Naydenov Nayden G, Feygin Alex, Wang Dongdong, Kuemmerle John F, Harris Gianni, Conti Mary Anne, Adelstein Robert S, Ivanov Andrei I
Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, VA23298.
Department of Internal Medicine, Virginia Commonwealth University, Richmond, VA 23298.
Sci Rep. 2016 Apr 11;6:24161. doi: 10.1038/srep24161.
The actin cytoskeleton is a critical regulator of intestinal mucosal barrier permeability, and the integrity of epithelial adherens junctions (AJ) and tight junctions (TJ). Non muscle myosin II (NM II) is a key cytoskeletal motor that controls actin filament architecture and dynamics. While NM II has been implicated in the regulation of epithelial junctions in vitro, little is known about its roles in the intestinal mucosa in vivo. In this study, we generated a mouse model with an intestinal epithelial-specific knockout of NM IIA heavy chain (NM IIA cKO) and examined the structure and function of normal gut barrier, and the development of experimental colitis in these animals. Unchallenged NM IIA cKO mice showed increased intestinal permeability and altered expression/localization of several AJ/TJ proteins. They did not develop spontaneous colitis, but demonstrated signs of a low-scale mucosal inflammation manifested by prolapses, lymphoid aggregates, increased cytokine expression, and neutrophil infiltration in the gut. NM IIA cKO animals were characterized by a more severe disruption of the gut barrier and exaggerated mucosal injury during experimentally-induced colitis. Our study provides the first evidence that NM IIA plays important roles in establishing normal intestinal barrier, and protection from mucosal inflammation in vivo.
肌动蛋白细胞骨架是肠道黏膜屏障通透性以及上皮黏附连接（AJ）和紧密连接（TJ）完整性的关键调节因子。非肌肉肌球蛋白II（NM II）是一种关键的细胞骨架马达蛋白，可控制肌动蛋白丝的结构和动力学。虽然NM II在体外已被证明与上皮连接的调节有关，但对其在体内肠道黏膜中的作用知之甚少。在本研究中，我们构建了一种肠道上皮特异性敲除NM IIA重链的小鼠模型（NM IIA cKO），并研究了这些动物正常肠道屏障的结构和功能，以及实验性结肠炎的发展情况。未经刺激的NM IIA cKO小鼠表现出肠道通透性增加，以及几种AJ/TJ蛋白的表达/定位改变。它们并未发生自发性结肠炎，但表现出低级别黏膜炎症的迹象，如肠道脱垂、淋巴滤泡聚集、细胞因子表达增加以及中性粒细胞浸润。在实验性诱导的结肠炎中，NM IIA cKO动物的肠道屏障破坏更为严重，黏膜损伤更为加剧。我们的研究首次证明，NM IIA在建立正常肠道屏障以及体内预防黏膜炎症方面发挥着重要作用。
