Pannexin 1 Channels Link Chemoattractant Receptor Signaling to Local Excitation and Global Inhibition Responses at the Front and Back of Polarized Neutrophils

Bao, Yi; Chen, Yu; Ledderose, Carola; Li, Linglin; Junger, Wolfgang G.

doi:10.1074/jbc.m113.476283

Cited by 91 publications

(132 citation statements)

References 42 publications

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“…We have previously demonstrated that neutrophil chemotaxis in response to chemokine receptor stimulation is regulated by cellular ATP release and autocrine purinergic signaling [3,8]. Breast cancer cells express the chemokine receptor CXCR4, and the CXCR4 receptor ligand SDF-1α has been reported to contribute to metastasis of breast cancer by recruiting cancer cells to secondary organs such as the lungs [27][28][29][30].…”

Section: Mda-mb-231 Cells Display Uncoordinated Motility Patternsmentioning

confidence: 99%

“…The released ATP stimulates P2Y2 receptors that contribute to gradient sensing and delineate the direction of cell migration [3,7]. Ectonucleotidases such as alkaline phosphatase, CD39, and CD73 convert the released ATP to adenosine, which promotes autocrine stimulation of A3 receptors at the front of cells and A2a receptors at the back [3,4,7,8]. Both receptors elicit excitatory and inhibitory feedback mechanisms, respectively, that maintain cell polarity and increase the migration speed of neutrophils in a chemotactic gradient field (Supplemental Fig.…”

Section: Breast Cancer Cells Express Ectonucleotidases That Promote Amentioning

confidence: 99%

“…Both receptors elicit excitatory and inhibitory feedback mechanisms, respectively, that maintain cell polarity and increase the migration speed of neutrophils in a chemotactic gradient field (Supplemental Fig. 1) [3,4,8]. We wondered whether similar purinergic signaling mechanisms define the motility patterns of breast cancer cells.…”

Section: Breast Cancer Cells Express Ectonucleotidases That Promote Amentioning

confidence: 99%

“…Endogenous adenosine formation and autocrine A3 receptor stimulation contribute to MDA-MB-231 cell motility Neutrophils generate local ATP and adenosine microenvironments at the front and back of cells to facilitate coordinated cell migration [3,8]. In analogy, we hypothesized that endogenous adenosine formation could regulate the motility of breast cancer cells.…”

Section: Breast Cancer Cells Express Ectonucleotidases That Promote Amentioning

confidence: 99%

“…Localized release of ATP at the leading edge of neutrophils and the conversion of ATP to adenosine and autocrine stimulation of A3 adenosine receptors are required for cell polarization and the coordinated migration of neutrophils in a chemotactic gradient field (Supplemental Fig. 1) [3][4][5][6][7][8]. Mounting evidence Carola Ledderose, Marco M. Hefti and Yu Chen contributed equally to this work.…”

Section: Introductionmentioning

confidence: 99%

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Adenosine arrests breast cancer cell motility by A3 receptor stimulation

Ledderose

Hefti

Chen

et al. 2016

Purinergic Signalling

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In neutrophils, adenosine triphosphate (ATP) release and autocrine purinergic signaling regulate coordinated cell motility during chemotaxis. Here, we studied whether similar mechanisms regulate the motility of breast cancer cells. While neutrophils and benign human mammary epithelial cells (HMEC) form a single leading edge, MDA-MB-231 breast cancer cells possess multiple leading edges enriched with A3 adenosine receptors. Compared to HMEC, MDA-MB-231 cells overexpress the ectonucleotidases ENPP1 and CD73, which convert extracellular ATP released by the cells to adenosine that stimulates A3 receptors and promotes cell migration with frequent directional changes. However, exogenous adenosine added to breast cancer cells or the A3 receptor agonist IB-MECA dose-dependently arrested cell motility by simultaneous stimulation of multiple leading edges, doubling cell surface areas and significantly reducing migration velocity by up to 75 %. We conclude that MDA-MB-231 cells, HMEC, and neutrophils differ in the purinergic signaling mechanisms that regulate their motility patterns and that the subcellular distribution of A3 adenosine receptors in MDA-MB-231 breast cancer cells contributes to dysfunctional cell motility. These findings imply that purinergic signaling mechanisms may be potential therapeutic targets to interfere with the motility of breast cancer cells in order to reduce the spread of cancer cells and the risk of metastasis.

