Mitochondrial double-stranded RNAs govern the stress response in chondrocytes to promote osteoarthritis development
Mitochondrial double-stranded RNAs govern the stress response in chondrocytes to promote osteoarthritis development
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DOI：
10.1016/j.celrep.2022.111178
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发表时间：
2022-08-09
期刊：
影响因子：
8.8
通讯作者：
Kim, Yoosik
中科院分区：
文献类型：
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作者：
Kim, Sujin;Lee, Keonyong;Kim, Yoosik
蛋白激酶 R (PKR) 是一种被双链 RNA (dsRNA) 激活的免疫反应蛋白。 PKR 过度激活与炎症退行性疾病有关，包括骨关节炎 (OA)，但 dsRNA 激活剂仍然很大程度上未知。在这里，我们发现在 OA 诱发条件下，软骨细胞中线粒体 dsRNA (mt-dsRNA) 的表达及其胞浆外流得到促进，从而导致先天免疫激活。此外，mt-dsRNA 被释放到细胞外空间并激活质膜上的 Toll 样受体 3。 OA 患者的滑液和受损软骨以及手术诱导的 OA 小鼠软骨中 mt-dsRNA 水平升高进一步支持了我们的数据。重要的是，自噬部分通过去除胞质 mtRNA 来防止 PKR 激活并保护软骨细胞免受线粒体应激。我们的研究提供了对 mt-dsRNA 在应激反应期间激活先天免疫的全面了解，这是 OA 发展的基础，并建议 mt-dsRNA 作为软骨保护干预的潜在靶标。
Protein kinase R (PKR) is an immune response protein that becomes activated by double-stranded RNAs (dsRNAs). PKR overactivation is associated with degenerative diseases with inflammation, including osteoarthritis (OA), but the dsRNA activator remains largely unknown. Here, we find that mitochondrial dsRNA (mt-dsRNA) expression and its cytosolic efflux are facilitated in chondrocytes under OA-eliciting conditions, leading to innate immune activation. Moreover, mt-dsRNAs are released to the extracellular space and activate Toll-like receptor 3 at the plasma membrane. Elevated levels of mt-dsRNAs in the synovial fluids and damaged cartilage of OA patients and in the cartilage of surgery-induced OA mice further support our data. Importantly, autophagy prevents PKR activation and protects chondrocytes from mitochondrial stress partly by removing cytosolic mtRNAs. Our study provides a comprehensive understanding of innate immune activation by mt-dsRNAs during stress responses that underlie the development of OA and suggests mt-dsRNAs as a potential target for chondroprotective intervention.