CCR2 and Disease: Atherosclerosis

Due to the fact that CCR2 and its ligands are heavily involved in monocyte infiltration, they have been characterised in diseases that have high levels of monocyte infiltrates. This includes atherosclerosis, rheumatoid arthritis, multiple sclerosis, delayed hypersensitivity reactions, bacterial infection, and renal disease. In order to explain the concepts of how and why CCR2 blockade is used for therapies, I am going to look firstly at what the disease is, how CCR2 activation contributes to the disease state and whether targetting CCR2 is beneficial in ameliorating the symptoms. For ease of understanding, I am going to collect all my findings with regards to drugs that are targeted at antagonising CCR2 and present them in a table.

Atherosclerosis

Atherosclerosis is characterised by plaque formation in the blood vessel walls which narrows the lumen and impedes normal blood flow, leading to consequences such as turbulence and blockage resulting in myocardial infarction. These plaques consist of fatty streaks and are a result of the infiltration of monocytes through the blood vessel walls and into the bloodstream. Hence, atherosclerosis is known as an inflammatory disease. MCP-1 contributes to this process by aiding the extravasation process of monocytes into the bloodstream.  Here is a little animation that hopefully will help you to understand MCP-1’s role in atherosclerosis(15).

Basically, the key point to take from this is that MCP-1 is important in turning the rolling leukocyte attachments (initiated by e-selectin binding to sialylated Lewis-X moieties on the monocyte) into firm adhesions so that the monocyte can pass between the vascular endothelial cells and into the lumen of the blood vessel. The MCP-1 is bound to the extracellular matrix of the blood vessel wall along with CXCL8 which also contributes although probably more to neutrophil chemotaxis than to monocyte recruitment (16). Here is an animation to demonstrate this process visually.

For more information on both MCP-1 and IL-8 contribution to atherosclerosis, follow this link to read a ‘Letters to Nature’ Journal on the topic:  http://www.nature.com/nature/journal/v398/n6729/pdf/398718a0.pdf

Why is this relevant to atherosclerosis?

Monocyte entry into arteries contributes to atherosclerotic lesion formation as these monocytes differentiate into macrophages on entering the intima of the blood vessel wall. They can then accumulate and eventually turn into a foam cells. The animation below shows how this is leads to atherosclerotic plaques.

As I have shown, MCP-1 and therefore activation of CCR2 receptors, has been shown to be crucial in the development of atherosclerosis with CCR2 being characterised as the most abundant chemokine receptor on the surface of human blood monocytes (as proved through antibody staining). For any budding scientist, pharmacologist or researcher of drug development this is an obvious signal to suggest CCR2 inihibition as a potential therapy to ameliorate monocyte infiltration and therefore decrease atherosclerosis development.