The development of inflammatory diseases is impaired in mice with targeted disruption of either the Osteopontin (OPN) or the CD44 genes, indicating the importance of the corresponding proteins in cell-mediated immunity. OPN is considered to be a ligand for CD44 and is associated with CD44 inside migrating embryonic fibroblasts. Objectives: Since rapid infiltration of leukocytes occurs early in inflammation, we investigated the role of OPN and CD44 in the chemotaxis of neutrophils and periotoneal macrophages using cells isolated from OPN-/-, CD44-/- and wild-type (WT) mice. Methods: The relationship between the OPN and CD44 in these cells was studied by double immunofluorescent staining and confocal microscopy, while the ability of leukocytes to polarize and migrate in gradients formed by fMLP and CSF-1 was analyzed using Zigmond and modified Boyden chambers. Results: Whereas OPN and CD44 were co-localized in cell processes in migrating macrophages, little evidence of co-localization was evident in migrating neutrophils. Moreover, whereas the formation of cell processes was reduced in OPN-/- and CD44-/- macrophages, such differences were not evident in neutrophils. Neutrophils and macrophages from CD44-/- mice showed severely reduced migration with fMLP and CSF-1 (~10-20% compared to WT) whereas OPN-/- macrophages, in which cell surface CD44 expression measured by flow cytometry is reduced ~50%, showed reduced migration (~60%) to fMLP only. Conclusions: These studies demonstrate the importance of CD44 in leukocyte migration and have revealed differences in the relationship between OPN and CD44 in neutrophils and macrophages which may relate to differences in response to chemotactic signals.

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