Long Matthew E, Eddy William E, Gong Ke-Qin, Lovelace-Macon Lara L, McMahan Ryan S, Charron Jean, Liles W Conrad, Manicone Anne M
Center for Lung Biology, Division of Pulmonary and Critical Care Medicine, University of Washington, Seattle, WA 98109.
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.
J Immunol. 2017 Jan 15;198(2):862-872. doi: 10.4049/jimmunol.1601059. Epub 2016 Dec 21.
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 LysMMek1 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.
巨噬细胞在调节炎症的及时促进和消退中发挥着重要的功能作用。尽管参与巨噬细胞促炎反应的许多细胞内信号通路已得到充分表征，但调节巨噬细胞修复特性的成分却了解较少。我们确定MEK1/2通路是巨噬细胞修复特性的关键调节因子。用MEK1/2抑制剂（MEKi）对MEK1/2通路进行药理学抑制，可显著增加小鼠骨髓来源的巨噬细胞和肺泡巨噬细胞中白细胞介素4/白细胞介素13（M2）反应性基因的表达。使用LysM-Mek1巨噬细胞作为另一种方法删除MEK1基因也产生了类似的结果。MEKi增强了信号转导和转录激活因子6（STAT6）的磷酸化，且MEKi诱导的M2极化变化依赖于STAT6。此外，MEKi处理显著增加了小鼠和人类巨噬细胞对凋亡细胞的吞噬作用，这与巨噬细胞极化和STAT6无关。这些表型与促进巨噬细胞吞噬作用的三种蛋白质——Mertk、Tyro3和Abca1的基因和蛋白表达增加有关。我们还研究了MEKi对体内巨噬细胞吞噬作用和极化的影响。经MEKi处理的小鼠对注入腹膜的凋亡多形核白细胞的吞噬作用增强。此外，在脂多糖诱导的肺损伤后给予MEKi可使体重恢复改善、肺泡腔中的中性粒细胞减少，并使巨噬细胞M2极化增强。总的来说，这些结果表明，抑制MEK1/2能够促进小鼠和人类巨噬细胞的修复特性。这些研究表明，MEK1/2通路可能是一个治疗靶点，可通过调节巨噬细胞功能来促进炎症的消退。
