Defective Association of the Platelet Glycoprotein Ib-IX Complex with the Glycosphingolipid-Enriched Membrane Domain Inhibits Murine Thrombus and Atheroma Formation

J Immunol. 2016 Jul 1;197(1):288-95. doi: 10.4049/jimmunol.1501946. Epub 2016 May 20.


Localization of the platelet glycoprotein Ib-IX complex to the membrane lipid domain is essential for platelet adhesion to von Willebrand factor and subsequent platelet activation in vitro. Yet, the in vivo importance of this localization has never been addressed. We recently found that the disulfide linkage between Ibα and Ibβ is critical for the association of Ibα with the glycosphingolipid-enriched membrane domain; in this study, we established a transgenic mouse model expressing this mutant human Ibα that is also devoid of endogenous Ibα (HαSSMα(-/-)). Characterization of this model demonstrated a similar dissociation of Ibα from murine platelet glycosphingolipid-enriched membrane to that expressed in Chinese hamster ovary cells, which correlates well with the impaired adhesion of the transgenic platelets to von Willebrand factor ex vivo and in vivo. Furthermore, we bred our transgenic mice into an atherosclerosis-prone background (HαSSMα(-/-)ApoE(-/-) and HαWTMα(-/-)ApoE(-/-)). We observed that atheroma formation was significantly inhibited in mutant mice where fewer platelet-bound CD11c(+) leukocytes were circulating (CD45(+)/CD11c(+)/CD41(+)) and residing in atherosclerotic lesions (CD45(+)/CD11c(+)), suggesting that platelet-mediated adhesion and infiltration of CD11c(+) leukocytes may be one of the mechanisms. To our knowledge, these observations provide the first in vivo evidence showing that the membrane GEM is physiologically and pathophysiologically critical in the function of the glycoprotein Ib-IX complex.

MeSH terms

  • Animals
  • Apolipoproteins E / genetics
  • Atherosclerosis / genetics
  • Atherosclerosis / immunology*
  • Blood Platelets / immunology*
  • CHO Cells
  • Calcium-Binding Proteins
  • Cricetulus
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Glycosphingolipids / metabolism*
  • Membrane Microdomains / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Microfilament Proteins
  • Plaque, Atherosclerotic / immunology*
  • Platelet Glycoprotein GPIb-IX Complex / metabolism*
  • Protein Binding
  • Thrombosis / immunology*
  • von Willebrand Factor / metabolism


  • AIF1 protein, human
  • Apolipoproteins E
  • Calcium-Binding Proteins
  • DNA-Binding Proteins
  • Glycosphingolipids
  • Microfilament Proteins
  • Platelet Glycoprotein GPIb-IX Complex
  • von Willebrand Factor