Extracellular proteolysis in macrophage migration: Losing grip for a breakthrough

Abstract

Macrophage tissue infiltration is a hallmark of several pathological situations including cancer, neurodegenerative disorders and chronic inflammation. Hence, deciphering the mechanisms of macrophage migration across a variety of tissues holds great potential for novel anti-inflammatory therapies. Leukocytes have long been thought to migrate through tissues by using the amoeboid (protease-independent) migration mode; however, recent evidence indicates that macrophages can use either the amoeboid or the mesenchymal (protease-dependent) migration mode depending on the environmental constraints. Proteolytic activity is required for several key processes including cell migration. Paradoxically, the role of proteases in macrophage migration has been poorly studied. Here, by focusing on the best characterized extracellular protease families -MMPs, cathepsins and urokinase-type plasminogen activator -we give an overview of their probable involvement in macrophage migration. These proteases appear to play a role in all of the situations encountered by migrating macrophages, i.e. diapedesis, 2D and 3D migration. Migration of macrophages across tissues seems to proceed through an integrative analysis of numerous environmental clues allowing the cells to adapt their migration mode (amoeboid/ mesenchymal) and secrete dedicated proteases to ensure efficient tissue infiltration, as discussed in this review. The role of proteases in macrophage migration is an emerging field of research, which deserves further work to allow a more precise understanding.Key words: Cathepsins . Macrophage . MMPs . Migration . Proteases IntroductionTrafficking of leukocytes is a key process for immune cell development and host defense (reviewed in [1]); however, the presence of phagocyte-infiltrated tissues often correlates with the aggravation of several diseases including cancers, neurodegenerative disorders, atherosclerosis and chronic inflammation.Given this, the specific targeting of phagocyte tissue infiltration, without affecting the migration of the other leukocyte subsets required for protective immunity, is a challenge for the future. The identification of the migration modes and molecular processes used by macrophages to infiltrate tissues will therefore be key for proposing new therapeutic approaches.Phagocytes are able to migrate through most tissues in the body and, in vivo, they encounter both 2-dimentional (2D) and 3-dimentional (3D) environments. 2D migration takes place along surfaces such as inner vessel walls and inner epithelial surfaces (peritoneal cavity or lung alveolae) and involves firm cell adhesion Mini-Review to the substratum. 3D migration takes place inside tissues composed of cells and extracellular matrix (ECM) components which constitute a complex and heterogeneous environment. It has been observed that for tumor cells 2D and 3D migration proceed through distinct molecular and cellular mechanisms [2,3]. Phagocyte migration in 2D and across endothelial surfaces has been studied using a large panel of in vitro model...

A specific subset of RabGTPases controls cell surface exposure of MT1-MMP, extracellular matrix degradation and 3D invasion of macrophages

“…5A). Consistent with previous reports (Van Goethem et al, 2010;Vérollet et al, 2011), we found formation of elongated protrusions, which showed F-actin enrichment at their tips. Strikingly, the tips were also enriched in MT1-MMP-mCherry, pointing to a potential degradative capacity of these structures (Fig.…”

“…Within tissues, however, cells are surrounded by a three-dimensional environment, which is expected to influence both regulatory pathways involved in matrix degradation as well as the matrix-degrading organelles themselves. Indeed, primary human macrophages in gelled collagen I matrix have been shown to form long, dynamic protrusions that enriched are at their tips in podosome components such as F-actin, cortactin, talin, vinculin and CD44 (Van Goethem et al, 2010;Vérollet et al, 2011). Colocalisation of these structures with matrix defects and also with fluorescence signals in the collagen dequenching assay support the idea that these structures exhibit degradative capacity (Van Goethem et al, 2010).…”

ADAM10 localization in temporomandibular joint disk with internal derangement: an ex vivo immunohistochemical study

“…TMJ disk displacement induces progressive degradation of connective tissue ECM and histopathological changes that eventually lead to permanent loss of function (Vérollet et al, 2011). Normal TMJ disk contains ECM macromolecules, i.e.…”

Podosomes are disrupted in PAPA syndrome

“…Migration in 3D dense matrices such as Matrigel requires ECM degradation for macrophages to create paths. 9 In these environments, macrophages form cell protrusions called 3D podosomes at the tip of which podosome proteins accumulate along with F-actin and matrix proteolytic activity.…”