Biol. Pharm. Bull. 30(7) 1231—1236 (2007)

taxis in immune responses and is believed to play a key role in several inflammatory diseases including atherosclerosis. In man, CXCR2 is expressed in neutrophils, monocytes and macrophages and binds several chemokines such as CXCL8 (IL-8), CXCL1 (GROa), and CXCL5 (ENA78). Similarly in mice, a receptor homologous to human IL-8 (CXC chemokine ligand 8 [CXCL8]) receptor, or mouse CXCR2 (mCXCR2) is expressed in these neutrophils, monocytes and macrophages. mCXCR2 binds several CXCL8-like CXC chemokines, most notably KC and MIP-2. KC and MIP-2 are related to the 3 human GRO chemokines (CXCL1/3). It has been demonstrated that KC and MIP-2 can bind to human CXCR2 (hCXCR2) with a similar affinity as for mCXCR2. We have previously generated hCXCR2 knockin (hCXCR2( / )) mice that carry hCXCR2 instead of its mouse homolog, and described the full characterization of this knockin model. The phenotype of the hCXCR2( / ) mouse in contrast to mCXCR2 knockout mice perfectly resembled that of wild-type mice, indicating that the hCXCR2 is capable of functionally replacing its mouse counterpart. One of the most potential advantages of generating this model is that it allows one to study the role of hCXCR2 in the development of diseases like atherosclerosis, rheumatoid arthritis and psoriasis in preclinical animal studies using either antibodies against hCXCR2 or human specific CXCR2 antagonists. However, before such studies can be planned, it should be demonstrated that hCXCR2 can functionally replace mCXCR2 in development of the chronic disease in mice. Therefore, we performed studies aimed at demonstrating that the latter is indeed true for atherosclerotic plaque formation in a preclinical animal model. As mouse models for atherosclerosis, two well-described ApoE( / ) and LDLR( / ) mice are known. Since our data for LDLR( / ) mice indicate a prominent role for CXCR2 and its ligands in development of atherosclerosis as compared to ApoE( / ) mice, the former model for atherosclerosis was chosen to study functional replacement of mCXCR2 by hCXCR2. Atherosclerosis, a pathological remodeling of the arteries, is the underlying basis of myocardial infarction, stroke and peripheral artery disease. Atherosclerosis can be considered as a form of chronic inflammation occurring within the artery wall. In the pathogenesis of atherosclerosis, monocyte recruitment and macrophage differentiation are shown to be crucial features. In fatty streaks, the earliest detectable lesions in atherosclerosis, macrophage-derived foam cells that differentiate from recruited blood monocytes are detected. Since CXCR2 is expressed in monocytes and macrophages and mediates migration of these cells to the site of inflammation, attention has been increasing on the crucial role of CXCR2 in atherogenesis in man. Indeed several investigators have reported the involvement of CXCR2 in the development of atherosclerosis in preclinical animal models. In this study, we sought to demonstrate functional validity of hCXCR2 in the development of atherosclerosis using a preclinical animal model in the LDLR( / ) mice. Within the field of chemokine receptors, low molecular weight (LMW) antagonists often turn out to be specific for the human chemokine receptors. This seriously hampers straightforward testing of such antagonists in animal models. Validation of functional replacement of hCXCR2 and demonstration of its role in the disease model opens the way July 2007 1231