Yoon Jimin, Lee Minseok, Ali Ahsan Ausaf, Oh Ye Rim, Choi Yong Seok, Kim Sujin, Lee Namseok, Jang Se Gwang, Park Seonghyeon, Chung Jin-Haeng, Kwok Seung-Ki, Hyon Joon Young, Cha Seunghee, Lee Yun Jong, Im Sung Gap, Kim Yoosik
Department of Chemical and Biomolecular Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Republic of Korea.
Medical Science Research Institute, Seoul National University Bundang Hospital, Seongnam 13620, Republic of Korea.
Mol Ther Nucleic Acids. 2022 Sep 27;30:257-269. doi: 10.1016/j.omtn.2022.09.020. eCollection 2022 Dec 13.
Sjӧgren's syndrome (SS) is a systemic autoimmune disease that targets the exocrine glands, resulting in impaired saliva and tear secretion. To date, type I interferons (I-IFNs) are increasingly recognized as pivotal mediators in SS, but their endogenous drivers have not been elucidated. Here, we investigate the role of mitochondrial double-stranded RNAs (mt-dsRNAs) in regulating I-IFNs and other glandular phenotypes of SS. We find that mt-dsRNAs are elevated in the saliva and tears of SS patients (n = 73 for saliva and n = 16 for tears) and in salivary glands of non-obese diabetic mice with salivary dysfunction. Using the in-house-developed 3D culture of immortalized human salivary gland cells, we show that stimulation by exogenous dsRNAs increase mt-dsRNAs, activate the innate immune system, trigger I-IFNs, and promote glandular phenotypes. These responses are mediated via the Janus kinase 1 (JAK1)/signal transducer and activator of transcription (STAT) pathway. Indeed, a small chemical inhibitor of JAK1 attenuates mtRNA elevation and immune activation. We further show that muscarinic receptor ligand acetylcholine ameliorates autoimmune characteristics by preventing mt-dsRNA-mediated immune activation. Last, direct suppression of mt-dsRNAs reverses the glandular phenotypes of SS. Altogether, our study underscores the significance of mt-dsRNA upregulation in the pathogenesis of SS and suggests mt-dsRNAs as propagators of a pseudo-viral signal in the SS target tissue.
干燥综合征（SS）是一种全身性自身免疫性疾病，主要累及外分泌腺，导致唾液和泪液分泌受损。迄今为止，I型干扰素（I-IFNs）在干燥综合征中越来越被认为是关键介质，但其内源性驱动因素尚未阐明。在此，我们研究线粒体双链RNA（mt-dsRNAs）在调节I-IFNs和干燥综合征其他腺体表型中的作用。我们发现，mt-dsRNAs在干燥综合征患者的唾液和泪液中升高（唾液样本73例，泪液样本16例），在患有唾液功能障碍的非肥胖糖尿病小鼠的唾液腺中也升高。利用自行研发的永生化人唾液腺细胞3D培养模型，我们发现外源性双链RNA刺激可增加mt-dsRNAs，激活先天免疫系统，触发I-IFNs，并促进腺体表型。这些反应是通过Janus激酶1（JAK1）/信号转导和转录激活因子（STAT）途径介导的。事实上，一种JAK1的小分子化学抑制剂可减弱mtRNA升高和免疫激活。我们进一步表明，毒蕈碱受体配体乙酰胆碱可通过阻止mt-dsRNA介导的免疫激活来改善自身免疫特征。最后，直接抑制mt-dsRNAs可逆转干燥综合征的腺体表型。总之，我们的研究强调了mt-dsRNA上调在干燥综合征发病机制中的重要性，并表明mt-dsRNAs是干燥综合征靶组织中假病毒信号的传播者。
