Department of Molecular Biomedicine, Cinvestav Zacatenco, Mexico City, Mexico.
Department of Physiology, Biophysics and Neurosciences, Cinvestav Zacatenco, Mexico City, Mexico.
Front Immunol. 2019 Jan 10;9:3118. doi: 10.3389/fimmu.2018.03118. eCollection 2018.
Intestinal macrophages are highly mobile cells with extraordinary plasticity and actively contribute to cytokine-mediated epithelial cell damage. The mechanisms triggering macrophage polarization into a proinflammatory phenotype are unknown. Here, we report that during inflammation macrophages enhance its intercellular adhesion properties in order to acquire a M1-phenotype. Using and models we demonstrate that intercellular adhesion is mediated by integrin-αVβ3 and relies in the presence of the unconventional class I myosin 1F (Myo1F). Intercellular adhesion mediated by αVβ3 stimulates M1-like phenotype in macrophages through hyperactivation of STAT1 and STAT3 downstream of ILK/Akt/mTOR signaling. Inhibition of integrin-αVβ3, Akt/mTOR, or lack of Myo1F attenuated the commitment of macrophages into a pro-inflammatory phenotype. In a model of colitis, Myo1F deficiency strongly reduces the secretion of proinflammatory cytokines, decreases epithelial damage, ameliorates disease activity, and enhances tissue repair. Together our findings uncover an unknown role for Myo1F as part of the machinery that regulates intercellular adhesion and polarization in macrophages.
肠道巨噬细胞是高度移动的细胞，具有非凡的可塑性，并积极促进细胞因子介导的上皮细胞损伤。触发巨噬细胞极化为促炎表型的机制尚不清楚。在这里，我们报告说，在炎症期间，巨噬细胞增强其细胞间黏附特性，以获得 M1 表型。使用 和 模型，我们证明细胞间黏附是由整合素-αVβ3 介导的，并且依赖于非典型 I 类肌球蛋白 1F（Myo1F）的存在。αVβ3 介导的细胞间黏附通过 ILK/Akt/mTOR 信号通路下游的 STAT1 和 STAT3 的过度激活刺激巨噬细胞中 M1 样表型。整合素-αVβ3 抑制、Akt/mTOR 缺失或 Myo1F 缺乏会减弱巨噬细胞向促炎表型的分化。在结肠炎模型中，Myo1F 缺乏强烈降低促炎细胞因子的分泌，减少上皮损伤，改善疾病活动，并增强组织修复。总之，我们的发现揭示了 Myo1F 作为调节巨噬细胞细胞间黏附和极化的机制的一部分的未知作用。
