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CC BY 4.0 · Thromb Haemost
DOI: 10.1055/a-2565-9496
Cellular Haemostasis and Platelets

Homophilic Interactions of Platelet F11R/JAM-A with Its Surface-Bound Counterpart Facilitate Thrombus Formation

Piotr Kamola
1   Department of Haemostatic Disorders, Medical University of Lodz, Lodz, Poland
,
Boguslawa Luzak
1   Department of Haemostatic Disorders, Medical University of Lodz, Lodz, Poland
,
Patrycja Przygodzka
2   Laboratory of Cellular and Molecular Biology, Institute of Medical Biology, Polish Academy of Sciences, Lodz, Poland
,
Cezary Watala
1   Department of Haemostatic Disorders, Medical University of Lodz, Lodz, Poland
,
Moro O. Salifu
3   Department of Medicine, State University of New York, Downstate Medical Center, Brooklyn, New York, United States
,
Anna Babinska
3   Department of Medicine, State University of New York, Downstate Medical Center, Brooklyn, New York, United States
,
Tomasz Przygodzki
1   Department of Haemostatic Disorders, Medical University of Lodz, Lodz, Poland
› Institutsangaben
Funding This work was supported by the National Science Centre grant OPUS (UMO-2020/37/B/NZ3/00301).
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Abstract

Background

F11Receptor/junctional adhesion molecule-A (F11R/JAM-A) is a transmembrane protein expressed in endothelial cells, epithelial cells, and in blood platelets. In blood platelets, F11R/JAM-A participates in adhesion under static conditions, suppresses the activation of the platelet αIIbβ3 integrin and was shown to activate blood platelets as soluble form via homophilic interactions.

Objectives

The purpose of presented study was to evaluate whether F11R/JAM-A is involved in platelet adhesion under flow conditions and in thrombus formation.

Methods

F11R/JAM-A contribution to platelet adhesion under flow conditions was assessed using flow chamber assay. Monoclonal antibodies and recombinant F11R/ JAM-A were used to assess the effects of F11R/JAM-A blockade on platelet aggregation and thrombus formation using total thrombus formation analysis system. Effects of F11R/JAM-A blockade on thrombus formation in vivo were evaluated in murine models of carotid artery injury.

Results

F11R/JAM-A was not capable of capturing flowing blood platelets alone but enhanced platelet adhesion to fibrinogen under flow conditions. Blocking of F11R/JAM-A homophilic interactions with specific monoclonal antibodies or with recombinant F11R/JAM-A impaired thrombus formation in vitro in human blood and in vivo in the models of thrombosis in mice.

Conclusion

Interactions of F11R/JAM-A located on flowing platelets with its surface-bound counterpart enhance platelet binding to fibrinogen under high shear stress conditions. Blocking of these homophilic interactions compromises thrombus formation. While previously published studies pointed at a significant role of soluble F11R/JAM-A in priming platelets during thrombus formation, our results highlight the role of surface-bound F11R/JAM-A in this process.

Keywords

junctional adhesion molecule-A (F11R/JAM-A) - platelets - adhesion - thrombosis

Supplementary Material



Publikationsverlauf

Eingereicht: 19. September 2024

Angenommen: 11. März 2025

Accepted Manuscript online:
25. März 2025

Artikel online veröffentlicht:
18. April 2025

© 2025. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/)

Georg Thieme Verlag KG
Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany

 

