title: MT1-MMP regulates the PI3Kδ·Mi-2/NuRD-dependent control of macrophage immune function.
abstract: Macrophages play critical roles in events ranging from host defense to obesity and cancer, where they infiltrate affected tissues and orchestrate immune responses in tandem with the remodeling of the extracellular matrix (ECM). Despite the dual roles played by macrophages in inflammation, the functions of macrophage-derived proteinases are typically relegated to tissue-invasive or -degradative events. Here we report that the membrane-tethered matrix metalloenzyme MT1-MMP not only serves as an ECM-directed proteinase, but unexpectedly controls inflammatory gene responses wherein MT1-MMP(-/-) macrophages mount exaggerated chemokine and cytokine responses to immune stimuli both in vitro and in vivo. MT1-MMP modulates inflammatory responses in a protease-independent fashion in tandem with its trafficking to the nuclear compartment, where it triggers the expression and activation of a phosphoinositide 3-kinase δ (PI3Kδ)/Akt/GSK3β signaling cascade. In turn, MT1-MMP-dependent PI3Kδ activation regulates the immunoregulatory Mi-2/NuRD nucleosome remodeling complex that is responsible for controlling macrophage immune response. These findings identify a novel role for nuclear MT1-MMP as a previously unsuspected transactivator of signaling networks central to macrophage immune responses.
authors.affiliation: Division of Molecular Medicine and Genetics, Department of Internal Medicine, University of Michigan, Ann Arbor, 48109, USA.
authors.forename: Ryoko
authors.initials: R
authors.lastname: Shimizu-Hirota
authors.forename: Wanfen
authors.initials: W
authors.lastname: Xiong
authors.forename: B Timothy
authors.initials: BT
authors.lastname: Baxter
authors.forename: Steven L
authors.initials: SL
authors.lastname: Kunkel
authors.forename: Ivan
authors.initials: I
authors.lastname: Maillard
authors.forename: Xiao-Wei
authors.initials: XW
authors.lastname: Chen
authors.forename: Farideh
authors.initials: F
authors.lastname: Sabeh
authors.forename: Rui
authors.initials: R
authors.lastname: Liu
authors.forename: Xiao-Yan
authors.initials: XY
authors.lastname: Li
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Weiss
mesh_terms: D000818:Animals; D002465:Cell Movement; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D058534:Class I Phosphatidylinositol 3-Kinases; D016207:Cytokines / Q000235:genetics; D005786:Gene Expression Regulation; D008264:Macrophages / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D008297:Male; D053511:Matrix Metalloproteinase 14 / Q000378:metabolism*; D056245:Mi-2 Nucleosome Remodeling and Deacetylase Complex / Q000378:metabolism*; D051379:Mice; D009707:Nucleosomes / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D021381:Protein Transport; D059748:Proteolysis
chemical_list: D058534:Class I Phosphatidylinositol 3-Kinases; D016207:Cytokines; D053511:Matrix Metalloproteinase 14; D056245:Mi-2 Nucleosome Remodeling and Deacetylase Complex; D009707:Nucleosomes; D019869:Phosphatidylinositol 3-Kinases; C507096:Mmp14 protein, mouse; C421683:Pik3cd protein, mouse