Chemokines and atherosclerosis: what Adam Smith has to say about vascular disease.

At the dawn of the industrial age, the social philosopher and economist Adam Smith wanted to explain how some countries were able to create what he called the “opulence” that other countries lacked. Smith suggested that the foremost driver of wealth was the division of labor because it directly results in increased productivity. In his famous example, one worker might make 20 pins a day, but when 10 workers divide the various tasks required to make a pin, they might make 48,000 a day, or an average of 4800 pins per worker per day. This concept is so powerful that it would be surprising if natural selection did not reward biological systems that do the same thing. To pursue this idea, one might, by straining credulity right to the breaking point, draw an analogy between inflammation and manufacturing. The “product” is effector cell infiltration into target tissues, which is a complex, multistep process involving alterations in cell adhesion, motility, and gene expression. The “workers” are chemokines, an equally complex family of 50 or so small secreted proteins that are chemoattractants for the leukocytes that make up the infiltrate (1). Here, then, is a system that seems tailor-made for the benefits of division of labor, and recent work on the function of chemokines in disease suggests that this is exactly what has happened. Chemokines and atherosclerosis One of the clearest examples of the essential role of chemokines in pathobiology involves atherosclerosis. In broad strokes, the inflammatory model of atherogenesis (2) suggests that insults to endothelial or smooth muscle cells, such as hypercholesterolemia or flow shear stress, stimulate the production of leukocyte chemoattractants that are both displayed on the luminal surface of endothelial cells and also secreted into the subendothelium. When these factors activate their receptors on rolling leukocytes, this induces firm integrindependent adhesion to the endothelium, followed by diapedesis into the subendothelium. Among the most important of the migrating cells in this model are monocytes, which differentiate in situ into macrophages and take up cholesterol to become the foam cells of the fatty streak. The target cell specificity of the aptly named monocyte chemoattractant protein-1 (MCP-1) makes this chemokine a superb candidate for the signal that brings circulating monocytes into the vessel wall; MCP-1 attracts monocytes but not neutrophils, and it stimulates the adhesion of monocytes to endothelial cells (3). Mice rendered genetically deficient for MCP-1 or its receptor, CCR2, are protected from vascular lesions in several atherosclerosis models (4–7). With such a tidy pathogenetic model available, perhaps it was understandable that many in the field have been disinclined to recognize the significance of studies implicating CXCR2 in atherogenesis. CXCR2 is the receptor for IL-8 and other CXC chemokines that have the three–amino acid glutamate-leucine-arginine (ELR) motif near their N-termini. These chemokines are potent chemoattractants for neutrophils and not monocytes, the converse of MCP-1. Nonetheless, the relevance of CXCR2 to atherogenesis was demonstrated in a complicated but illuminating study in which atherosclerosis-prone mice were lethally irradiated and reconstituted with bone marrow donated by wild-type or CXCR2 knockout mice (8). In the chimeras made with CXCR2–/– bone marrow, hematopoietic cells (including, of course, monocytes) were CXCR2-deficient, and these mice had significantly less vascular disease than chimeras made with CXCR2+/+ bone marrow. The paradox posed by this study is that although CXCR2 is important for neutrophil chemoattraction, neutrophils are absent from this atherosclerosis model. What is CXCR2 doing here?