Disruption of neutrophil migration in a conditional transgenic model: Evidence for CXCR2 desensitization in vivo

We developed transgenic mice conditionally expressing the neutrophil chemoa ttracting chemokine KC and the beta -galactosidase gene in multiple tissues . In these transgenic mice, doxycycline treatment induced a strong up-regul ation in the expression of KC in several tissues, including heart, liver, k idney, skin, and skeletal muscle. Expression of KC within these tissues led to a rapid and substantial increase in the serum levels of KC (serum KC le vels were higher than 200 ng/ml 24 h after treatment). Accordingly, beta -g alactosidase expression was also detected after injection of doxycycline an d was highest in skeletal muscle, pancreas, and liver. Surprisingly, despit e expression of KC in multiple tissues, no neutrophil infiltration was obse rved in any of the tissues examined, including skin. Doxycycline treatment of nontransgenic mice grafted with transgenic skin caused dense neutrophili c infiltration of the grafts, but not the surrounding host skin, indicating that the KC produced in transgenic tissues was biologically active. In sep arate experiments, neutrophil migration toward a localized source of recomb inant KC was impaired in animals overexpressing KC but was normal in respon se to other neutrophil chemoattractants. Analysis of transgenic neutrophils revealed that high concentrations of KC in transgenic blood had no influen ce on L-selectin cell surface expression but caused desensitization of the receptor for KC, CXCR2. These results confirm the neutrophil chemoattractan t properties of KC and provide a mechanistic explanation for the paradoxica l lack of leukocyte infiltration observed in the presence of elevated conce ntrations of this chemokine.