Arf6 regulates energy metabolism in neutrophils

Gamara, Jouda; Davis, Lynn; Leong, Andrew Z.; Pagé, Nathalie; Rollet-Labelle, Emmanuelle; Chang, Zhao; Hongu, Tsunaki; Funakoshi, Yuji; Kanaho, Yasunori; Aoudji, Fawzi; Pelletier, Martin; Bourgoin, Sylvain G.

doi:10.1016/j.freeradbiomed.2021.07.001

Cited by 12 publications

(10 citation statements)

References 92 publications

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“…ARF6 regulates numerous processes of critical importance in PAH, such as endocytotic trafficking, actin polymerization, cell migration, proliferation, angiogenesis and energy metabolism (5, 8). ARF6 has been implicated in the regulation of membrane trafficking of bone morphogenetic protein receptor 2 (BMPRII), the protein critically involved in vascular remodelling in PAH (4).…”

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

“…This study is first to describe ARF6-induced changes in pulmonary endothelial proteome and reveal a novel link between ARF6 with HIF-2 signalling, important in the pathogenesis of PAH. ARF6 regulates numerous processes of critical importance in PAH, such as endocytotic trafficking, actin polymerization, cell migration, proliferation, angiogenesis and energy metabolism (5,8). ARF6 has been implicated in the regulation of membrane trafficking of bone morphogenetic protein receptor 2 (BMPRII), the protein critically involved in vascular remodelling in PAH (4).…”

Section: Discussionmentioning

confidence: 99%

“…Considering that ARF6 is expressed, to a varying degree, in all cells and tissues and has a broad spectrum of effectors, future studies should address the role of ARF6 signalling in other cell types. Regulation of inflammatory cell responses, critical in PAH, may be of particular interest (8,36,37). CTC (also known as 'aureomycin') is a cell permeant first-generation antibiotic of the tetracyclin family, clinically approved for treatment of topical infections and widely used in veterinary medicine.…”

Section: Discussionmentioning

confidence: 99%

“…ARF6 is primarily known as a regulator of membrane receptor trafficking, vesicle transport, actin remodelling and cell motility in various cell types, including metastatic cancer cells (7). Recent studies suggest that ARF6 may act as a modulator of hypoxic signalling in certain cell types (8) but specific mechanisms have not been delineated. PAH has a complex and multi-faceted pathophysiology, including perturbed endothelial function and a heightened response to hypoxia.…”

Section: Introductionmentioning

confidence: 99%

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ARF6 as a novel activator of HIF-2α in pulmonary arterial hypertension

Fellows,

Chen,

Xie

et al. 2023

Preprint

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ADP-ribosylation factor 6 (ARF6), a GTPase associated with cancer metastasis, is activated in the lung endothelium in pulmonary arterial hypertension (PAH). To identify ARF6-regulated pathways relevant to PAH, we performed a state-of-the-art proteomic analysis of human pulmonary artery endothelial cells (HPAECs) overexpressing the wildtype, constitutively active, fast-cycling and dominant negative mutants of ARF6. The analysis revealed a novel link of ARF6 with hypoxia-inducible factor (HIF), in addition to endocytotic vesicle trafficking, cell proliferation, angiogenesis, oxidative stress and lipid metabolism. Active ARF6 markedly increased expression and activity of HIF-2, critical in PAH, with HIF-1 relatively unaffected. Hypoxic ARF6 activation was a prerequisite for HIF-2 activation and HIF-dependent gene expression in HPAECs, PAH blood-derived late outgrowth endothelial colony forming cells (ECFCs) and hypoxic mouse lungs in vivo. A novel ARF6 inhibitor, chlortetracycline (CTC), reduced hypoxia-induced HIF-2 activation, proliferation and angiogenesis in HPAECs and reduced HIF-2 expression in lung and heart tissues of hypoxic mice. PAH ECFCs showed elevated expression and activity of ARF6 and HIF2, which was attenuated by CTC. Oral CTC attenuated development of PH in chronically hypoxic mice. In conclusion, we are first to demonstrate a key role of ARF6 in the regulation of HIF-2alpha activation in vitro and in vivo and show that HIF-2alpha, a master-regulator of vascular remodelling in PAH, can be targeted by a clinically approved antibiotic chlortetracycline.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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ARF6 as a novel activator of HIF-2α in pulmonary arterial hypertension

Fellows,

Chen,

Xie

et al. 2023

Preprint

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Transcriptome profiling explores the immune defence mechanism of triploid Pacific oyster (Crassostrea gigas) blood against Vibrio alginolyticus based on protein interaction networks

Zhang

Lv³

et al. 2023

Developmental & Comparative Immunology

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IL-4/IL-4R axis signaling drives resistance to immunotherapy by inducing the upregulation of Fcγ receptor IIB in M2 macrophages

Zhang,

Dong,

et al. 2024

Cell Death Dis

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In recent years, immunotherapy, particularly PD-1 antibodies, have significantly enhanced the outcome of gastric cancer patients. Despite these advances, some patients do not respond well to treatment, highlighting the need to understand resistance mechanisms and develop predictive markers of treatment effectiveness. This study retrospectively analyzed data from 106 patients with stage IV gastric cancer who were treated with first-line immunotherapy in combination with chemotherapy. By comparing plasma cytokine levels between patients resistant and sensitive to PD-1 antibody therapy, the researchers identified elevated IL-4 expression in the resistant patients. Mechanical investigations revealed that IL-4 induces metabolic changes in macrophages that activate the PI3K/AKT/mTOR pathway. This alteration promotes ATP production, enhances glycolysis, increases lactic acid production, and upregulates FcγRIIB expression in macrophages. Ultimately, these changes lead to CD8+ T cell dysfunction and resistance to PD-1 antibody therapy in gastric cancer. These findings highlight the role of IL-4-induced macrophage polarization and metabolic reprogramming in immune resistance and verify IL-4 as potential targets for improving treatment outcomes in gastric cancer patients.

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Arf6 regulates energy metabolism in neutrophils

Cited by 12 publications

References 92 publications

ARF6 as a novel activator of HIF-2α in pulmonary arterial hypertension

ARF6 as a novel activator of HIF-2α in pulmonary arterial hypertension

Transcriptome profiling explores the immune defence mechanism of triploid Pacific oyster (Crassostrea gigas) blood against Vibrio alginolyticus based on protein interaction networks

IL-4/IL-4R axis signaling drives resistance to immunotherapy by inducing the upregulation of Fcγ receptor IIB in M2 macrophages

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