Podoplanin‐expressing inflammatory macrophages activate murine platelets via CLEC‐2

Kerrigan, AM; Navarro-Núñez, Leyre; Pyż, Elwira; Finney, Brenda; Willment, Janet A.; Watson, Steve P.; Gd, Brown

doi:10.1111/j.1538-7836.2011.04614.x

Cited by 81 publications

(92 citation statements)

References 12 publications

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“…However, a cellular source for podoplanin has not yet been identified in the skin. Alternatively, podoplanin could be "delivered" to sites of inflammation by infiltrating macrophages, a recently identified source of this molecule (42). Our observations that both GPVI and CLEC2 contributed to a similar extent to platelet-dependent vascular integrity in the lung and skin are consistent with a tissue-independent source of podoplanin as the trigger of platelet CLEC2 signaling.…”

Section: Discussionsupporting

confidence: 78%

Platelet ITAM signaling is critical for vascular integrity in inflammation

Boulaftali¹,

Hess²,

Getz³

et al. 2013

J. Clin. Invest.

180

264

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Platelets play a critical role in maintaining vascular integrity during inflammation, but little is known about the underlying molecular mechanisms. Here we report that platelet immunoreceptor tyrosine activation motif (ITAM) signaling, but not GPCR signaling, is critical for the prevention of inflammation-induced hemorrhage. To generate mice with partial or complete defects in these signaling pathways, we developed a protocol for adoptive transfer of genetically and/or chemically inhibited platelets into thrombocytopenic (TP) mice. Unexpectedly, platelets with impaired GPCR signaling, a crucial component of platelet plug formation and hemostasis, were indistinguishable from WT platelets in their ability to prevent hemorrhage at sites of inflammation. In contrast, inhibition of GPVI or genetic deletion of Clec2, the only ITAM receptors expressed on mouse platelets, significantly reduced the ability of platelets to prevent inflammation-induced hemorrhage. Moreover, transfusion of platelets without ITAM receptor function or platelets lacking the adapter protein SLP-76 into TP mice had no significant effect on vascular integrity during inflammation. These results indicate that the control of vascular integrity is a major function of immune-type receptors in platelets, highlighting a potential clinical complication of novel antithrombotic agents directed toward the ITAM signaling pathway.

show abstract

Section: Discussionsupporting

confidence: 78%

Platelet ITAM signaling is critical for vascular integrity in inflammation

Boulaftali¹,

Hess²,

Getz³

et al. 2013

J. Clin. Invest.

180

264

View full text Add to dashboard Cite

show abstract

“…CLEC-2 Binding Assays-CLEC-2 reporter cells (BWZ.36-CLEC-2/CD3) and dectin1 control reporter cells (BWZ.36-dectin1/CD3) were kindly provided by Prof. Gordon Brown (University of Aberdeen) and cultured as previously described (23,24). CLEC-2 activation studies were performed as previously described (23,25).…”

Section: Methodsmentioning

confidence: 99%

“…mPdpnT34A-Fc Showed a Reduced Ability to Activate and Bind to CLEC-2 Reporter Cells-To test the CLEC-2 binding and activation ability of the two mPdpn-Fc isoforms, we utilized CLEC-2 reporter cells (BWZ.36 CLEC-2/CD3) and dectin1 reporter cells (BWZ.36 dectin1/CD3) expressing a control C-type lectin receptor (24). This cellular reporter system is based on BWZ.36 cells as described by others (30).…”

Section: Characterization Of Two Recombinant Mouse Podoplanin-fcmentioning

confidence: 99%

Mutation of Threonine 34 in Mouse Podoplanin-Fc Reduces CLEC-2 Binding and Toxicity in Vivo While Retaining Anti-lymphangiogenic Activity

Bianchi

Fischer

Yuen

et al. 2014

Journal of Biological Chemistry

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Background: Podoplanin-Fc inhibits lymphangiogenesis, but also causes a bleeding disorder by binding to CLEC-2 expressed on platelets. Results: Mutation of threonine 34 in mouse Pdpn-Fc reduces 30-fold the binding to CLEC-2 and does not hamper its antilymphangiogenic activity. Conclusion: PdpnT34A-Fc is an active lymphangiogenesis inhibitor with a better tolerability. Significance: Mutagenesis of Pdpn-Fc is a valid approach to improve this tool for anti-lymphangiogenic therapy.

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“…Platelet CLEC-2 can engage with tumor cells expressing podoplanin, contributing to cancer metastasis (104). Interaction of platelet CLEC-2 with podoplanin expressing inflammatory macrophages can activate platelets (107). Consistent with an immune role for platelets, CLEC-2 on platelets can also capture human immunodeficiency virus type 1 (34).…”

Section: Overview Of Plateletsmentioning

confidence: 99%

Platelets and Their Interactions with Other Immune Cells

Lam

Vijayan

Rumbaut

2015

Comprehensive Physiology

116

119

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Platelets are anucleate blood cells, long known to be critically involved in hemostasis and thrombosis. In addition to their role in blood clots, increasing evidence reveals significant roles for platelets in inflammation and immunity. However, the notion that platelets represent immune cells is not broadly recognized in the field of Physiology. This manuscript reviews the role of platelets in inflammation and immune responses, and highlights their interactions with other immune cells, including examples of major functional consequences of these interactions.

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Podoplanin‐expressing inflammatory macrophages activate murine platelets via CLEC‐2

Cited by 81 publications

References 12 publications

Platelet ITAM signaling is critical for vascular integrity in inflammation

Platelet ITAM signaling is critical for vascular integrity in inflammation

Mutation of Threonine 34 in Mouse Podoplanin-Fc Reduces CLEC-2 Binding and Toxicity in Vivo While Retaining Anti-lymphangiogenic Activity

Platelets and Their Interactions with Other Immune Cells

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