Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, Shanghai, China.
Nantong Institute of Liver Disease, Department of Gastroenterology and Hepatology, Nantong Third People's Hospital, Nantong University, Jiangsu, China.
Hepatology. 2018 Jan;67(1):232-246. doi: 10.1002/hep.29418. Epub 2017 Nov 17.
There is increasing awareness of the immunologic roles of liver mononuclear populations, including myeloid-derived suppressor cells (MDSCs). We took advantage of a large well-defined cohort of 148 patients with liver inflammation and 45 healthy controls to focus on the qualitative and quantitative characteristics of MDSCs. We investigated the frequency, phenotype, and functional capacities of MDSCs by using peripheral blood MDSCs in a cohort of 55 patients with primary biliary cholangitis (PBC), 40 with autoimmune hepatitis, 39 with chronic hepatitis B, 14 with nonalcoholic fatty liver disease, and 45 healthy controls. This was followed by a liver-targeted determination in 27 patients with PBC, 27 with autoimmune hepatitis, 20 with chronic hepatitis B, 14 with nonalcoholic fatty liver disease, and 6 controls. We then focused on mechanisms of this expansion with PBC as an example, using both ursodeoxycholic acid-naive and treated patients. HLA-DR CD33 CD11b CD14 CD15 monocytic MDSCs were elevated in diseases characterized by liver inflammation compared to healthy controls. Using PBC as a focus, there was a significant correlation between levels of circulating MDSCs and disease-related biochemical markers (alkaline phosphatase, total bilirubin). We found higher amounts of MDSCs in patients with PBC who were responsive to ursodeoxycholic acid. MDSCs from PBC were found to manifest a potent immunosuppressive function. There was a significant correlation in the accumulation of hepatic MDSCs in the inflamed lesions of PBC with histologic changes, such as fibrosis. We also found that cysteine-rich protein 61 (CCN1), a highly expressed protein in impaired cholangiocytes and hepatocytes, contributes to MDSC expansion and MDSC inducible nitric oxide synthase-associated immune suppression.
CCN1 modulates expansion and a suppressive function of MDSCs. Our data highlight the potential functions of CCN1 on MDSCs and suggest therapeutic implications in inflammatory liver diseases. (Hepatology HEPATOLOGY 2018;67:232-246).
人们越来越意识到肝单核细胞群体（包括髓样来源的抑制细胞[MDSC]）的免疫作用。我们利用包括 148 例肝炎症患者和 45 例健康对照者在内的大型明确队列，重点研究 MDSC 的定性和定量特征。我们通过对 55 例原发性胆汁性胆管炎（PBC）、40 例自身免疫性肝炎、39 例慢性乙型肝炎、14 例非酒精性脂肪性肝病和 45 例健康对照者的外周血 MDSC，研究了 MDSC 的频率、表型和功能能力。随后，我们对 27 例 PBC、27 例自身免疫性肝炎、20 例慢性乙型肝炎、14 例非酒精性脂肪性肝病和 6 例对照者进行了肝脏靶向测定。然后，我们以 PBC 为例，重点研究了这种扩张的机制，同时使用了未经熊去氧胆酸（UDCA）治疗和已用 UDCA 治疗的患者。与健康对照组相比，在以肝炎症为特征的疾病中，HLA-DR CD33 CD11b CD14 CD15 单核 MDSC 升高。以 PBC 为重点，发现循环 MDSC 水平与疾病相关的生化标志物（碱性磷酸酶、总胆红素）之间存在显著相关性。我们发现对 UDCA 有反应的 PBC 患者中 MDSC 数量更多。来自 PBC 的 MDSC 表现出强大的免疫抑制功能。在 PBC 炎症病变中，MDSC 的积累与纤维化等组织学变化呈显著相关。我们还发现富含半胱氨酸蛋白 61（CCN1），一种在受损胆管细胞和肝细胞中高表达的蛋白，有助于 MDSC 的扩增和 MDSC 诱导型一氧化氮合酶相关的免疫抑制。
CCN1 调节 MDSC 的扩增和抑制功能。我们的数据突出了 CCN1 在 MDSC 上的潜在功能，并提示其在炎症性肝病中的治疗意义。（《肝脏病学》HEPATOLOGY 2018；67：232-246）
