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Pharmacy Information
Vol. 12  No. 04 ( 2023 ), Article ID: 68769 , 8 pages
10.12677/PI.2023.124039

Smad3对Th17细胞分化与转分化的 调控作用与机制

刘思远，戴岳*

中国药科大学中药学院，江苏 南京

收稿日期：2023年6月11日；录用日期：2023年7月7日；发布日期：2023年7月17日

摘要

Th17细胞属于效应T细胞亚群，能够保护机体免受外来病原体的侵害，维持组织的完整性，但其数目增多或过度活化可导致和加剧自身免疫性疾病。转化生长因子β (TGF-β)是诱导Th17细胞分化的重要细胞因子，但其经典下游信号分子Smad3可负性调节Th17细胞分化与功能，诱导Th17细胞转分化，提示TGF-β信号对Th17细胞分化具有复杂的作用。本文综述Smad3对Th17细胞分化及转分化的调控作用与机制，为构建靶向Th17细胞的新型治疗策略和药物开发提供参考。

关键词

Th17细胞，Smad3，分化，转分化

The Role and Mechanism of Smad3 in the Regulation of Th17 Cell Differentiation and Transdifferentiation

Siyuan Liu, Yue Dai*

School of Traditional Chinese Medicine, China Pharmaceutical University, Nanjing jiangsu

Received: Jun. 11th, 2023; accepted: Jul. 7th, 2023; published: Jul. 17th, 2023

ABSTRACT

Th17 cells belong to a subset of effector T cells that protect the body from foreign pathogens and maintain tissue integrity, but their increased numbers or over-activation can cause and exacerbate autoimmune diseases. Transforming growth factor β (TGF-β) is an important cytokine that induces Th17 cell differentiation; however, its classical downstream signaling molecule Smad3 negatively regulates Th17 cell differentiation, inhibits Th17 cell function, and induces Th17 cell transdifferentiation, suggesting a complex role of TGF-β signaling on Th17 cell differentiation. This paper reviews the regulatory roles and mechanisms of Smad3 on Th17 cell differentiation and transdifferentiation, and provides a reference for the construction of novel therapeutic strategies targeting Th17 cells.

Keywords:Th17 Cell, Smad3, Differentiation, Transdifferentiation

Copyright © 2023 by author(s) and Hans Publishers Inc.

This work is licensed under the Creative Commons Attribution International License (CC BY 4.0).

http://creativecommons.org/licenses/by/4.0/

1. 引言

Th17细胞是继Th1和Th2细胞后发现的第三种T辅助细胞，其特征细胞因子为IL-17。靶向IL-17A的单克隆抗体在银屑病和类风湿性关节炎中，均取得较好的临床实验结果 ‎[1] 。靶向Th17细胞分化的核心转录因子RORγt的小分子抑制剂，如JTE-151、JTE-451、ARN-6039、PF-06763809、ABBV-157和SAR-441169被报道用于银屑病等自身免疫性疾病的临床研究 ‎[2] ；IL-23对于Th17细胞的致病性至关重要，靶向IL-23 p40亚基的单抗Stelara® (ustekinumab)临床上表现出极佳的抗结肠炎效果 ‎[3] ，是治疗溃疡性结肠炎的一线药物。

Th17细胞分化需要TGF-β的参与 ‎[4] ‎[5] 。TGF-β通过与受体结合并使其活化，招募并磷酸化下游的Smad2/3蛋白复合物，磷酸化的Smad2/3与Smad4结合形成三聚体复合物，然后转移到细胞核中介导靶基因转录，此过程为经典的TGF-β信号传导(图1)。另一方面，其受体具有丝氨酸–苏氨酸激酶活性，可以激活ERK ‎[6] 、JNK ‎[7] 、MAPKs ‎[8] 、PI3K/AKT5和RhoA/ROCK ‎[9] ‎[10] 等信号通路，这些称为非经典的TGF-β信号通路。

Figure 1. TGF-β signals via canonical Smad and non-Smad signaling pathways to regulate cell fate: (a) Classic TGF-β signaling transduction; (b) TGF-β/non-Smad signaling pathway

图1. TGF-β通过典型Smad和非Smad信号通路调节细胞命运：(a)经典的TGF-β信号通路示意图；(b)非经典的TGF-β信号通路示意图

Smad3和Smad2同属于经典的TGF-β信号通路的胞内信号分子，但对Th17细胞分化的贡献截然相反 ‎[11] - ‎[17] 。Smad2激活与IL-17A的产生密切相关 ‎[18] 。不仅如此，Smad2还可上调IL-6R表达 ‎[15] ，也可作为STAT3的共激活因子诱导Th17谱系基因的表达 ‎[11] 。当T细胞中Smad2激活缺陷时，Th17细胞体外分化受损 ‎[19] 。而Smad3可整合多种受体信号，控制早期分化信号网络，调控CD4+ T细胞的命运 ‎[20] 。Smad3能与STAT3相互作用并招募激活STAT3蛋白抑制因子(protein inhibitor of activated STAT3, PIAS3)，介导STAT3的转录活性抑制，阻遏Th17细胞分化 ‎[18] 。此外，Smad3密切参与Th17细胞的转分化，能作用于Th17细胞的IL-10基因启动子，促进其转录，使Th17细胞转变为抗炎表型。Smad3可能是TGF-β信号发挥免疫抑制的关键信号蛋白。鉴于TGF-β在Th17细胞分化与转分化中的参与和作用，本文综述Smad3对Th17分化及转分化的作用和机制，深入了解TGF-β信号通路对Th17细胞命运的调控，为自身免疫病的细胞治疗提供参考。

