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Int J Med Sci 2023; 20(10):1256-1271. doi:10.7150/ijms.83801 This issue Cite

Research Paper

Lactate-induced mtDNA Accumulation Activates cGAS-STING Signaling and the Inflammatory Response in Sjögren's Syndrome

Jiabao Xu^1,2,3,4,5,6*, Changyu Chen^2,3,4,5,7*, Junhao Yin^2,3,4,5,7, Jiayao Fu^2,3,4,5,7, Xiujuan Yang^2,3,7, Baoli Wang^2,3,7, Chuangqi Yu^2,3,7, Lingyan Zheng^2,3,7✉, Zhiyuan Zhang^1,2,3,5,6✉

1. Department of Oral and Maxillofacial-Head Neck Oncology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
2. National Clinical Research Center for Oral Diseases, National Center for Stomatology, Shanghai, China.
3. Shanghai Key Laboratory of Stomatology, Shanghai, China.
4. Laboratory of Oral Microbiota and Systematic Diseases, Shanghai Ninth People's Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
5. Shanghai Research Institute of Stomatology, Shanghai, China.
6. Research Unit of Oral and Maxillofacial Regenerative Medicine, Chinese Academy of Medical Sciences, Shanghai, China.
7. Department of Oral Surgery, Ninth People's Hosptial, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
^* These authors contributed equally.

✉ Corresponding authors: Zhiyuan Zhang, Zhiyuan.Zhangorg.cn; Lingyan Zheng, zhenglingyan73com.

Abstract

Acinar epithelial cell atrophy in secretory glands is a hallmark of primary Sjögren's syndrome (pSS), the cause of which is far from elucidated. We examined the role of acinar atrophy by focusing on the metabolism of glandular epithelial cells and mitochondria in the pSS environment. After confirming the presence of a high-lactate environment in the labial glands of human pSS patients, we used the A253 cell line and NOD/Ltj mice as models to investigate the metabolic changes in salivary gland epithelial cells in a high-lactate environment in vitro and in vivo. We found that epithelial cells produced high levels of IL-6, IL-8, IFN-α, IFN-β and TNF-α and exhibited significant NF-κB and type I IFN-related pathway activation. The results confirmed that lactate damaged mitochondrial DNA (mtDNA) and led to its leakage, which subsequently activated the cGAS-STING pathway. Inflammatory cytokine production and pathway activation were inhibited in vivo and in vitro by the lactate scavenger sodium dichloroacetate (DCA). Our study provides new insights into the etiology and treatment of pSS from the perspective of cell metabolism.

Keywords: Lactate, mtDNA, Sjögren's Syndrome, Sodium Dichloroacetate, Salivary acinar cells

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