Target ablation-induced regulation of macrophage recruitment into the olfactory epithelium of Mip-1alpha-/- mice and restoration of function by exogenous MIP-1alpha

Abstract

The chemokine macrophage inflammatory protein (MIP)-1alpha recruits macrophages to sites of epithelial remodeling. We showed previously that mRNA and protein levels of MIP-1alpha in the olfactory epithelium (OE) increased significantly at 3 days after bilateral olfactory bulbectomy (OBX). The first aim of this study was to investigate the effect of the absence of MIP-1alpha on macrophage recruitment to the OE 3 days after OBX in Mip-1alpha(-/-) mice compared with C57BL/6 mice and to test whether chemokine function could be restored by MIP-1alpha protein injection into Mip-1alpha(-/-) mice. OBX was performed on C57BL/6 and Mip-1alpha(-/-) mice. The mice received six subcutaneous injections at 12-h intervals of either 10 mug/ml MIP-1alpha protein in carrier or carrier only. Macrophage recruitment was evaluated with antibodies to CD68 for all macrophages and F4/80 for activated macrophages. Compared with C57BL/6 mice, at 3 days post-OBX the numbers of CD68(+) and F4/80(+) macrophages were significantly lower in carrier-injected Mip-1alpha(-/-) mice and were comparable in MIP-1alpha protein-injected Mip-1alpha(-/-) mice. The second aim was to determine the identity of genes regulated at 3 days post-OBX in the OE of carrier-injected Mip-1alpha(-/-) mice compared with carrier-injected C57BL/6 mice. Total RNA from the OE was hybridized to Affymetrix microarrays. A number of chemokine-, cytokine-, and growth factor-related genes were significantly regulated in the Mip-1alpha(-/-) mice and were restored in MIP-1alpha protein-injected Mip-1alpha(-/-) mice. The results illustrated that MIP-1alpha played a key role in recruitment of macrophages to the OE and provided insight into the genomic regulation involved in OE remodeling.