Department of Internal Medicine, Wexner Medical Center at The Ohio State University, Columbus, OH 43210, USA.
Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, TX 79106, USA.
Cells. 2019 Aug 16;8(8):908. doi: 10.3390/cells8080908.
Rheumatoid arthritis (RA) is an immune-mediated inflammatory disease, and Krüppel-like factor 2 (KLF2) regulates immune cell activation and function. Herein, we show that in our experiments 50% global deficiency of KLF2 significantly elevated arthritic inflammation and pathogenesis, osteoclastic differentiation, matrix metalloproteinases (MMPs), and inflammatory cytokines in K/BxN serum-induced mice. The severities of RA pathogenesis, as well as the causative and resultant cellular and molecular factors, were further confirmed in monocyte-specific KLF2 deficient mice. In addition, induction of RA resulted in a decreased level of KLF2 in monocytes isolated from both mice and humans along with higher migration of activated monocytes to the RA sites in humans. Mechanistically, overexpression of KLF2 decreased the level of MMP9; conversely, knockdown of KLF2 increased MMP9 in monocytes along with enrichment of active histone marks and histone acetyltransferases on the MMP9 promoter region. These findings define the critical regulatory role of myeloid KLF2 in RA pathogenesis.
类风湿关节炎（RA）是一种免疫介导的炎症性疾病，而 Krüppel 样因子 2（KLF2）调节免疫细胞的激活和功能。在此，我们的实验表明，KLF2 全身性缺失 50%会显著增加 K/BxN 血清诱导的小鼠的关节炎炎症和发病机制、破骨细胞分化、基质金属蛋白酶（MMPs）和炎症细胞因子。在单核细胞特异性 KLF2 缺陷小鼠中进一步证实了 RA 发病机制的严重程度以及致病和结果性的细胞和分子因素。此外，诱导 RA 会导致从人和小鼠分离的单核细胞中 KLF2 水平降低，同时激活的单核细胞向 RA 部位的迁移增加。从机制上讲，KLF2 的过表达降低了 MMP9 的水平；相反，KLF2 的敲低增加了单核细胞中的 MMP9，并富集了 MMP9 启动子区域上的活性组蛋白标记和组蛋白乙酰转移酶。这些发现定义了骨髓细胞 KLF2 在 RA 发病机制中的关键调节作用。
