Chemokine atherosclerosis with

Chemokines have been shown to be associated with a number of autoinflammatory diseases including multiple sclerosis, rheumatoid arthritis, atherosclerosis, dermatitis, and organ transplant rejection. Evidence, reviewed below, is mounting that chemokines may play a major role in the pathophysiology of these diseases and thus chemokine receptor antagonists could prove to be useful therapeutics in treating these and other proinflammatory diseases. 

The chemotaxis of mononuclear leukocytes and the migration, growth, and activation of the multiple cell types within atherosclerotic lesions are critical for the chronic inflammatory and fibroproliferative response in atherosclerosis (Ml). Chemokine-mediated attraction of leukocytes to tissues has been shown in atherosclerotic lesions (G8). Studies using knockout and transgenic murine models indicated that chemokine receptor/ligand interactions are crucial in the development of atherosclerosis (P6). Moreover, chemokines may also interfere with smooth muscle cell migration and growth, and platelet activation and other well-defined features of the atherosclerotic process (A2). 

Fig. 5. Scavenger receptors (SRs). Structural features of scavenger receptors with proposed roles in atherosclerosis. The plasma membrane or the endosomal membrane (for CD68, which is mainly found in the endosomal compartment) is indicated by the vertical line, with the cytoplasmic domains to the left. The individual structural domains are described in the box. SRCL, SR with C-type lectin MARCO, macrophage receptor with collagenous structure SREC, SR expressed by endothelial cells SR-PSOX/CXCL16, membrane-bound chemokine L16 other SRs are described in the text (Section 7). Not drawn to scale.

Bale JF, Jr., O Neil ME (1989) Detection of murine cytomegalovirus DNA in circulating leukocytes harvested during acute infection of mice. J Virol 63 2667-2673 Bazan JF, Bacon KB, Hardiman G, Wang W, Soo K, Rossi D, Greaves DR, Zlotnik A, Schall TJ (1997) A new class of membrane-bound chemokine with a CX3C motif. Nature 385 640-644 Boisvert WA, Curtiss LK, Terkeltaub RA (2000) Interleukin-8 and its receptor CXCR2 in atherosclerosis. Immunol Res 21 129-137... 

Extensive research has been performed in mice to determine the factors involved in the pathogenesis of atherosclerosis (see Table 6.7). Two knock-out mouse strains were used apolipoprein E (ApoE ) mice that develop spontaneous atherosclerosis that progresses to myocardial infarction and stroke and LDL receptor (Ldlr ) mice that develop hypercholesterolemia and lesion development upon fat feeding [175]. Crossbreeding of this mice with mice that carry deletions in genes of the immune system indicate an essential role of chemokines and their receptors in the early phase of atherosclerosis (for excellent reviews, see [176, 177]). 

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