  • References

  • 1 Martìn-Padura I, Lostaglio S, Schneemann M. et al. Junctional adhesion molecule, a novel member of the immunoglobulin superfamily that distributes at intercellular junctions and modulates monocyte transmigration. J Cell Biol 1998; 142 (01) 117-127
    PubMedSuche in Google Scholar
  • 2 Mandell KJ, Parkos CA. The JAM family of proteins. Adv Drug Deliv Rev 2005; 57 (06) 857-867
    PubMedSuche in Google Scholar
  • 3 Kornecki E, Walkowiak B, Naik UP, Ehrlich YH. Activation of human platelets by a stimulatory monoclonal antibody. J Biol Chem 1990; 265 (17) 10042-10048
    PubMedSuche in Google Scholar
  • 4 Williams LA, Martin-Padura I, Dejana E, Hogg N, Simmons DL. Identification and characterisation of human Junctional Adhesion Molecule (JAM). Mol Immunol 1999; 36 (17) 1175-1188
    PubMedSuche in Google Scholar
  • 5 Azari BM, Marmur JD, Salifu MO. et al. Silencing of the F11R gene reveals a role for F11R/JAM-A in the migration of inflamed vascular smooth muscle cells and in atherosclerosis. Atherosclerosis 2010; 212 (01) 197-205
    PubMedSuche in Google Scholar
  • 6 Bazzoni G, Martinez-Estrada OM, Mueller F. et al. Homophilic interaction of junctional adhesion molecule. J Biol Chem 2000; 275 (40) 30970-30976
    PubMedSuche in Google Scholar
  • 7 Songyang Z, Fanning AS, Fu C. et al. Recognition of unique carboxyl-terminal motifs by distinct PDZ domains. Science 1997; 275 (5296) 73-77
    PubMedSuche in Google Scholar
  • 8 Monteiro AC, Luissint AC, Sumagin R. et al. Trans-dimerization of JAM-A regulates Rap2 and is mediated by a domain that is distinct from the cis-dimerization interface. Mol Biol Cell 2014; 25 (10) 1574-1585
    PubMedSuche in Google Scholar
  • 9 Ostermann G, Weber KS, Zernecke A, Schröder A, Weber C. JAM-1 is a ligand of the beta(2) integrin LFA-1 involved in transendothelial migration of leukocytes. Nat Immunol 2002; 3 (02) 151-158
    PubMedSuche in Google Scholar
  • 10 Naik UP, Ehrlich YH, Kornecki E. Mechanisms of platelet activation by a stimulatory antibody: cross-linking of a novel platelet receptor for monoclonal antibody F11 with the Fc gamma RII receptor. Biochem J 1995; 310 (Pt 1): 155-162
    PubMedSuche in Google Scholar
  • 11 Babinska A, Kedees MH, Athar H. et al. F11-receptor (F11R/JAM) mediates platelet adhesion to endothelial cells: role in inflammatory thrombosis. Thromb Haemost 2002; 88 (05) 843-850
    PubMedSuche in Google Scholar
  • 12 Schmitt MM, Megens RT, Zernecke A. et al. Endothelial junctional adhesion molecule-a guides monocytes into flow-dependent predilection sites of atherosclerosis. Circulation 2014; 129 (01) 66-76
    PubMedSuche in Google Scholar
  • 13 Sobocka MB, Sobocki T, Babinska A. et al. Signaling pathways of the F11 receptor (F11R; a.k.a. JAM-1, JAM-A) in human platelets: F11R dimerization, phosphorylation and complex formation with the integrin GPIIIa. J Recept Signal Transduct Res 2004; 24 (1–2): 85-105
    PubMedSuche in Google Scholar
  • 14 Naik MU, Caplan JL, Naik UP. Junctional adhesion molecule-A suppresses platelet integrin αIIbβ3 signaling by recruiting Csk to the integrin-c-Src complex. Blood 2014; 123 (09) 1393-1402
    PubMedSuche in Google Scholar
  • 15 Naik MU, Stalker TJ, Brass LF, Naik UP. JAM-A protects from thrombosis by suppressing integrin αIIbβ3-dependent outside-in signaling in platelets. Blood 2012; 119 (14) 3352-3360
    PubMedSuche in Google Scholar
  • 16 Azari BM, Marmur JD, Salifu MO, Ehrlich YH, Kornecki E, Babinska A. Transcription and translation of human F11R gene are required for an initial step of atherogenesis induced by inflammatory cytokines. J Transl Med 2011; 9: 98
