Department of Pathology and Experimental Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan.
Department of Infectious Disease, The First Hospital of China Medical University, Liaoning, China.
J Adv Res. 2021 Apr 20;35:71-86. doi: 10.1016/j.jare.2021.03.014. eCollection 2022 Jan.
Mitogen-activated protein kinases (MAPKs) are involved in T cell-mediated liver damage. However, the inhibitory mechanism(s) that controls T cell-mediated liver damage remains unknown.
We investigated whether Spred2 (Sprouty-related, EVH1 domain-containing protein 2) that negatively regulates ERK-MAPK pathway has a biological impact on T cell-mediated liver damage by using a murine model.
We induced hepatotoxicity in genetically engineered mice by intravenously injecting Concanavalin A (Con A) and analyzed the mechanisms using serum chemistry, histology, ELISA, qRT-PCR, Western blotting and flow cytometry.
Spred2-deficient mice (Spred2) developed more sever liver damage than wild-type (WT) mice with increased interferon-γ (IFNγ) production. Hepatic ERK phosphorylation was enhanced in Spred2 mice, and pretreatment of Spred2 mice with the MAPK/ERK inhibitor U0126 markedly inhibited the liver damage and reduced IFNγ production. Neutralization of IFNγ abolished the damage with decreased hepatic Stat1 activation in Spred2 mice. IFNγ was mainly produced from CD4 and CD8 T cells, and their depletion decreased liver damage and IFNγ production. Transplantation of CD4 and/or CD8 T cells from Spred2 mice into RAG1 mice deficient in both T and B cells caused more severe liver damage than those from WT mice. Hepatic expression of T cell attractants, CXCL9 and CXCL10, was augmented in Spred2 mice as compared to WT mice. Conversely, liver damage, IFNγ production and the recruitment of CD4 and CD8 T cells in livers after Con A challenge were lower in Spred2 transgenic mice, and Spred2-overexpressing CD4 and CD8 T cells produced lower levels of IFNγ than WT cells upon stimulation with Con A .
We demonstrated, for the first time, that Spred2 functions as an endogenous regulator of T cell IFNγ production and Spred2-mediated inhibition of ERK-MAPK pathway may be an effective remedy for T cell-dependent liver damage.
丝裂原活化蛋白激酶（MAPK）参与 T 细胞介导的肝损伤。然而，控制 T 细胞介导的肝损伤的抑制机制尚不清楚。
我们通过使用一种小鼠模型，研究了 Spred2（Sprouty 相关，EVH1 结构域蛋白 2）是否通过负调控 ERK-MAPK 通路对 T 细胞介导的肝损伤具有生物学影响。
我们通过静脉注射 Concanavalin A（Con A）在基因工程小鼠中诱导肝毒性，并使用血清化学、组织学、ELISA、qRT-PCR、Western blot 和流式细胞术分析机制。
Spred2 缺陷型（Spred2）小鼠比野生型（WT）小鼠发生更严重的肝损伤，IFNγ（干扰素-γ）产生增加。Spred2 小鼠肝 ERK 磷酸化增强，MAPK/ERK 抑制剂 U0126 预处理显著抑制肝损伤并减少 IFNγ 产生。Spred2 小鼠中 IFNγ 的中和消除了肝 Stat1 激活减少的损伤。IFNγ 主要由 CD4 和 CD8 T 细胞产生，其耗竭减少了肝损伤和 IFNγ 产生。来自 Spred2 小鼠的 CD4 和/或 CD8 T 细胞移植到缺乏 T 和 B 细胞的 RAG1 小鼠中会导致比 WT 小鼠更严重的肝损伤。与 WT 小鼠相比，Spred2 小鼠肝内 T 细胞趋化因子 CXCL9 和 CXCL10 的表达增强。相反，与 WT 细胞相比，Spred2 转基因小鼠中 Con A 挑战后肝损伤、IFNγ 产生和 CD4 和 CD8 T 细胞在肝脏中的募集均较低，Spred2 过表达的 CD4 和 CD8 T 细胞在 Con A 刺激下产生的 IFNγ 水平低于 WT 细胞。
我们首次证明 Spred2 作为 T 细胞 IFNγ 产生的内源性调节剂发挥作用，Spred2 介导的 ERK-MAPK 通路抑制可能是治疗 T 细胞依赖性肝损伤的有效方法。
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