鸟嘌呤核苷酸交换因子cytohesin-2(ARNO)是小GTP酶ARF6的主要激活剂,已被证明在细胞粘附中起重要作用。各种细胞类型和疾病模型中的迁移和细胞骨架重组。有趣的是,细胞迁移失调,伴随着高炎症反应,是慢性炎症性关节疾病期间与活化的滑膜成纤维细胞(SF)相关的标志之一,比如类风湿性关节炎.ARNO在此过程中的作用以前尚未被研究过,但我们假设局部发炎的关节的促炎环境诱导SF中ARNO介导的途径的激活,促进最终导致骨骼和软骨损伤的侵袭性细胞表型。因此,我们使用小干扰RNA研究ARNO对小鼠SFs病理性迁移和炎症反应的影响,揭示了一个可以被IL-1β快速激活的全功能ARNO-ARF6通路。这种信号传导促进细胞迁移和粘着斑的形成。出乎意料的是,ARNO还被证明可以调节SF炎症反应,指示其精确的细胞因子和趋化因子表达谱。我们的结果揭示了ARNO在SF依赖性炎症中的新作用,这可能将致病性迁移与局部关节炎症的开始联系起来,为慢性关节炎和关节疾病中的成纤维细胞区室提供了新的靶向方法。
The guanine nucleotide exchange factor cytohesin-2 (
ARNO) is a major activator of the small GTPase ARF6 that has been shown to play an important role(s) in cell adhesion, migration and cytoskeleton reorganization in various cell types and models of disease. Interestingly, dysregulated cell migration, in tandem with hyper-inflammatory responses, is one of the hallmarks associated with activated synovial fibroblasts (SFs) during chronic inflammatory joint diseases, like rheumatoid arthritis. The role of ARNO in this process has previously been unexplored but we hypothesized that the pro-inflammatory milieu of inflamed joints locally induces activation of
ARNO-mediated pathways in SFs, promoting an invasive cell phenotype that ultimately leads to bone and cartilage damage. Thus, we used small interference RNA to investigate the impact of
ARNO on the pathological migration and inflammatory responses of murine SFs, revealing a fully functional
ARNO-ARF6 pathway which can be rapidly activated by IL-1β. Such signalling promotes cell migration and formation of focal adhesions. Unexpectedly,
ARNO was also shown to modulate SF-inflammatory responses, dictating their precise cytokine and chemokine expression profile. Our results uncover a novel role for ARNO in SF-dependent inflammation, that potentially links pathogenic migration with initiation of local joint inflammation, offering new approaches for targeting the fibroblast compartment in chronic arthritis and joint disease.