Functional replacement of murine CXCR2 by its human homologue in the development of atherosclerosis in LDLR knockout mice.
The CXC chemokine receptor CXCR2 has been implicated in the pathogenesis of several chronic diseases including atherosclerosis. To enable animal studies towards understanding the role of human CXCR2 (hCXCR2) in disease development, we previously generated hCXCR2 knockin (hCXCR2(+/+)) mice. We have demonstrated that the phenotype and the acute immune response of the hCXCR2(+/+) mice was identical to that of wild-type mice, indicating that hCXCR2 indeed takes over the function of endogenous mouse CXCR2 (mCXCR2). In the present paper, we extend these findings by studying whether hCXCR2 functionally replaces the role of mCXCR2 in a chronic disease model for atherosclerosis. We first defined which of two well-described atherosclerosis models (ApoE(-/-) or LDLR(-/-) mice) is most suited for this purpose. When expression of mCXCR2 and that of its ligands in atherosclerotic lesions were compared in these mice, increased expression levels were observed only in LDLR(-/-) mice. Further, cultured atherosclerotic aortas from LDLR(-/-) mice did secrete significantly higher levels of CXCR2 ligands compared to aortas from healthy controls. Since these results support the role of CXCR2 in the atherogenesis in the LDLR(-/-) mice, double mutant hCXCR2(+/+)/LDLR(-/-) mice were generated and diet-induced atherosclerosis in these mice was compared to that in LDLR(-/-) mice. Upon an atherogenic diet, the hCXCR2(+/+)/LDLR(-/-) mice developed plaque lesions in a similar manner to those in LDLR(-/-) mice, indicating successful functional replacement of mCXCR2 by hCXCR2 in this disease model. We conclude that hCXCR2(+/+)/LDLR(-/-) mice present an attractive model to study the role of hCXCR2 in atherosclerosis development and for future testing of novel pharmaceuticals designed to antagonize hCXCR2.
Mihara
Katsuhiro
K
Department of Pharmacology, N. V. Organon, Molenstraat, Oss, The Netherlands. katsuhiro.mihara@organon.com
Spansier
Mirjam
M
Rooseboom
Martijn
M
Smit
Martin-Jan
MJ
Dokter
Wim
W
D000818:Animals; D001057:Apolipoproteins E / Q000502:physiology; D050197:Atherosclerosis / Q000209:etiology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D023063:Receptors, Interleukin-8B / Q000502:physiology*; D011973:Receptors, LDL / Q000502:physiology*
D001057:Apolipoproteins E; D023063:Receptors, Interleukin-8B; D011973:Receptors, LDL