Purinergic Signaling: A Fundamental Mechanism in Neutrophil Activation

Chen, Yu; Yao, Yongli; Sumi, Yasuo; Li, Andrew; To, Uyen; Elkhal, Abdallah; Inoue, Yoshiaki; Woehrle, Tobias; Zhang, Qin; Hauser, Carl J.; Junger, Wolfgang G.

doi:10.1126/scisignal.2000549

Cited by 182 publications

(249 citation statements)

References 45 publications

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“…Our previous work has shown that neutrophils possess a highly structured and tightly regulated purinergic signaling system that defines various aspects of chemotaxis [3,7,8,40]. Our present study revealed that MDA-MB-231 breast cancer cells possess a variant of this purinergic signaling system.…”

Section: Discussionsupporting

confidence: 52%

“…Adenosine receptors comprise four different members: A1, A2a, A2b, and A3 receptors [2]. We have previously demonstrated a key role for A3 receptors in the regulation of neutrophil chemotaxis [3][4][5][6][7]. Specifically, we found that stimulation of neutrophils causes the release of cellular ATP.…”

Section: Introductionmentioning

confidence: 94%

“…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].…”

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: Discussionsupporting

confidence: 52%

Section: Introductionmentioning

confidence: 94%

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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“…This cycle of cell recruitment is often self‐amplified and sustained in MI/R and leads to further cell necrosis, scar formation, and cardiac dysfunction 6, 7, 8, 9, 10, 11. Adenine nucleotides such as ATP and AMP are potent danger‐associated molecular patterns that trigger chemotactic migration, vessel wall adhesion, and pro‐inflammatory cytokine production by early infiltrating leukocytes such as neutrophils and macrophages 12, 13, 14, 15. However, these adenine nucleotides can be dephosphorylated to adenosine.…”

Section: Introductionmentioning

confidence: 99%

Adenosine Production by Biomaterial‐Supported Mesenchymal Stromal Cells Reduces the Innate Inflammatory Response in Myocardial Ischemia/Reperfusion Injury

Shin

Wang

Zemskova

et al. 2018

JAHA

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BackgroundDuring myocardial ischemia/reperfusion (MI/R) injury, there is extensive release of immunogenic metabolites that activate cells of the innate immune system. These include ATP and AMP, which upregulate chemotaxis, migration, and effector function of early infiltrating inflammatory cells. These cells subsequently drive further tissue devitalization. Mesenchymal stromal cells (MSCs) are a potential treatment modality for MI/R because of their powerful anti‐inflammatory capabilities; however, the manner in which they regulate the acute inflammatory milieu requires further elucidation. CD73, an ecto‐5′‐nucleotidase, may be critical in regulating inflammation by converting pro‐inflammatory AMP to anti‐inflammatory adenosine. We hypothesized that MSC‐mediated conversion of AMP into adenosine reduces inflammation in early MI/R, favoring a micro‐environment that attenuates excessive innate immune cell activation and facilitates earlier cardiac recovery.Methods and ResultsAdult rats were subjected to 30 minutes of MI/R injury. MSCs were encapsulated within a hydrogel vehicle and implanted onto the myocardium. A subset of MSCs were pretreated with the CD73 inhibitor, α,β‐methylene adenosine diphosphate, before implantation. Using liquid chromatography/mass spectrometry, we found that MSCs increase myocardial adenosine availability following injury via CD73 activity. MSCs also reduce innate immune cell infiltration as measured by flow cytometry, and hydrogen peroxide formation as measured by Amplex Red assay. These effects were dependent on MSC‐mediated CD73 activity. Finally, through echocardiography we found that CD73 activity on MSCs was critical to optimal protection of cardiac function following MI/R injury.Conclusions MSC‐mediated conversion of AMP to adenosine by CD73 exerts a powerful anti‐inflammatory effect critical for cardiac recovery following MI/R injury.

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“Find Me” and “Eat Me” signals: tools to drive phagocytic processes for modulating antitumor immunity

Xiao,

Zhang,

Guo

et al. 2024

Cancer Communications

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Phagocytosis, a vital defense mechanism, involves the recognition and elimination of foreign substances by cells. Phagocytes, such as neutrophils and macrophages, rapidly respond to invaders; macrophages are especially important in later stages of the immune response. They detect “find me” signals to locate apoptotic cells and migrate toward them. Apoptotic cells then send “eat me” signals that are recognized by phagocytes via specific receptors. “Find me” and “eat me” signals can be strategically harnessed to modulate antitumor immunity in support of cancer therapy. These signals, such as calreticulin and phosphatidylserine, mediate potent pro‐phagocytic effects, thereby promoting the engulfment of dying cells or their remnants by macrophages, neutrophils, and dendritic cells and inducing tumor cell death. This review summarizes the phagocytic “find me” and “eat me” signals, including their concepts, signaling mechanisms, involved ligands, and functions. Furthermore, we delineate the relationships between “find me” and “eat me” signaling molecules and tumors, especially the roles of these molecules in tumor initiation, progression, diagnosis, and patient prognosis. The interplay of these signals with tumor biology is elucidated, and specific approaches to modulate “find me” and “eat me” signals and enhance antitumor immunity are explored. Additionally, novel therapeutic strategies that combine “find me” and “eat me” signals to better bridge innate and adaptive immunity in the treatment of cancer patients are discussed.

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Purinergic Signaling: A Fundamental Mechanism in Neutrophil Activation

Cited by 182 publications

References 45 publications

Adenosine arrests breast cancer cell motility by A3 receptor stimulation

Adenosine arrests breast cancer cell motility by A3 receptor stimulation

Adenosine Production by Biomaterial‐Supported Mesenchymal Stromal Cells Reduces the Innate Inflammatory Response in Myocardial Ischemia/Reperfusion Injury

“Find Me” and “Eat Me” signals: tools to drive phagocytic processes for modulating antitumor immunity

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