MEK1/2 Inhibition Promotes Macrophage Reparative Properties [INNATE IMMUNITY AND INFLAMMATION]

Abstract

Macrophages have important functional roles in regulating the timely promotion and resolution of inflammation. Although many of the intracellular signaling pathways involved in the proinflammatory responses of macrophages are well characterized, the components that regulate macrophage reparative properties are less well understood. We identified the MEK1/2 pathway as a key regulator of macrophage reparative properties. Pharmacological inhibition of the MEK1/2 pathway by a MEK1/2 inhibitor (MEKi) significantly increased expression of IL-4/IL-13 (M2)-responsive genes in murine bone marrow–derived and alveolar macrophages. Deletion of the MEK1 gene using LysMCre+/+Mek1fl/fl macrophages as an alternate approach yielded similar results. MEKi enhanced STAT6 phosphorylation, and MEKi-induced changes in M2 polarization were dependent on STAT6. In addition, MEKi treatment significantly increased murine and human macrophage efferocytosis of apoptotic cells, independent of macrophage polarization and STAT6. These phenotypes were associated with increased gene and protein expression of Mertk, Tyro3, and Abca1, three proteins that promote macrophage efferocytosis. We also studied the effects of MEKi on in vivo macrophage efferocytosis and polarization. MEKi-treated mice had increased efferocytosis of apoptotic polymorphonuclear leukocytes instilled into the peritoneum. Furthermore, administration of MEKi after LPS-induced lung injury led to improved recovery of weight, fewer neutrophils in the alveolar compartment, and greater macrophage M2 polarization. Collectively, these results show that MEK1/2 inhibition is capable of promoting the reparative properties of murine and human macrophages. These studies suggest that the MEK1/2 pathway may be a therapeutic target to promote the resolution of inflammation via modulation of macrophage functions.

Footnotes

  • This work was supported by National Heart, Lung, and Blood Institute, National Institutes of Health Grants R01 HL116514 (to A.M.M.) and T32 HL007828 (to M.E.L.) and by University of Washington Cystic Fibrosis Foundation Research Development Program SINGH15R0 (to M.E.L.).

  • The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Heart, Lung, and Blood Institute, the National Institutes of Health, or the Cystic Fibrosis Foundation.

  • The online version of this article contains supplemental material.

  • Abbreviations used in this article:

    AC
    apoptotic cell
    AM
    alveolar macrophage
    BAL
    bronchoalveolar lavage
    BALF
    BAL fluid
    BMDM
    bone marrow–derived macrophage
    Ct
    cycle threshold
    M1
    macrophage (LPS)
    M2
    macrophage (IL-4/IL-13)
    MDM
    monocyte-derived macrophage
    Meki
    MEK1/2 inhibitor
    MFI
    mean fluorescence intensity
    ΔMFI
    change in mean fluorescence intensity
    PMN
    polymorphonuclear leukocyte
    qPCR
    quantitative real-time PCR
    RQ
    relative quantification
    WT
    wild-type.
  • Received June 17, 2016.
  • Accepted November 16, 2016.

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