MT1-MMP Is Required for Myeloid Cell Fusion via Regulation of Rac1 Signaling

Gonzalo, Pilar; Guadamillas, Marta C.; Hernández-Riquer, María Victoria; Pollán, Ángela; Grande-García, A.; Bartolomé, Rubén A.; Vasanji, Amit; Ambrogio, Chiara; Chiarle, Roberto; Teixidó, Joaquı́n; Risteli, Juha; Apte, Suneel S.; Pozo, Miguel Á. del; Arroyo, Alicia G.

doi:10.1016/j.devcel.2009.11.012

Cited by 109 publications

(123 citation statements)

References 55 publications

(82 reference statements)

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“…A recent study has implicated MT1-MMP, a membrane-bound MMP, in the process of fusion via interaction with the adaptor protein p130Cas, leading to regulation of Rac1 activity. 45 However, integration of MT1-MMP signaling with signals propagated by IL-4 via DAP12, TREM-2, and DC-STAMP has not been defined.…”

Section: Discussionmentioning

confidence: 99%

Lack of TNF-α–Induced MMP-9 Production and Abnormal E-Cadherin Redistribution Associated with Compromised Fusion in MCP-1–Null Macrophages

Skokos

Charokopos

Khan

et al. 2011

The American Journal of Pathology

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Homotypic cell fusion occurs in several cell types including macrophages in the formation of foreign body giant cells. Previously, monocyte chemoattractant protein-1 (MCP-1) was demonstrated to be required for foreign body giant cell formation in the foreign body response. The present study investigated the fusion defect in MCP-1-null macrophages by implanting biomaterials intraperitoneally in wildtype and MCP-1-null mice and monitoring the macrophage response at 12 hours to 4 weeks. MCP-1-null mice exhibited reduced accumulation and fusion of macrophages on implants, which was associated with attenuation of the foreign body response. Consistent with previous in vitro findings, the level of matrix metalloproteinase-9 (MMP-9) was reduced in MCP-1-null macrophages adherent to implants. In contrast, CCR2 expression was unaffected. In vitro studies revealed reduced tumor necrosis factor-␣ (TNF-␣) production and abnormal subcellular redistribution of E-cadherin and ␤-catenin during fusion in MCP-1-null macrophages. Exogenous TNF-␣ caused an increase in the production of MMP-9 and rescued the fusion defect. Addition of GM6001 (MMP inhibitor) or NSC23766 (Rac1 inhibitor) indicated two distinct induction pathways, one for E-cadherin/␤-catenin and one for MCP-1, TNF-␣, and MMP-9. Considered together, these observations demonstrate that induction of E-cadherin/␤-catenin is not sufficient for fusion in the absence of MCP-1 or the downstream mediators TNF-␣ and MMP-9. Moreover, attenuation of the foreign body response in intraperitoneal implants in MCP-1-null mice demonstrates that the process depends on tissue-specific factors.

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Section: Discussionmentioning

confidence: 99%

Lack of TNF-α–Induced MMP-9 Production and Abnormal E-Cadherin Redistribution Associated with Compromised Fusion in MCP-1–Null Macrophages

Skokos

Charokopos

Khan

et al. 2011

The American Journal of Pathology

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“…Nef is associated with lysosomes in macrophages where it colocalizes with cathepsin D. Because p61Hck activation has been associated with mobilization and exocytosis of lysosomes (29,30,47,(79)(80)(81)(82), it is conceivable that lysosomes, which contain several enzyme subsets, including proteases, hydrolases, and v-ATPase, could facilitate the cleavage of surface proteins and glycocalyx from opposite cells to interact more closely and hence facilitate cell fusion. Additionally, lysosomal proteases could modulate surface receptor activity and signaling involved in cell-cell fusion (53,68,69,(83)(84)(85). Lysosomal proteases have been implicated in the formation of myotubes (60,61) and found in the secretome of HIV-1-infected giant human macrophages (86).…”

