Hypoxia-inducible factor-1α regulation of myeloid cells

Stothers, Cody L.; Luan, Liming; Fensterheim, Benjamin A.; Bohannon, Julia K.

doi:10.1007/s00109-018-1710-1

Cited by 34 publications

(23 citation statements)

References 133 publications

(158 reference statements)

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“…This has been shown to be dependent on a shift from oxidative phosphorylation toward glycolysis through an Akt/mTOR/HIF-1α dependent pathway (183,186). We recently reviewed regulation and function of HIF-1α in myeloid cells (187). On the other hand, TLR ligands (such as LPS, MPLA, and CPG) increase aerobic glycolysis in concert with increased antimicrobial functions (such as respiratory burst and phagocytosis) as well as induce mitochondrial biogenesis and increased oxidative metabolism (47).…”

Section: Metabolic Reprogramming and Innate Immune Memorymentioning

confidence: 99%

The Metabolic Basis of Immune Dysfunction Following Sepsis and Trauma

et al. 2020

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Critically ill, severely injured and high-risk surgical patients are vulnerable to secondary infections during hospitalization and after hospital discharge. Studies show that the mitochondrial function and oxidative metabolism of monocytes and macrophages are impaired during sepsis. Alternatively, treatment with microbe-derived ligands, such as monophosphoryl lipid A (MPLA), peptidoglycan, or β-glucan, that interact with toll-like receptors and other pattern recognition receptors on leukocytes induces a state of innate immune memory that confers broad-spectrum resistance to infection with common hospital-acquired pathogens. Priming of macrophages with MPLA, CPG oligodeoxynucleotides (CpG ODN), or β-glucan induces a macrophage metabolic phenotype characterized by mitochondrial biogenesis and increased oxidative metabolism in parallel with increased glycolysis, cell size and granularity, augmented phagocytosis, heightened respiratory burst functions, and more effective killing of microbes. The mitochondrion is a bioenergetic organelle that not only contributes to energy supply, biosynthesis, and cellular redox functions but serves as a platform for regulating innate immunological functions such as production of reactive oxygen species (ROS) and regulatory intermediates. This review will define current knowledge of leukocyte metabolic dysfunction during and after sepsis and trauma. We will further discuss therapeutic strategies that target leukocyte mitochondrial function and might have value in preventing or reversing sepsis-and trauma-induced immune dysfunction.

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Section: Metabolic Reprogramming and Innate Immune Memorymentioning

confidence: 99%

The Metabolic Basis of Immune Dysfunction Following Sepsis and Trauma

et al. 2020

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“…Just as succinate stabilizes HIF, also other metabolites, such as fumarate, pyruvate, and lactate, can inhibit PHD resulting in HIF stabilization . The upregulation of glycolysis by HIF1α and subsequent activation of HIF1α by glycolytic enzymes and TCA intermediates creates a positive feedback loop that drives macrophages to produce IL1β and ROS resulting in eradication of the invading pathogens .…”

Section: Crosstalk Between Hif and Sepsismentioning

confidence: 99%

“…For an extensive review on the role of HIF1α in myeloid cells, we refer to the recent review of Stothers et al . . Here, we will discuss briefly the role of HIF1α in monocyte, neutrophil, and DC function.…”

Section: Crosstalk Between Hif and Sepsismentioning

confidence: 99%

Hypoxia‐inducible factors in metabolic reprogramming during sepsis

2020

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Sepsis is a highly heterogeneous syndrome that is caused by an imbalanced host response to infection. Despite huge investments, sepsis remains a contemporary threat with significant burden on health systems. Vascular dysfunction and elevated oxygen consumption by highly metabolically active immune cells result in tissue hypoxia during inflammation. The transcription factor hypoxia-inducible factor-1a (HIF1a), and its family members, plays an important role in cellular metabolism and adaptation to cellular stress caused by hypoxia. In this review, we discuss the role of HIF in sepsis. We show possible mechanisms by which the inflammatory response activated during sepsis affects the HIF pathway. The activated HIF pathway in turn changes the metabolism of both innate and adaptive immune cells. As HIF expression in leukocytes of septic patients can be directly linked with mortality, we discuss multiple ways of interfering with the HIF signaling pathway.

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“…Since activation of immune cells under normoxic conditions already triggers a switch to glycolytic energy generation, these cells are well prepared to operate in inflamed areas, which are very likely to display low oxygen levels. The hypoxia-inducible factor (HIF) plays an important role not only for the adaptation of cells to oxygen-poor environments (reviewed: [49,50]), but also under normoxic conditions (reviewed: [39,42,[44][45][46]51]). Therefore, we will very briefly review the molecular mechanisms that result in HIF stabilization in myeloid cells and we will describe the role of HIF in the immunobiology of neutrophils, macrophages, and dendritic cells.…”

Section: Metabolic Response Of Innate Immune Cells To Hypoxiamentioning

confidence: 99%

“…In the absence of oxygen, its co-substrate or co-factors, the PHD activity is suppressed, which in turn triggers subsequent HIF1α activation (reviewed: [49,50,52,61]). HIFα governs the expression of a plethora of different genes involved in metabolism, immune system regulation, and in general cellular functions in response to hypoxia (reviewed: [39,42,[44][45][46]51]). A detailed global assessment of HIF1α and HIF2α binding sites in MCF7 breast cancer cells, for instance, revealed that many of these sites bound HIF1α and HIF2α equally well, while there were only very few sites that bound HIF2α exclusively [62].…”

Section: Hypoxic Hif Stabilizationmentioning

confidence: 99%

Mechanisms controlling bacterial infection in myeloid cells under hypoxic conditions

Hayek

Schatz

Bogdan

et al. 2020

Cell. Mol. Life Sci.

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Various factors of the tissue microenvironment such as the oxygen concentration influence the host–pathogen interaction. During the past decade, hypoxia-driven signaling via hypoxia-inducible factors (HIF) has emerged as an important factor that affects both the pathogen and the host. In this chapter, we will review the current knowledge of this complex interplay, with a particular emphasis given to the impact of hypoxia and HIF on the inflammatory and antimicrobial activity of myeloid cells, the bacterial responses to hypoxia and the containment of bacterial infections under oxygen-limited conditions. We will also summarize how low oxygen concentrations influence the metabolism of neutrophils, macrophages and dendritic cells. Finally, we will discuss the consequences of hypoxia and HIFα activation for the invading pathogen, with a focus on Pseudomonas aeruginosa, Mycobacterium tuberculosis, Coxiella burnetii, Salmonella enterica and Staphylococcus aureus. This includes a description of the mechanisms and microbial factors, which the pathogens use to sense and react to hypoxic conditions.

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Hypoxia-inducible factor-1α regulation of myeloid cells

Cited by 34 publications

References 133 publications

The Metabolic Basis of Immune Dysfunction Following Sepsis and Trauma

The Metabolic Basis of Immune Dysfunction Following Sepsis and Trauma

Hypoxia‐inducible factors in metabolic reprogramming during sepsis

Mechanisms controlling bacterial infection in myeloid cells under hypoxic conditions

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