Verdoni Angela M, Smith Richard S, Ikeda Akihiro, Ikeda Sakae
Department of Medical Genetics, University of Wisconsin-Madison, Madison, Wisconsin, United States of America.
PLoS One. 2008 Jul 16;3(7):e2701. doi: 10.1371/journal.pone.0002701.
Destrin (DSTN) is a member of the ADF/cofilin family of proteins and is an important regulator of actin dynamics. The primary function of destrin is to depolymerize filamentous actin into its monomeric form and promote filament severing. While progress has been made in understanding the biochemical functions of the ADF/cofilin proteins, the study of an animal model for cells deficient for DSTN provides an opportunity to investigate the physiological processes regulated by proper actin dynamics in vivo. A spontaneous mouse mutant, corneal disease 1(corn1), is deficient for DSTN, which causes epithelial hyperproliferation and neovascularization in the cornea. Dstn(corn1) mice exhibit an actin dynamics defect in the cornea as evidenced by the formation of actin stress fibers in the epithelial cells. Previously, we observed a significant infiltration of leukocytes into the cornea of Dstn(corn1) mice as well as the upregulation of proinflammatory molecules. In this study, we sought to characterize this inflammatory condition and explore the physiological mechanism through which a loss of Dstn function leads to inflammation.
METHODOLOGY/PRINCIPAL FINDINGS: Through immunofluorescent analyses, we observed a significant recruitment of neutrophils and macrophages to the Dstn(corn1) cornea, demonstrating that the innate immune system is spontaneously activated in this mutant. The inflammatory chemokine, CXCL5, was ectopically expressed in the corneal epithelial cells of Dstn(corn1) mice, and targeting of the receptor for this chemokine inhibited neutrophil recruitment. An inflammatory reaction was not observed in the cornea of allelic mutant strain, Dstn(corn1-2J), which has a milder defect in actin dynamics in the corneal epithelial cells.
CONCLUSIONS/SIGNIFICANCE: This study shows that severe defects in actin dynamics lead to an autoinflammatory condition that is mediated by the expression of CXC chemokines.
肌动蛋白去聚合因子（DSTN）是肌动蛋白解聚因子/丝切蛋白（ADF/cofilin）家族蛋白的成员之一，是肌动蛋白动力学的重要调节因子。DSTN的主要功能是将丝状肌动蛋白解聚为单体形式，并促进丝切断。虽然在理解ADF/cofilin蛋白的生化功能方面取得了进展，但对DSTN缺陷细胞的动物模型的研究为在体内研究由适当的肌动蛋白动力学调节的生理过程提供了机会。一种自发的小鼠突变体，角膜病1（corn1），缺乏DSTN，这导致角膜上皮细胞过度增殖和新生血管形成。Dstn（corn1）小鼠角膜出现肌动蛋白动力学缺陷，上皮细胞中形成肌动蛋白应力纤维证明了这一点。此前，我们观察到Dstn（corn1）小鼠角膜中有大量白细胞浸润以及促炎分子上调。在本研究中，我们试图描述这种炎症状态，并探索Dstn功能丧失导致炎症的生理机制。
方法/主要发现：通过免疫荧光分析，我们观察到中性粒细胞和巨噬细胞大量募集到Dstn（corn1）角膜，表明该突变体中先天性免疫系统被自发激活。炎症趋化因子CXCL5在Dstn（corn1）小鼠角膜上皮细胞中异位表达，针对该趋化因子受体的靶向作用抑制了中性粒细胞募集。在等位基因突变株Dstn（corn1-2J）的角膜中未观察到炎症反应，该突变株在角膜上皮细胞中的肌动蛋白动力学缺陷较轻。
结论/意义：本研究表明，肌动蛋白动力学的严重缺陷导致一种由CXC趋化因子表达介导的自身炎症状态。
