title: MEK1/2 Inhibition Promotes Macrophage Reparative Properties.
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/flmacrophages 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.
authors.affiliation: Center for Lung Biology, Division of Pulmonary and Critical Care Medicine, University of Washington, Seattle, WA 98109.
authors.forename: Matthew E
authors.initials: ME
authors.lastname: Long
authors.affiliation: Center for Lung Biology, Division of Pulmonary and Critical Care Medicine, University of Washington, Seattle, WA 98109.
authors.forename: William E
authors.initials: WE
authors.lastname: Eddy
authors.affiliation: Center for Lung Biology, Division of Pulmonary and Critical Care Medicine, University of Washington, Seattle, WA 98109.
authors.forename: Ke-Qin
authors.identifier: 0000-0002-3290-849X
authors.initials: KQ
authors.lastname: Gong
authors.affiliation: Center for Lung Biology, Division of Pulmonary and Critical Care Medicine, University of Washington, Seattle, WA 98109.
authors.forename: Lara L
authors.identifier: 0000-0002-4884-2835
authors.initials: LL
authors.lastname: Lovelace-Macon
authors.affiliation: Center for Lung Biology, Division of Pulmonary and Critical Care Medicine, University of Washington, Seattle, WA 98109.
authors.forename: Ryan S
authors.identifier: 0000-0003-3489-6127
authors.initials: RS
authors.lastname: McMahan
authors.affiliation: Centre de Recherche sur le Cancer de l'Université Laval, Centre de Recherche du Centre Hospitalier Universitaire de Québec, L'Hôtel-Dieu de Québec, Quebec G1R 3S3, Canada; and.|Department of Molecular Biology, Medical Biochemistry and Pathology, Laval University, Quebec G1V 0A6, Canada.
authors.forename: Jean
authors.initials: J
authors.lastname: Charron
authors.affiliation: Center for Lung Biology, Division of Pulmonary and Critical Care Medicine, University of Washington, Seattle, WA 98109.
authors.forename: W Conrad
authors.initials: WC
authors.lastname: Liles
authors.affiliation: Center for Lung Biology, Division of Pulmonary and Critical Care Medicine, University of Washington, Seattle, WA 98109; manicone@uw.edu.
authors.forename: Anne M
authors.initials: AM
authors.lastname: Manicone
mesh_terms: D000818:Animals; D015153:Blotting, Western; D005434:Flow Cytometry; D055785:Gene Knockdown Techniques; D006801:Humans; D048369:MAP Kinase Kinase 1 / Q000037:antagonists & inhibitors / Q000276:immunology*; D048370:MAP Kinase Kinase 2 / Q000037:antagonists & inhibitors / Q000276:immunology*; D008264:Macrophages / Q000201:enzymology / Q000276:immunology*; D051379:Mice; D010587:Phagocytosis / Q000276:immunology*; D016133:Polymerase Chain Reaction; D015398:Signal Transduction / Q000276:immunology*
chemical_list: D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2