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乳酸诱导的 mtDNA 积累激活 Sjögren 综合征中的 cGAS-STING 信号和炎症反应。

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

机构信息

Department of Oral and Maxillofacial-Head Neck Oncology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

National Clinical Research Center for Oral Diseases, National Center for Stomatology, Shanghai, China.

出版信息

Int J Med Sci. 2023 Aug 15;20(10):1256-1271. doi: 10.7150/ijms.83801. eCollection 2023.

DOI:10.7150/ijms.83801
PMID:37786436
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10542019/
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 and . 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 and 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.

摘要

分泌腺的腺泡上皮细胞萎缩是原发性干燥综合征（pSS）的一个标志，其病因还远未阐明。我们通过关注 pSS 环境中腺泡上皮细胞和线粒体的代谢来研究腺泡萎缩的作用。在确认人类 pSS 患者唇腺中存在高乳酸环境后，我们使用 A253 细胞系和 NOD/Ltj 小鼠作为模型，研究高乳酸环境中唾液腺上皮细胞的代谢变化。我们发现上皮细胞产生高水平的 IL-6、IL-8、IFN-α、IFN-β 和 TNF-α，并表现出明显的 NF-κB 和 I 型 IFN 相关途径激活。结果证实乳酸损伤了线粒体 DNA（mtDNA）并导致其漏出，从而激活了 cGAS-STING 途径。乳酸清除剂二氯乙酸钠（DCA）抑制了炎症细胞因子的产生和途径激活。我们的研究从细胞代谢的角度为 pSS 的病因和治疗提供了新的见解。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/80f1/10542019/4133c50386c5/ijmsv20p1256g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/80f1/10542019/24f4457e9527/ijmsv20p1256g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/80f1/10542019/b45ec6f358d8/ijmsv20p1256g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/80f1/10542019/994104873535/ijmsv20p1256g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/80f1/10542019/f04105e1ceb2/ijmsv20p1256g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/80f1/10542019/fbba970efb0c/ijmsv20p1256g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/80f1/10542019/4133c50386c5/ijmsv20p1256g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/80f1/10542019/24f4457e9527/ijmsv20p1256g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/80f1/10542019/b45ec6f358d8/ijmsv20p1256g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/80f1/10542019/994104873535/ijmsv20p1256g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/80f1/10542019/f04105e1ceb2/ijmsv20p1256g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/80f1/10542019/fbba970efb0c/ijmsv20p1256g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/80f1/10542019/4133c50386c5/ijmsv20p1256g006.jpg

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本文引用的文献

[1]
Emerging role of the cGAS-STING signaling pathway in autoimmune diseases: Biologic function, mechanisms and clinical prospection.

Autoimmun Rev. 2022-9

[2]
Hyperresponsive cytosolic DNA-sensing pathway in monocytes from primary Sjögren's syndrome.

Rheumatology (Oxford). 2022-8-3

[3]
TBK1 recruitment to STING mediates autoinflammatory arthritis caused by defective DNA clearance.

J Exp Med. 2022-1-3

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Rheb-regulated mitochondrial pyruvate metabolism of Schwann cells linked to axon stability.

Dev Cell. 2021-11-8

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Dysfunctional mitochondria as critical players in the inflammation of autoimmune diseases: Potential role in Sjögren's syndrome.

Autoimmun Rev. 2021-8

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Dysbiosis exacerbates colitis by promoting ubiquitination and accumulation of the innate immune adaptor STING in myeloid cells.

Immunity. 2021-6-8

[7]
Mitochondrial DNA leakage induces odontoblast inflammation via the cGAS-STING pathway.

Cell Commun Signal. 2021-5-20

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Epithelial-immune cell interplay in primary Sjögren syndrome salivary gland pathogenesis.

Nat Rev Rheumatol. 2021-6

[9]
The cGAS-STING pathway as a therapeutic target in inflammatory diseases.

Nat Rev Immunol. 2021-9

[10]
TBK1 recruitment to STING activates both IRF3 and NF-κB that mediate immune defense against tumors and viral infections.

Proc Natl Acad Sci U S A. 2021-4-6

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