    PubMedSuche in Google Scholar
  • 17 Ozaki H, Ishii K, Arai H. et al. Junctional adhesion molecule (JAM) is phosphorylated by protein kinase C upon platelet activation. Biochem Biophys Res Commun 2000; 276 (03) 873-878
    PubMedSuche in Google Scholar
  • 18 Rath D, Rapp V, Schwartz J. et al. Homophilic interaction between transmembrane-JAM-A and soluble JAM-A regulates thrombo-inflammation: implications for coronary artery disease. JACC Basic Transl Sci 2022; 7 (05) 445-461
    PubMedSuche in Google Scholar
  • 19 Babinska A, Clement CC, Przygodzki T. et al. A peptide antagonist of F11R/JAM-A reduces plaque formation and prolongs survival in an animal model of atherosclerosis. Atherosclerosis 2019; 284: 92-101
    PubMedSuche in Google Scholar
  • 20 Berg S, Kutra D, Kroeger T. et al. ilastik: interactive machine learning for (bio)image analysis. Nat Methods 2019; 16 (12) 1226-1232
    CrossrefPubMedSuche in Google Scholar
  • 21 Pike JA, Simms VA, Smith CW. et al. An adaptable analysis workflow for characterization of platelet spreading and morphology. Platelets 2021; 32 (01) 54-58
    PubMedSuche in Google Scholar
  • 22 Franchi F, Ortega-Paz L, Rollini F. et al. Cangrelor in patients with coronary artery disease pretreated with ticagrelor: the switching antiplatelet (SWAP)-5 study. JACC Cardiovasc Interv 2023; 16 (01) 36-46
    PubMedSuche in Google Scholar
  • 23 Oda Y, Ito T, Yamada Y. et al. Cardiovascular risk factors are associated with augmented thrombogenicity in healthy individuals: analysis using the total thrombus-formation analysis system. Thromb J 2021; 19 (01) 88
    PubMedSuche in Google Scholar
  • 24 Mandell KJ, McCall IC, Parkos CA. Involvement of the junctional adhesion molecule-1 (JAM1) homodimer interface in regulation of epithelial barrier function. J Biol Chem 2004; 279 (16) 16254-16262
    PubMedSuche in Google Scholar
  • 25 Terral G, Champion T, Debaene F. et al. Epitope characterization of anti-JAM-A antibodies using orthogonal mass spectrometry and surface plasmon resonance approaches. MAbs 2017; 9 (08) 1317-1326
    PubMedSuche in Google Scholar
  • 26 Woodfin A, Reichel CA, Khandoga A. et al. JAM-A mediates neutrophil transmigration in a stimulus-specific manner in vivo: evidence for sequential roles for JAM-A and PECAM-1 in neutrophil transmigration. Blood 2007; 110 (06) 1848-1856
    PubMedSuche in Google Scholar
  • 27 Mathews R, Setthavongsack N, Le-Cook A. et al. Role of platelet count in a murine stasis model of deep vein thrombosis. Platelets 2024; 35 (01) 2290916
    CrossrefPubMedSuche in Google Scholar
  • 28 Morowski M, Vögtle T, Kraft P, Kleinschnitz C, Stoll G, Nieswandt B. Only severe thrombocytopenia results in bleeding and defective thrombus formation in mice. Blood 2013; 121 (24) 4938-4947
    CrossrefPubMedSuche in Google Scholar
  • 29 Mause SF, von Hundelshausen P, Zernecke A, Koenen RR, Weber C. Platelet microparticles: a transcellular delivery system for RANTES promoting monocyte recruitment on endothelium. Arterioscler Thromb Vasc Biol 2005; 25 (07) 1512-1518
    PubMedSuche in Google Scholar
  • 30 Nicolai L, Schiefelbein K, Lipsky S. et al. Vascular surveillance by haptotactic blood platelets in inflammation and infection. Nat Commun 2020; 11 (01) 5778
    CrossrefPubMedSuche in Google Scholar
  • 31 Agbani EO, Poole AW. Procoagulant platelets: generation, function, and therapeutic targeting in thrombosis. Blood 2017; 130 (20) 2171-2179
    CrossrefPubMedSuche in Google Scholar