Shanghai Key Laboratory for Prevention and Treatment of Bone and Joint Diseases with Integrated Chinese-Western Medicine, Shanghai Institute of Traumatology and Orthopedics, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, 197 Ruijin 2nd Road, Shanghai 200025, People's Republic of China.
Department of Orthopedics, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, 197 Ruijin 2nd Road, Shanghai 200025, People's Republic of China.
Cell Death Dis. 2017 Nov 2;8(11):e3165. doi: 10.1038/cddis.2017.534.
Pattern recognition receptors (PRRs), including Toll-like receptor 3 (TLR3), are involved in arthritic responses; however, whether interleukin-33 (IL-33) is involved in TLR3-mediated cartilage degeneration is unknown. Here, we found that IL-33 was abundantly increased in chondrocytes of osteoarthritis, especially the chondrocytes of weight-bearing cartilage. Furthermore, double-stranded RNA (dsRNA) released from damaged articular chondrocytes induced by mechanical stretching upregulated IL-33 expression to a greater degree than IL-1β and tumor necrosis factor-α. dsRNA induced IL-33 expression via the TLR3-p38 mitogen-activated protein kinase-nuclear factor-κB (NF-κB) pathway. In addition, formation of the p65 and peroxisome proliferator-activated receptor-γ transcriptional complex was required for dsRNA-induced IL-33 expression. IL-33, in turn, acted on chondrocytes to induce matrix metalloproteinase-1/13 and inhibit type II collagen expression. These findings reveal that dsRNA released from damaged articular chondrocytes promotes cartilage degeneration via the TLR3-IL-33 pathway.
模式识别受体（PRRs），包括 Toll 样受体 3（TLR3），参与关节炎反应；然而，白细胞介素-33（IL-33）是否参与 TLR3 介导的软骨退化尚不清楚。在这里，我们发现白细胞介素-33在骨关节炎的软骨细胞中大量增加，尤其是承重软骨的软骨细胞。此外，机械拉伸引起的受损关节软骨细胞释放的双链 RNA（dsRNA）比白细胞介素-1β和肿瘤坏死因子-α更能显著上调 IL-33 的表达。dsRNA 通过 TLR3-p38 丝裂原活化蛋白激酶-核因子-κB（NF-κB）通路诱导 IL-33 的表达。此外，dsRNA 诱导的 IL-33 表达需要形成 p65 和过氧化物酶体增殖物激活受体-γ 转录复合物。反过来，白细胞介素-33 作用于软骨细胞，诱导基质金属蛋白酶-1/13 的表达，并抑制 II 型胶原的表达。这些发现表明，受损关节软骨细胞释放的 dsRNA 通过 TLR3-IL-33 途径促进软骨退化。
