Double-Negative T Cells Regulate Hepatic Stellate Cell Activation to Promote Liver Fibrosis Progression via NLRP3

被引：7
作者：
Yang, Yi [1 ]
Sheng, Yongjia [1 ]
Wang, Jin [1 ]
Zhou, Xiaohong [1 ]
Li, Wenyan [1 ]
Zhang, Caiqun [2 ]
Guo, Li [3 ]
Han, Chenyang [1 ]
机构：
[1] Jiaxing Univ, Dept Pharm, Affiliated Hosp 2, Jiaxing, Peoples R China
[2] Jiaxing Univ, Dept Neurol, Affiliated Hosp 2, Jiaxing, Peoples R China
[3] Jiaxing Univ, Dept Ctr Lab, Affiliated Hosp 2, Jiaxing, Peoples R China
来源：
FRONTIERS IN IMMUNOLOGY | 2022年 / 13卷
关键词：
double-negative T cells; liver fibrosis; NLRP3; TNFR1; hepatic stellate cells; KAPPA-B; BETA;
D O I：
10.3389/fimmu.2022.857116
中图分类号：
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号：
100102 ;
摘要：
AimWe mainly explored the role and mechanism of double-negative T cells (DNTs) in liver fibrosis. MethodsDNTs were co-cultured with mouse hepatic stellate cells (HSCs). Later, cell viability was detected by Cell Counting Kit-8 (CCK-8) assay; alpha-SMA expression was measured through fluorescence staining; TNF-alpha, IL-6, and MMP-9 levels were measured by ELISA; and the expression of Bcl-2, TGF-beta 1, NLRP3, ASC, and TNFR1 proteins in HSCs was detected by Western blotting (WB) assay. At the same time, HSC-NLRP3(-/-) and HSC-TNFR1(-/-) are used to explore the mechanism. In mouse experiments, mice were intraperitoneally injected with DNTs; afterward, the hepatic tissue fibrosis degree was detected by Masson staining, alpha-SMA expression was measured through immunohistochemistry (IHC) assay, and histopathological changes were detected by sirius-red staining and H&E staining. ResultsThe results suggested that DNTs promoted HSC activation and NLRP3 activation. The effect of DNTs on activating HSC-NLRP3(-/-) was suppressed, and the difference was significant as compared with HSCs. HSC-TNFR1(-/-) activation was also inhibited. To explore the mechanism of DNT-secreted TNF-alpha in TNFR1-NLRP3 activation, we transfected DNTs with TNF-alpha siRNA; as a result, DNTs with TNF-alpha silencing did not significantly affect HSC activation. DNTs promoted hepatic tissue fibrosis progression and HSC activation; after treatment with NLRP3 inhibitor, the effect of DNTs on promoting fibrosis was suppressed. ConclusionWe discovered that DNTs played an important role in liver fibrosis and that DNTs promoted HSC activation via the TNF-alpha-TNFR1-NLRP3 signal axis, thus further promoting liver fibrosis progression.
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页数：12
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