MT1-MMP regulates the PI3Kδ-Mi-2/NuRD-dependent control of macrophage immune function

Ryoko Shimizu-Hirota, Wanfen Xiong, B. Timothy Baxter, Steven L. Kunkel, Ivan Maillard, Xiao Wei Chen, Farideh Sabeh, Rui Liu, Xiao Yan Li, Stephen J. Weiss

Research output: Contribution to journalArticle

52 Citations (Scopus)

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 d (PI3Kδ)/Akt/GSK3b 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.

Original languageEnglish
Pages (from-to)395-413
Number of pages19
JournalGenes and Development
Volume26
Issue number4
DOIs
Publication statusPublished - 2012 Feb 15
Externally publishedYes

Keywords

  • Immune response
  • MT1-MMP
  • Macrophage
  • Nucleosome remodeling
  • PI3Kδ

ASJC Scopus subject areas

  • Genetics
  • Developmental Biology

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  • Cite this

    Shimizu-Hirota, R., Xiong, W., Baxter, B. T., Kunkel, S. L., Maillard, I., Chen, X. W., Sabeh, F., Liu, R., Li, X. Y., & Weiss, S. J. (2012). MT1-MMP regulates the PI3Kδ-Mi-2/NuRD-dependent control of macrophage immune function. Genes and Development, 26(4), 395-413. https://doi.org/10.1101/gad.178749.111