Section: Discussionmentioning

confidence: 99%

HIV-1 Nef Triggers Macrophage Fusion in a p61Hck- and Protease-Dependent Manner

Vérollet

Zhang

Cabec

et al. 2010

The Journal of Immunology

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Macrophages are a major target of HIV-1 infection. HIV-1–infected macrophages form multinucleated giant cells (MGCs) using poorly elucidated mechanisms. In this study, we show that MGC formation was reduced when human macrophages were infected with nef-deleted HIV-1. Moreover, expression of Nef, an HIV-1 protein required in several aspects of AIDS, was sufficient to trigger the formation of MGCs in RAW264.7 macrophages. Among Nef molecular determinants, myristoylation was dispensable, whereas the polyproline motif was instrumental for this phenomenon. Nef has been shown to activate hematopoietic cell kinase (Hck), a Src tyrosine kinase specifically expressed in phagocytes, through a well-described polyproline–SH3 interaction. Knockdown approaches showed that Hck is involved in Nef-induced MGC formation. Hck is expressed as two isoforms located in distinct subcellular compartments. Although both isoforms were activated by Nef, only p61Hck mediated the effect of Nef on macrophage fusion. This process was abolished in the presence of a p61Hck kinase-dead mutant or when p61Hck was redirected from the lysosome membrane to the cytosol. Finally, lysosomal proteins including vacuolar adenosine triphosphatase and proteases participated in Nef-induced giant macrophage formation. We conclude that Nef participates in HIV-1–induced MGC formation via a p61Hck- and lysosomal enzyme-dependent pathway. This work identifies for the first time actors of HIV-1–induced macrophage fusion, leading to the formation of MGCs commonly found in several organs of AIDS patients.

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“…In this model, MMP2 and MMP9 produced by macrophages are necessary for macrophage migration across the parenchymal basement membrane to enter into the brain [45]. MT1-MMP is involved in transendothelial migration of monocytes as demonstrated by approaches such as knock-out, knock-down or anti-MT1-MMP antibodies [26,27,46].…”

Section: Role Of Proteases In Diapedesismentioning

confidence: 99%

“…Chemotactic migration of monocytes on fibronectin is inhibited by antibodies directed against MT1-MMP [26] and MT1-MMP À/À BM macrophages have defective chemotactic migration and reduced mobility [27]. MT1-MMP is also involved in macrophage 2D migration in a proteolyticindependent manner, thanks to its intra-cytoplasmic tail signaling ability [27,28]. Thus, MT1-MMP is likely a key player in 2D monocyte/macrophage migration through multiple pathways.…”

Section: Introductionmentioning

confidence: 99%

“…MT1-MMP expression is up-regulated upon monocyte attachment to fibronectin and enriched at the leading edge of migrating monocytes [26]. Chemotactic migration of monocytes on fibronectin is inhibited by antibodies directed against MT1-MMP [26] and MT1-MMP À/À BM macrophages have defective chemotactic migration and reduced mobility [27]. MT1-MMP is also involved in macrophage 2D migration in a proteolyticindependent manner, thanks to its intra-cytoplasmic tail signaling ability [27,28].…”

Section: Introductionmentioning

confidence: 99%

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Extracellular proteolysis in macrophage migration: Losing grip for a breakthrough

et al. 2011

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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...

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MT1-MMP Is Required for Myeloid Cell Fusion via Regulation of Rac1 Signaling

Cited by 109 publications

References 55 publications

Lack of TNF-α–Induced MMP-9 Production and Abnormal E-Cadherin Redistribution Associated with Compromised Fusion in MCP-1–Null Macrophages

Lack of TNF-α–Induced MMP-9 Production and Abnormal E-Cadherin Redistribution Associated with Compromised Fusion in MCP-1–Null Macrophages

HIV-1 Nef Triggers Macrophage Fusion in a p61Hck- and Protease-Dependent Manner

Extracellular proteolysis in macrophage migration: Losing grip for a breakthrough

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