Crosstalk between CX3CL1 and the Cytoskeleton during Vascular Inflammation

The ability of the cortical actin cytoskeleton to regulate the lateral diffusion of plasma membrane molecules is a fundamental guiding principle underlying many cellular processes. By creating and stabilizing diffusional barriers, the cytoskeleton can precisely regulate the association or dissociation of molecules in both time and space, ultimately dictating the signalling output of a cell. In this dissertation, I explore how modulation of the cortical actin cytoskeleton contributes to two critical aspects of vascular inflammation. Initially in Chapter 2, I focus specifically on endothelial cells and the unique transmembrane chemokine, CX3CL1, which is strongly implicated in the recruitment of leukocytes to the vascular intima and the progression of atherosclerosis. I document a novel cytoskeletal regulatory mechanism that limits the interactions between CX3CL1 and the membrane-associated protease ADAM10, thereby controlling the proteolytic release of soluble chemokine. Moreover, I discuss the implications of this mechanism in the recruitment of leukocytes during atherosclerosis, as well as the implications for membrane protease-substrate interactions in general. In Chapter 3, I explore how the proteolytically released, soluble species of CX3CL1 can subsequently influence the macrophage cytoskeleton and feed-forward to enhance the lateral diffusion and clustering of the scavenger receptor CD36. Consequently, CD36 more readily engages and internalizes cholesterol-rich, oxidized low-density lipoproteins, leading to the accumulation of cholesterol esters within macrophages, and thus, the acceleration of foam cell formation. These findings reveal a novel function of chemokines in priming macrophages for the engagement of multivalent ligand. Taken together, the body of work described in this dissertation emphasizes the role of the cytoskeleton in tuning cellular responses and demonstrates how cytoskeletal dysregulation can contribute to the progression of inflammation.

Department dc:contributor.department

Medical Science

Year dc:date.issued

2016

Author dc:creator

• Wong, Harikesh

Advisor dc:contributor.advisor

• Robinson, Lisa

• Atherosclerosis
• Cytoskeleton
• Receptors
• Signal integration
• Single-molecule imaging
• Vascular inflammation

Handle dc:identifier.uri

http://hdl.handle.net/1807/73195

OAI identifier oai:identifier

oai:utoronto.scholaris.ca:1807/73195