Experimental and Translational Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China.
Beijing Clinical Research Institute, Beijing, China.
FASEB J. 2019 Jul;33(7):8490-8503. doi: 10.1096/fj.201802534RR. Epub 2019 Apr 5.
The liver is a central immunologic organ with a high density of myeloid and lymphoid immune cells that play important roles in the development and progression of nonalcoholic steatohepatitis (NASH). However, the immune-cell-mediated regulation of NASH and its underlying mechanisms remain obscure. In this study, mice showed significantly higher plasma alanine transaminase levels, with increased liver fat accumulation, lobular inflammation, and focal necrosis compared with wild-type (WT) mice after 4 wk of feeding on a methionine- and choline-deficient diet (MCD) or 16 wk of feeding on a high-fat diet. Perforin deficiency promoted the M1 polarization of infiltrated monocytes. Moreover, MCD-fed mice exhibited increased accumulation, survival, activation, and proinflammatory cytokine production of CD8 T cells but not NK cells or CD4 T cells. Adoptive transfer of CD8 T cells or NK cells from WT or mice, together with non-CD8 cells or non-NK cells from WT mice, indicated that CD8 T-cell-derived perforin participates in the mechanism regulating liver inflammation and thus plays a protective role in the development of NASH. Perforin-deficient CD8 T cells exhibited decreased cytotoxicity toward bone marrow-derived M1 monocytes and macrophages. According to the RNA sequencing data, the perforin deficiency inhibited cell apoptosis and enhanced the activation, migration, and proinflammatory cytokine production of CD8 T cells in mice with NASH. Furthermore, we found higher plasma soluble perforin levels and hepatic perforin expression in NASH patients, suggesting clinical relevance of the findings. We have elucidated an important role for the cytotoxic immune effector molecule perforin from CD8 T cells in restricting hepatic inflammation in mice with NASH and suggest that therapies designed to maximize the function of endogenous perforin in CD8 T cells might have potential benefits as NASH treatments.-Wang, T., Sun, G., Wang, Y., Li, S., Zhao, X., Zhang, C., Jin, H., Tian, D., Liu, K., Shi, W., Tian, Y., Zhang, D. The immunoregulatory effects of CD8 T-cell-derived perforin on diet-induced nonalcoholic steatohepatitis.
肝脏是一个免疫中枢器官，具有高密度的髓样和淋巴样免疫细胞，这些细胞在非酒精性脂肪性肝炎（NASH）的发展和进展中发挥重要作用。然而，免疫细胞介导的 NASH 调节及其潜在机制仍不清楚。在这项研究中，与野生型（WT）小鼠相比，经过 4 周的蛋氨酸和胆碱缺乏饮食（MCD）喂养或 16 周的高脂肪饮食喂养后，敲除穿孔素的小鼠表现出明显更高的血浆丙氨酸转氨酶水平，肝脂肪堆积增加，小叶炎症和局灶性坏死增加。穿孔素缺陷促进浸润单核细胞的 M1 极化。此外，MCD 喂养的 小鼠表现出 CD8 T 细胞的积累、存活、激活和促炎细胞因子产生增加，但 NK 细胞或 CD4 T 细胞没有增加。从 WT 或 小鼠中过继转移 CD8 T 细胞或 NK 细胞，以及从 WT 小鼠中过继转移非 CD8 细胞或非 NK 细胞，表明 CD8 T 细胞来源的穿孔素参与调节肝脏炎症的机制，并因此在 NASH 的发展中发挥保护作用。穿孔素缺陷型 CD8 T 细胞对骨髓来源的 M1 单核细胞和巨噬细胞的细胞毒性降低。根据 RNA 测序数据，穿孔素缺陷抑制 NASH 小鼠中 CD8 T 细胞的细胞凋亡，并增强其激活、迁移和促炎细胞因子的产生。此外，我们发现 NASH 患者的血浆可溶性穿孔素水平和肝穿孔素表达升高，提示这些发现具有临床相关性。我们已经阐明了来自 CD8 T 细胞的细胞毒性免疫效应分子穿孔素在限制 NASH 小鼠肝内炎症中的重要作用，并表明旨在最大限度地发挥内源性穿孔素在 CD8 T 细胞中的功能的治疗方法可能作为 NASH 治疗具有潜在益处。