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Section: Mda-mb-231 Cells Display Uncoordinated Motility Patternsmentioning

confidence: 99%

Section: Breast Cancer Cells Express Ectonucleotidases That Promote Amentioning

confidence: 99%

Section: Breast Cancer Cells Express Ectonucleotidases That Promote Amentioning

confidence: 99%

Section: Breast Cancer Cells Express Ectonucleotidases That Promote Amentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Adenosine arrests breast cancer cell motility by A3 receptor stimulation

Ledderose

Hefti

Chen

et al. 2016

Purinergic Signalling

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Frontline Science: Escherichia coli use LPS as decoy to impair neutrophil chemotaxis and defeat antimicrobial host defense

Kondo

Ledderose

Slubowski

et al. 2019

Journal of Leukocyte Biology

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Bacterial infections and sepsis are leading causes of morbidity and mortality in critically ill patients. Currently, there are no effective treatments available to improve clinical outcome in sepsis. Here, we elucidated a mechanism by which Escherichia coli (E. coli) bacteria impair neutrophil (PMN) chemotaxis and we studied whether this mechanism can be therapeutically targeted to improve chemotaxis and antimicrobial host defense. PMNs detect bacteria with formyl peptide receptors (FPR). FPR stimulation triggers mitochondrial ATP production and release. Autocrine stimulation of purinergic receptors exerts excitatory and inhibitory downstream signals that induce cell polarization and cell shape changes needed for chemotaxis. Here we show that the bacterial cell wall product LPS dose-dependently impairs PMN chemotaxis. Exposure of human PMNs to LPS triggered excessive mitochondrial ATP production and disorganized intracellular trafficking of mitochondria, resulting in global ATP release that disrupted purinergic signaling, cell polarization, and chemotaxis. In mice infected i.p. with E. coli, LPS treatment increased the spread of bacteria at the infection site and throughout the systemic circulation. Removal of excessive systemic ATP with apyrase improved chemotaxis of LPS-treated human PMNs in vitro and enhanced the clearance of E. coli in infected and LPS-treated mice. We conclude that systemic ATP accumulation in response to LPS is a potential therapeutic target to restore PMN chemotaxis and to boost the antimicrobial host immune defense in sepsis. K E Y W O R D S apyrase, ATP release, bacterial clearance, endotoxin, purinergic signaling 1 INTRODUCTION ATP is an energy carrier that fuels virtually all cellular processes. Damaged and dying cells release ATP into the extracellular space, where ATP acts as a "danger signal" that promotes inflammation and regulates immune responses. 1,2 Elevated plasma ATP levels in the peripheral circulation of trauma and critical care patients may contribute to the systemic inflammatory response and multiple-organ dysfunction syndrome that are the hallmarks of sepsis. 3-5

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A Modular View of the Signaling System Regulating Chemotaxis

Iglesias

2015

Physical Models of Cell Motility

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Pannexin 1 Channels Link Chemoattractant Receptor Signaling to Local Excitation and Global Inhibition Responses at the Front and Back of Polarized Neutrophils

Cited by 91 publications

References 42 publications

Adenosine arrests breast cancer cell motility by A3 receptor stimulation

Adenosine arrests breast cancer cell motility by A3 receptor stimulation

Frontline Science: Escherichia coli use LPS as decoy to impair neutrophil chemotaxis and defeat antimicrobial host defense

A Modular View of the Signaling System Regulating Chemotaxis

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