HIF2α is a direct regulator of neutrophil motility

Sormendi, Sundary; Deygas, Mathieu; Sinha, Anupam; Bernard, Mathilde; Krüger, Anja; Kourtzelis, Ioannis; Lay, Gregoire Le; Sáez, Pablo J.; Gerlach, Michael; Franke, Kristin; Meneses, Ana; Kräter, Martin; Palladini, Alessandra; Guck, Jochen; Coskun, Ünal; Chavakis, Triantafyllos; Vargas, Pablo Agustín; Wielockx, Ben

doi:10.1182/blood.2020007505

Cited by 16 publications

(13 citation statements)

References 68 publications

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“…More recent studies have expanded our understanding of the effects of HIF on immune cell function, with the identification of roles for HIF in innate lymphoid cell plasticity in the gut 167 , regulatory T cell abundance 168 and neutrophil motility 169 . These studies further support a central role for HIF in immunity that is heavily cell-type and context specific.…”

Section: Implications Of Hif-mediated Changes In Cell Metabolismmentioning

confidence: 99%

The effect of HIF on metabolism and immunity

2022

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Cellular hypoxia occurs when the demand for sufficient molecular oxygen needed to produce the levels of ATP required to perform physiological functions exceeds the vascular supply, thereby leading to a state of oxygen depletion with the associated risk of bioenergetic crisis. To protect against the threat of hypoxia, eukaryotic cells have evolved the capacity to elicit oxygen-sensitive adaptive transcriptional responses driven primarily (although not exclusively) by the hypoxia-inducible factor (HIF) pathway. In addition to the canonical regulation of HIF by oxygen-dependent hydroxylases, multiple other input signals, including gasotransmitters, non-coding RNAs, histone modifiers and post-translational modifications, modulate the nature of the HIF response in discreet cell types and contexts. Activation of HIF induces various effector pathways that mitigate the effects of hypoxia, including metabolic reprogramming and the production of erythropoietin. Drugs that target the HIF pathway to induce erythropoietin production are now approved for the treatment of chronic kidney disease-related anaemia. However, HIF-dependent changes in cell metabolism also have profound implications for functional responses in innate and adaptive immune cells, and thereby heavily influence immunity and the inflammatory response. Preclinical studies indicate a potential use of HIF therapeutics to treat inflammatory diseases, such as inflammatory bowel disease. Understanding the links between HIF, cellular metabolism and immunity is key to unlocking the full therapeutic potential of drugs that target the HIF pathway.

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Section: Implications Of Hif-mediated Changes In Cell Metabolismmentioning

confidence: 99%

The effect of HIF on metabolism and immunity

2022

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“…Indeed, HIFs are involved in crucial immune cell features, including survival and glycolysis in neutrophils, and promoting inflammatory functions of certain innate immune cells such as dendritic cells, mast cells, and macrophages [140]. Furthermore, we have recently described a central role for HIF2α in the migration of neutrophils through very confined microenvironments, both ex vivo and under various inflammatory settings in vivo [141]. Conversely, HIFs suppress the adaptive immune response by promoting the differentiation of regulatory T-cells and negatively regulating CD4 + and CD8 + T-cells [139].…”

Section: The Role Of Inflammation In Angiogenesismentioning

confidence: 99%

Hypoxia Pathway Proteins and Their Impact on the Blood Vasculature

Rodríguez

Watts

Gaete

et al. 2021

IJMS

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Every cell in the body requires oxygen for its functioning, in virtually every animal, and a tightly regulated system that balances oxygen supply and demand is therefore fundamental. The vascular network is one of the first systems to sense oxygen, and deprived oxygen (hypoxia) conditions automatically lead to a cascade of cellular signals that serve to circumvent the negative effects of hypoxia, such as angiogenesis associated with inflammation, tumor development, or vascular disorders. This vascular signaling is driven by central transcription factors, namely the hypoxia inducible factors (HIFs), which determine the expression of a growing number of genes in endothelial cells and pericytes. HIF functions are tightly regulated by oxygen sensors known as the HIF-prolyl hydroxylase domain proteins (PHDs), which are enzymes that hydroxylate HIFs for eventual proteasomal degradation. HIFs, as well as PHDs, represent attractive therapeutic targets under various pathological settings, including those involving vascular (dys)function. We focus on the characteristics and mechanisms by which vascular cells respond to hypoxia under a variety of conditions.

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“…To gain further insights into the cytoskeletal rearrangements stimulated by CXCL12 in restricted microenvironments, we analyzed LifeAct-GFP neutrophils migrating through custom microfabricated microchannels (3 μm wide by 4 μm high) ( 10 , 12 ). Within microchannels, cells move in only 1D, facilitating the analysis of cell trajectories, organelle positioning, and the organization of the cytoskeleton ( 14 ).…”

Section: Resultsmentioning

confidence: 99%

“…Because CXCL12 has a key role in regulating the maturation of neutrophils, their release from the bone marrow, and their retention at inflammatory sites (9), we first assessed the contribution of CXCL12 in modulating the migratory behavior of neutrophils. We purified primary neutrophils from the bone marrow of healthy wild-type mice and analyzed their motility in 3D collagen gels with customized, homemade polydimethylsiloxane (PDMS) chambers as previously described (10)(11)(12). Briefly, neutrophils were seeded in a highdensity collagen gel (4 mg/ml; pore size: 1.173 ± 0.1507 μm; fig.…”

Section: Cxcl12 Enhances Nuclear Adaptation Of Mouse Neutrophils To C...mentioning

confidence: 99%

Atypical CXCL12 signaling enhances neutrophil migration by modulating nuclear deformability

et al. 2022

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To reach inflamed tissues from the circulation, neutrophils must overcome physical constraints imposed by the tissue architecture, such as the endothelial barrier or the three-dimensional (3D) interstitial space. In these microenvironments, neutrophils are forced to migrate through spaces smaller than their own diameter. One of the main challenges for cell passage through narrow gaps is the deformation of the nucleus, the largest and stiffest organelle in cells. Here, we showed that chemokines, the extracellular signals that guide cell migration in vivo, modulated nuclear plasticity to support neutrophil migration in restricted microenvironments. Exploiting microfabricated devices, we found that the CXC chemokine CXCL12 enhanced the nuclear pliability of mouse bone marrow–derived neutrophils to sustain their migration in 3D landscapes. This previously uncharacterized function of CXCL12 was mediated by the atypical chemokine receptor ACKR3 (also known as CXCR7), required protein kinase A (PKA) activity, and induced chromatin compaction, which resulted in enhanced cell migration in 3D. Thus, we propose that chemical cues regulate the nuclear plasticity of migrating leukocytes to optimize their motility in restricted microenvironments.

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HIF2α is a direct regulator of neutrophil motility

Cited by 16 publications

References 68 publications

The effect of HIF on metabolism and immunity

The effect of HIF on metabolism and immunity

Hypoxia Pathway Proteins and Their Impact on the Blood Vasculature

Atypical CXCL12 signaling enhances neutrophil migration by modulating nuclear deformability

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