Institute of Musculoskeletal Medicine, University Hospital Muenster, Albert-Schweitzer-Campus 1, Bldg. D3, 48149, Muenster, Germany.
Department of Pediatric Rheumatology and Immunology, University Hospital Muenster, Muenster, Germany.
Sci Rep. 2021 Jul 8;11(1):14145. doi: 10.1038/s41598-021-93599-6.
The interactions of fibroblast-like synoviocyte (FLS)-derived pro-inflammatory cytokines/chemokines and immune cells support the recruitment and activation of inflammatory cells in RA. Here, we show for the first time that the classical myokine myostatin (GDF-8) is involved in the recruitment of Th17 cells to inflammatory sites thereby regulating joint inflammation in a mouse model of TNFalpha-mediated chronic arthritis. Mechanistically, myostatin-deficiency leads to decreased levels of the chemokine CCL20 which is associated with less infiltration of Th17 cells into the inflamed joints. In vitro, myostatin alone or in combination with IL-17A enhances the secretion of CCL20 by FLS whereas myostatin-deficiency reduces CCL20 secretion, associated with an altered transmigration of Th17 cells. Thus, the communication between activated FLS and Th17 cells through myostatin and IL-17A may likely contribute to a vicious cycle of inflammation, accounting for the persistence of joint inflammation in chronic arthritis. Blockade of the CCL20-CCR6 axis by inhibition of myostatin may, therefore, be a promising treatment option for chronic inflammatory diseases such as arthritis.
成纤维样滑膜细胞（FLS）衍生的促炎细胞因子/趋化因子与免疫细胞的相互作用支持 RA 中炎症细胞的募集和激活。在这里，我们首次表明经典的肌肉因子肌肉生长抑制素（GDF-8）参与 Th17 细胞向炎症部位的募集，从而调节 TNFalpha 介导的慢性关节炎小鼠模型中的关节炎症。从机制上讲，肌肉生长抑制素缺乏会导致趋化因子 CCL20 的水平降低，这与 Th17 细胞浸润到发炎关节的减少有关。在体外，肌肉生长抑制素单独或与 IL-17A 一起增强 FLS 分泌 CCL20，而肌肉生长抑制素缺乏会降低 CCL20 的分泌，这与 Th17 细胞的迁移方式改变有关。因此，激活的 FLS 和 Th17 细胞之间通过肌肉生长抑制素和 IL-17A 的交流可能有助于炎症的恶性循环，从而导致慢性关节炎中关节炎症的持续存在。通过抑制肌肉生长抑制素来阻断 CCL20-CCR6 轴可能是治疗关节炎等慢性炎症性疾病的一种有前途的治疗选择。
