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Genes & Dev. 26 (4): 395-413

Copyright © 2012 by Cold Spring Harbor Laboratory Press.

MT1-MMP regulates the PI3K{delta}·Mi-2/NuRD-dependent control of macrophage immune function

Ryoko Shimizu-Hirota1, Wanfen Xiong2, B. Timothy Baxter2, Steven L. Kunkel3, Ivan Maillard4,5, Xiao-Wei Chen4, Farideh Sabeh1, Rui Liu1, Xiao-Yan Li1,, and Stephen J. Weiss1,6

1 Division of Molecular Medicine and Genetics, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan 48109, USA;
2 Department of Surgery, University of Nebraska Medical Center, Omaha, Nebraska 68198, USA;
3 Department of Pathology,
4 Life Sciences Institute,
5 Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, Michigan 48109, USA

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 {delta} (PI3K{delta})/Akt/GSK3β signaling cascade. In turn, MT1-MMP-dependent PI3K{delta} 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.

Key Words: MT1-MMP • macrophage • PI3K{delta} • immune response • nucleosome remodeling

Received for publication September 9, 2011. Accepted for publication January 3, 2012.


6 Corresponding author.

E-mail sjweiss{at}umich.edu.

Supplemental material is available for this article.

Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.178749.111.


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