Th2 Cell Activation in Chronic Liver Disease Is Driven by Local IL33 and Contributes to IL13-Dependent Fibrogenesis,Cellular and Molecular Gastroenterology and Hepatology

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Th2 Cell Activation in Chronic Liver Disease Is Driven by Local IL33 and Contributes to IL13-Dependent Fibrogenesis
Cellular and Molecular Gastroenterology and Hepatology ( IF 7.1 ) Pub Date : 2023-12-28 , DOI: 10.1016/j.jcmgh.2023.12.011
Johanna Reißing ₁ , Marie Berres ₁ , Pavel Strnad ₁ , Alexander Wree ₂ , Maria Eugenia Inzaugarat ₁ , Christian Trautwein ₁ , Tony Bruns ₁ , Henning Wolfgang Zimmermann ₁

Affiliation

Type 2 immune responses contribute to liver fibrosis in parasite infections, but their role in other liver diseases is less well understood. Here, we aimed at unravelling mechanisms involved in T helper 2 (Th2) T-cell polarization, activation, and recruitment in human liver fibrosis and cirrhosis. Tissues, cells, and serum from human livers were analyzed using quantitative reverse-transcription polymerase chain reaction, enzyme-linked immunosorbent assay, fluorescence in situ hybridization, immunostaining, flow cytometry, and various functional in vitro assays. Cellular interactions and soluble mediators involved in T-cell polarization and recruitment were studied, as well as their effect on hepatic stellate cell (HSC) activation, proliferation, and extracellular matrix synthesis. In human liver fibrosis, a stage-dependent increase in Th2-related transcription factors, Th2 cytokines, and trans-acting T-cell–specific transcription factor–expressing T cells was observed, and was highest in cirrhotic livers. The alarmin interleukin (IL)33 was found to be increased in livers and sera from patients with cirrhosis, to act as a chemotactic agent for Th2 cells, and to induce type 2 polarization of CD4+ T cells. Oval cells, liver sinusoidal endothelial cells, intrahepatic macrophages, and migrating monocytes were identified as sources of IL33. IL33-activated T cells, but not IL33 alone, induced HSC activation, as shown by Ki67 and α-smooth muscle actin staining, increased collagen type I alpha 1 chain messenger RNA expression, and wound healing assays. The profibrotic effect of IL33-activated T cells was contact-independent and could be antagonized using monoclonal antibodies against IL13. In patients with chronic liver disease, the alarmin IL33 promotes the recruitment and activation of CD4+ T cells with Th2-like properties, which activate paracrine HSC in an IL13-dependent manner and promotes fibrogenesis.

中文翻译：

慢性肝病中的 Th2 细胞激活由局部 IL33 驱动，并有助于 IL13 依赖性纤维形成

2 型免疫反应会导致寄生虫感染中的肝纤维化，但其在其他肝脏疾病中的作用尚不清楚。在这里，我们的目的是揭示人类肝纤维化和肝硬化中辅助 T 细胞 2 (Th2) T 细胞极化、激活和募集的机制。使用定量逆转录聚合酶链反应、酶联免疫吸附测定、荧光原位杂交、免疫染色、流式细胞术和各种功能性体外测定来分析人肝脏的组织、细胞和血清。研究了参与 T 细胞极化和募集的细胞相互作用和可溶性介质，以及它们对肝星状细胞 (HSC) 激活、增殖和细胞外基质合成的影响。在人类肝纤维化中，观察到 Th2 相关转录因子、Th2 细胞因子和表达反式作用 T 细胞特异性转录因子的 T 细胞呈阶段依赖性增加，并且在肝硬化肝脏中最高。研究发现，肝硬化患者肝脏和血清中的警报素白细胞介素 (IL)33 含量增加，可作为 Th2 细胞的趋化剂，并诱导 CD4+ T 细胞的 2 型极化。卵圆细胞、肝窦内皮细胞、肝内巨噬细胞和迁移单核细胞被确定为 IL33 的来源。 Ki67 和 α-平滑肌肌动蛋白染色显示，IL33 激活的 T 细胞（而非单独的 IL33）可诱导 HSC 激活、I 型胶原 α1 链信使 RNA 表达增加以及伤口愈合测定。 IL33 激活的 T 细胞的促纤维化作用是接触无关的，并且可以使用针对 IL13 的单克隆抗体来拮抗。在慢性肝病患者中，警报蛋白 IL33 促进具有 Th2 样特性的 CD4+ T 细胞的募集和激活，从而以 IL13 依赖性方式激活旁分泌 HSC 并促进纤维形成。

更新日期：2023-12-28

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