricarboxylic acid (TCA) cycle, and plays a crucial role in adenosine triphosphate (ATP) generation in mitochondria. Recently, new roles for succinate outside metabolism have emerged. Succinate stabilizes the transcription factor hypoxia-inducible factor-1a (HIF-1a) in specific tumors and in activated macrophages, and stimulates dendritic cells via its receptor succinate receptor 1. Furthermore, succinate has been shown to post-translationally modify proteins. This expanding repertoire of functions for succinate suggests a broader role in cellular activation. We review the new roles of succinate and draw parallels to other metabolites such as NAD + and citrate whose roles have expanded beyond metabolism and into signaling. Metabolic alterations influence the immune responseThe immune system acts as an internal shield defending against invading pathogens and is made up of an innate system, including macrophages, neutrophils, and dendritic cells (DCs), and an adaptive system composed of T and B lymphocytes. Cells of the innate immune system recognize pathogen-associated molecular patterns (PAMPs) via pattern recognition receptors (PRRs), such as Toll-like receptors (TLRs), present on their cell surface and in the cytosol [1]. Once activated, innate immune cells can initiate adaptive immunity to fight infection further and to generate immunological memory. In resting conditions these cells are relatively inactive; however, upon recognition of foreign material they have the ability to respond rapidly, producing a wide array of mediators such as cytokines, chemokines, and antimicrobial peptides to clear the infection.Such rapid induction of immunity represents a significant metabolic demand. In recent years it has become evident that immune cells have the ability to shift their metabolism under varying conditions and that this is essential for proper immune function [2]. Stimulation of DCs and macrophages can result in a decrease in oxidative phosphorylation, which is normally employed under resting conditions, with a concomitant increase in glycolysis and the pentose-phosphate pathway [3,4]. This switch to glycolysis rapidly generates ATP to maintain mitochondrial membrane potential and energy homeostasis, ultimately ensuring cell viability [5]. It also provides biosynthetic precursors required for proliferating cells and for cells with a prodigious biosynthetic capacity, such as macrophages when they are activated to produce cytokines. This altered metabolism is similar to the Warburg effect (aerobic glycolysis) observed in tumor cells [6] (Figure 1, Box 1). Indeed, the metabolic sensor HIF-1a can determine the growth and fate of both tumor cells and immune cells. For example, HIF-1a activation favors differentiation of T lymphocytes into proinflammatory Th17 cells and attenuates regulatory T cell development [7]. Importantly, as well as global changes in metabolism that occur in activated immune cells, individual metabolites, including succinate, citrate, and NAD + , have been d...

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“…In dendritic cells (DCs), HIF-1 has been shown to promote cell survival, interferon synthesis, differentiation, and migration (36)(37)(38). Furthermore, recent studies have suggested a role for HIF-1α in determining the antigen-presenting function of DCs.…”

Section: Hif and Immunitymentioning

confidence: 99%