Role of platelet CLEC‐2 and podoplanin in inflammation and vascular integrity

Lombard, Stephanie Eileen (2017). Role of platelet CLEC‐2 and podoplanin in inflammation and vascular integrity. University of Birmingham. Ph.D.

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Abstract

Introduction: The platelet receptor CLEC‐2 is believed to play a key role in many of the newly emerging roles of platelets, such as development and inflammation. The aim of this thesis was to look further into the interaction of CLEC‐2 and podoplanin and to investigate the role these proteins play in inflammation.
Methods: In‐vitro flow experiments using recombinant podoplanin and whole blood were used to investigate the interaction of CLEC‐2 and podoplanin under shear stress. The role of CLEC‐2 in inflammation was investigated using a range of mouse models such as LPS induced peritonitis model, DSS induced colitis and a mouse model of atherosclerosis.
Results: Mouse podoplanin induces platelet aggregation under arterial rates of shear through the receptor CLEC‐2. The aggregation is likely due to the high affinity interaction between mouse CLEC‐2 and podoplanin. The results of role of CLEC‐2 in inflammation revealed a lack of CLEC‐2 from inception causes a more acute inflammatory reaction to LPS. CLEC‐2 (removed post development) also plays a protective role in an acute model of ulcerative colitis. Mice lacking CLEC‐2 do not upregulate podoplanin on lymphatic endothelial cells and epithelial cells in the colon to the same degree as their wildtype counterparts following induction of colitis. CLEC‐2 is also protective against atherosclerosis however there was a greater upregulation of podoplanin in the plaques of atheroprone platelet CLEC‐2 deficient mice. The results of this thesis highlight the complicated role of CLEC‐2 in inflammatory disorders. There is also a clear difference in the affinity of mouse and human forms of CLEC‐2 and podoplanin which has important consequences for the interpretation of mouse models examining the role of these proteins in human diseases.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

Supervisor(s):