Discoidin domain receptor 1 isoform-a (DDR1a) promotes migration of leukocytes in three-dimensional collagen lattices

Although integrins are crucial for migration of leukocytes through endothel ium, integrin-independent mechanisms appear to take over and mediate the mi gration of leukocytes through extracellular matrix (ECM) in a three-dimensi onal tissue microenvironment. Discoidin domain receptor (DDR) 1 is a recept or tyrosine kinase activated by collagen, the most abundant ECM protein. In the present study, we detected that peripheral blood mononuclear cells (PB MC) and polymorphonuclear neutrophils were induced to express DDR1 after in cubation in RPMI 1640. The expression level of DDR1 in PBMC was increased f urther by stimulation with tumor necrosis factor-alpha, interleukin-1 beta, granulocyte-macrophage colony-stimulating factor, lipopolysaccharide, or p hytohemagglutinin, but not with interferon-gamma. In vivo, DDR1 mRNA was de tectable in mononuclear leukocytes infiltrating human renal tumor tissue. A mong three DDR1 isoforms, DDR1a was the major transcript in leukocytes. Fun ctionally, overexpression of either DDR1a or DDR1b in THP-1 cells resulted in increased adherence to collagen-coated plates in a beta1-integrin indepe ndent manner. However, only DDR1a-, but not DDR1b-, overexpressing cells ex hibited marked pseudopod extension and migrated successfully through three- dimensional collagen lattices. Consequently, we propose that the interactio n of DDR1a with collagen of the ECM results in a requisite intracellular si gnaling that enables leukocytes to migrate in a tissue microenvironment and participate in host defense.