Control of macrophage 3D migration: a therapeutic challenge to limit tissue infiltration

Macrophages are professional migrating cells found in all body tissues from the early embryonic stages till the end of the adult life. Tissue macrophages do not only play beneficial roles. In several diseases, macrophages recruited from blood monocytes have a deleterious action such as favoring cancer progression and destroying tissues in chronic inflammation. To migrate in 3D environments, all leukocytes use the amoeboid movement while macrophages use the amoeboid and the mesenchymal migration modes. Mesenchymal migration takes place in dense matrices and involves podosomes and proteolysis of the extracellular matrix to create paths. Podosome disruption has been correlated with reduced mesenchymal migration of macrophages and unaffected amoeboid migration. Therefore, podosomes are proposed as a therapeutic target. Inhibiting podosome regulators that are only expressed in macrophages and few cell types would avoid collateral effects often encountered when ubiquitous proteins are used as drug targets. With the current status of our knowledge on human macrophage podosomes and 3D migration, the tyrosine kinase Hck appears to be a good candidate.