Human CXCR2 (hCXCR2) takes over functionalities of its murine homolog in hCXCR2 knockin mice.
Human CXCR2 (hCXCR2) has been implicated in diverse inflammatory diseases. When roles of this receptor studied in animal models are extrapolated into men, large species differences in expression of the receptor and its ligands must be considered. These differences seriously weaken conclusions toward the role of hCXCR2 in the development of human diseases. It furthermore hampers straightforward testing of CXCR2 antagonists, especially when compounds discriminate between human and other species' receptors. Using gene targeting in embryonic stem cells, a hCXCR2 knockin mouse strain was generated in which endogenous murine CXCR2 (mCXCR2) sequences are replaced by the hCXCR2 gene. Correct targeting and expression on neutrophils were confirmed by Southern blot and immunohistochemical analyses. A phenotypic analysis of the hCXCR2 knockin mice, in comparison to wild-type and CXCR2 knockout mice, confirmed proper function of the hCXCR2 gene. In vivo migratory responses of neutrophils were intact in hCXCR2 knockin mice. Finally, an experiment with a CXCR2 antagonist demonstrated that the knockin model is indeed useful for in vivo evaluation of low-molecular weight compounds. In conclusion, our data unequivocally show that hCXCR2 can functionally replace mCXCR2, making this an attractive model to test novel pharmaceuticals designed to antagonize human CXCR2 in vivo.
Mihara
Katsuhiro
K
Department of Pharmacology, NV Organon, Oss, The Netherlands.
Smit
Martin-Jan
MJ
Krajnc-Franken
Magda
M
Gossen
Jan
J
Rooseboom
Martijn
M
Dokter
Wim
W
D000818:Animals; D002118:Calcium / Q000276:immunology; D002465:Cell Movement / Q000187:drug effects / Q000276:immunology; D018925:Chemokines / Q000276:immunology; D004195:Disease Models, Animal; D005260:Female; D018390:Gene Targeting; D006801:Humans; D007249:Inflammation / Q000276:immunology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009504:Neutrophils / Q000166:cytology / Q000276:immunology; D010538:Peritonitis / Q000139:chemically induced / Q000276:immunology*; D023063:Receptors, Interleukin-8B / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology*; D013234:Stem Cells; D013864:Thioglycolates / Q000494:pharmacology
D018925:Chemokines; D023063:Receptors, Interleukin-8B; D013864:Thioglycolates; D002118:Calcium