Lee Heedoo, Zhang Duo, Wu Jingxuan, Otterbein Leo E, Jin Yang
Division of Pulmonary and Critical Care Medicine, Department of Medicine, Boston University, Boston, MA 02118; and.
Department of Surgery, Harvard Medical School, Beth Israel Deaconess Medical Center, Boston, MA 02215.
J Immunol. 2017 Aug 15;199(4):1453-1464. doi: 10.4049/jimmunol.1700165. Epub 2017 Jul 3.
Robust lung inflammation is one of the prominent features in the pathogenesis of acute lung injury (ALI). Macrophage migration and recruitment are often seen at the early stage of lung inflammatory responses to noxious stimuli. Using an acid inhalation-induced lung injury model, we explored the mechanisms by which acid exposure initiates macrophage recruitment and migration during development of ALI. The lung epithelium comprises a large surface area and functions as a first-line defense against noxious insults. We found that acid exposure induced a remarkable microvesicle (MV) release from lung epithelium as detected in bronchoalveolar lavage fluid. Significantly elevated RNA, rather than protein, was found in these epithelium-derived MVs after acid and included several highly elevated microRNAs, including microRNA (miR)-17 and miR-221. Acid-induced epithelial MV release promoted macrophage migration in vitro and recruitment into the lung in vivo and required, in part, MV shuttling of miR-17 and/or miR-221. Mechanistically, acid-induced epithelial MV miR-17/221 promoted β integrin recycling and presentation back onto the surface of macrophages, in part via a Rab11-mediated pathway. Integrin β is known to play an essential role in regulating macrophage migration. Taken together, acid-induced ALI results in epithelial MV shuttling of miR-17/221 that in turn modulates macrophage β integrin recycling, promoting macrophage recruitment and ultimately contributing to lung inflammation.
强烈的肺部炎症是急性肺损伤（ALI）发病机制中的突出特征之一。在肺部对有害刺激的炎症反应早期，常可见巨噬细胞迁移和募集。我们利用酸吸入诱导的肺损伤模型，探讨了在ALI发展过程中酸暴露引发巨噬细胞募集和迁移的机制。肺上皮具有较大的表面积，是抵御有害刺激的第一道防线。我们发现，酸暴露可诱导肺上皮显著释放微泡（MV），这在支气管肺泡灌洗液中可检测到。酸刺激后，这些上皮来源的MV中RNA显著升高，而非蛋白质，且包括几种高度升高的微小RNA，如微小RNA（miR）-17和miR-221。酸诱导的上皮MV释放促进了体外巨噬细胞迁移和体内巨噬细胞向肺内募集，这部分需要miR-17和/或miR-221通过MV转运。从机制上讲，酸诱导的上皮MV miR-17/221促进β整合素循环，并部分通过Rab11介导的途径重新呈现在巨噬细胞表面。已知整合素β在调节巨噬细胞迁移中起重要作用。综上所述，酸诱导的ALI导致上皮MV转运miR-17/221，进而调节巨噬细胞β整合素循环，促进巨噬细胞募集并最终导致肺部炎症。
