Department of Stomatology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, College of Stomatology, Shanghai Jiao Tong University, Shanghai, China.
Department of Pathology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Comput Biol Med. 2024 Jun;175:108511. doi: 10.1016/j.compbiomed.2024.108511. Epub 2024 Apr 23.
Mitochondria are the metabolic hubs of cells, regulating energy production and antigen presentation, which are essential for activation, proliferation, and function of immune cells. Recent evidence indicates that mitochondrial antigen presentation may have an impact on diseases such as Parkinson's disease (PD) and autoimmune diseases. However, there is limited knowledge about the mechanisms that regulate the presentation of mitochondrial antigens in these diseases.
In the current study, RNA sequencing was performed on labial minor salivary gland (LSG) from 25 patients with primary Sjögren's syndrome (pSS) and 14 non-pSS aged controls. Additionally, we obtained gene expression omnibus datasets associated with PD patients from NCBI Gene Expression Omnibus (GEO) databases. Single-sample Gene Set Enrichment Analysis (ssGSEA), ESTIMATE and Spearman correlations were conducted to explore the association between mitochondrial related genes and the immune system. Furthermore, we applied weighted Gene Co-expression Network Analysis (WGCNA) to identify hub mitochondria-related genes and investigate the correlated networks in both diseases. Single cell transcriptome analysis, immunohistochemical (IHC) staining and quantitative real-time PCR (qRT-PCR) were used to verify the activation of the hub mitochondria-related pathway. Pearson correlations and the CIBERSORT algorithms were employed to further reveal the correlation between hub mitochondria-related pathways and immune infiltration.
The transcriptome analysis revealed the presence of overlapping mitochondria-related genes and mitochondrial DNA damage in patients with pSS and PD. Reactive oxygen species (ROS), the senescence marker p53, and the inflammatory markers CD45 and Bcl-2 were found to be regionally distributed in LSGs of pSS patients. WGCNA analysis identified the STING pathway as the central mitochondria-related pathway closely associated with the immune system. Single cell analysis, IHC staining, and qRT-PCR confirmed the activation of the STING pathway. Subsequent, bioinformatic analysis revealed the proportion of infiltrating immune cells in the STING-high and STING-low groups of pSS and PD. Furthermore, the study demonstrated the association of the STING pathway with innate and adaptive immune cells, as well as functional cells, in the immune microenvironment of PD and pSS.
Our study uncovered a central pathway that connects mitochondrial dysfunction and the immune microenvironment in PD and pSS, potentially offering valuable insights into therapeutic targets for these conditions.
线粒体是细胞的代谢中心，调节能量产生和抗原呈递，这对于免疫细胞的激活、增殖和功能至关重要。最近的证据表明，线粒体抗原呈递可能对帕金森病 (PD) 和自身免疫性疾病等疾病产生影响。然而，对于调节这些疾病中线粒体抗原呈递的机制知之甚少。
本研究对 25 例原发性干燥综合征 (pSS) 患者和 14 例非 pSS 年龄匹配对照者的唇小唾液腺 (LSG) 进行了 RNA 测序。此外，我们从 NCBI Gene Expression Omnibus (GEO) 数据库中获得了与 PD 患者相关的基因表达综合组数据集。进行了单样本基因集富集分析 (ssGSEA)、ESTIMATE 和 Spearman 相关性分析，以探讨与免疫系统相关的线粒体相关基因。此外，我们应用加权基因共表达网络分析 (WGCNA) 来鉴定与疾病相关的枢纽线粒体相关基因，并研究相关网络。单细胞转录组分析、免疫组织化学 (IHC) 染色和实时定量 PCR (qRT-PCR) 用于验证枢纽线粒体相关途径的激活。Pearson 相关性和 CIBERSORT 算法用于进一步揭示枢纽线粒体相关途径与免疫浸润的相关性。
转录组分析显示 pSS 和 PD 患者存在重叠的线粒体相关基因和线粒体 DNA 损伤。发现活性氧 (ROS)、衰老标志物 p53 以及炎症标志物 CD45 和 Bcl-2 在 pSS 患者的 LSG 中呈区域性分布。WGCNA 分析确定 STING 途径为与免疫系统密切相关的中央线粒体相关途径。单细胞分析、IHC 染色和 qRT-PCR 证实了 STING 途径的激活。随后，生物信息学分析揭示了 pSS 和 PD 中 STING-高和 STING-低组中浸润免疫细胞的比例。此外，该研究表明 STING 途径与 PD 和 pSS 免疫微环境中的固有和适应性免疫细胞以及功能细胞相关。
本研究揭示了 PD 和 pSS 中线粒体功能障碍与免疫微环境之间的中心途径，这可能为这些疾病的治疗靶点提供有价值的见解。
