Welcome to the website of Dr. Isabelle Maridonneau-Parini and her research team
at the Institute of Pharmacology and Structural Biology!
Our objective is to characterize the molecular and cellular mechanisms involved in Macrophage migration in 3D environments and determine whether they can be influenced by pathogens.
Phagocytes, including monocyte/macrophages constitute the first line of host defence against microorganisms. To reach an infectious site, they leave the blood and migrate in tissues, a 3D environment, and ultimately perform microbicidal activity and tissue repair. 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 protective immunology. In several diseases, macrophages recruited from blood monocytes have a deleterious action such as favoring cancer progression and destroying tissues in chronic inflammation. Our team has investigated how macrophages migrate in 3D environments. While all leukocytes use the amoeboid movement, macrophages use the amoeboid and the mesenchymal migration modes, depending on the matrix architecture. 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. In contrast, by increasing the stability and the proteolytic activity of podosomes, the mesenchymal migration of macrophages is enhanced. Therefore, podosomes are proposed as a therapeutic target to reduce macrophage tissue infiltration in mentioned diseases. Our strategy is to inhibit podosome regulators that are only expressed in macrophages and few cell types to avoid collateral effects often encountered when ubiquitous proteins are used as drug targets. We have identified the phagocyte-specific Hck and the hematopoietic cell-restricted protein WASP as two podosome components involved in the mesenchymal migration. To further decipher the structure-function of podosomes and elucidate the respective role of podosome protein components, we have designed a new method called protrusion force microscopy allowing measurement of the protrusive force exerted by podosomes on the extracellular environment. We observed that podosomes possess mechanosensing properties, which requires them to exert forces on the environment to probe its mechanical properties by a combined action of actin polymerisation and acto-myosin contraction. Finally, we are learning how pathogens (HIV-1 and M. tuberculosis) using macrophages as a host cell modulate their migration in 3D environments.