2. Smad3的结构与功能

Smad3蛋白，类似于果蝇“mothers against decapentaplegic (Mad)”基因和秀丽隐杆线虫Sma基因的产物，是TGF-β信号的胞内信号传导分子，将信号从细胞表面传递到细胞核，从而调节相关靶基因的转录，介导TGF-β的生物学效应。一方面Smad3可与其他Smad蛋白形成复合物并结合于靶基因启动子上，调节基因转录；另一方面Smad3又可作为转录因子单独发挥作用。人和鼠Smad3蛋白均由425个氨基酸构成，氨基酸序列高度同源，仅269位不同(图2(a))。根据其氨基酸序列序列，Smad3蛋白可分为三个功能域，从N端到C端分别为MH1、linker和MH2 domain，每个结构域都有其特有的功能(图2(b)，表1)。各种Smads蛋白MH1和MH2结构域高度保守，各结构域中含有不同的微型结构，这使得各种Smads结构产生区别，确保其发挥准确的生物学功能。Smad3和Smad2最显著的区别在N末端MH1结构域上，Smad2的MH1结构域独特插入外显子3编译的蛋白，从而阻止其与核输入受体蛋白之间相互作用，Smad3无此氨基酸序列，从而使得Smad3能与TGF-β响应序列结合而充当转录因子 ‎[21] ；所有Smad家族蛋白其MH2结构域中均含有与Ⅰ型受体相互作用的L3环结构，但I-Smad MH2结构域末端不含SSXS基序，无法被受体磷酸化激活 ‎[22] 。Smad3除被Ⅰ型受体在特定的位点上磷酸化外，还可被多种激酶磷酸化(表2)，介导信号网络之间的交互。Smad3作为转录因子，其一方面可通过与Smad4合作，共同完成核易位，这也是经典的TGF-β/Smad3信号传导模式，另一方面Smad3的MH1结构域中含有核定位序列(NLS)，能与核输入受体蛋白β1 (importin-β1)相互作用，介导核易位 ‎[23] 。MH2结构域中含有核输出序列(NES)，能与核输出受体蛋白4 (exportin-4)相互作用，介导核转位，从而完成Smad3的胞质胞核之间的穿梭。

Figure 2. Structure and function of Smad3 protein: (a) Amino acid sequence difference of Smad3 protein in human and mouse; (b) Smad3 protein domain and its function

图2. Smad3蛋白结构域和功能：(a)人和鼠Smad3蛋白氨基酸序列的不同；(b) Smad3蛋白结构域与其对应的功能

Table 1. Smad3 domain and its corresponding amino acid sequence

表1. Smad3结构域及其所对应的氨基酸序列

Table 2. Smad3 phosphorylated site

表2. Smad3磷酸化位点

3. Smad3在Th17细胞反应中的参与和作用

Th17细胞活化是多种自身免疫性疾病的致病因素 ‎[2] ，转录调节因子Smad3是TGF-β介导的免疫抑制的重要介质，Smad3对抗炎及自身免疫耐受很重要：人全基因组研究发现Smad3是IBD (炎症性肠病)的易感基因 ‎[24] ，遗传学研究已经揭示，Smad3与IBD的发病密切相关 ‎[25] ，Smad3信号缺陷引起的炎症性疾病在胃肠道中尤为突出，IBD患者肠道固有层细胞中可以观察到TGF-β/Smad3信号是缺陷的，表现为Smad3磷酸化水平降低，Smad7的水平显著上调 ‎[26] ，尽管他们体内有较于正常人更高的TGF-β水平 ‎[27] 。Smad3敲除鼠会自发细菌性结肠炎，是一种常用的IBD模型 ‎[28] 小鼠表现出大肠T细胞浸润和黏膜愈合受损 ‎[19] 。事实上，增强TGF-β/Smad3信号的Smad7 siRNA是治疗IBD的潜在候选药物 ‎[29] 。除此之外在多种自身免疫病模型中均伴随着Smad3激活的受损。在鼻窦炎模型小鼠的淋巴细胞中，可以观察到Smad3激活的抑制，改善Smad3的激活能够调节免疫细胞亚型治疗疾病 ‎[30] 。同样的，在急性移植物抗宿主病(aGVHD)模型小鼠的皮肤、肠、肺和肝脏中可观察到Smad3的磷酸化水平的降低 ‎[31] 。恢复模型小鼠Smad3磷酸化能改善炎症 ‎[29] ‎[31] 。Smad3基因突变会影响自身耐受性，造成自身免疫失调。50%的Smad3突变携带者患有过敏性疾病，尤其是哮喘(23%)和过敏性结膜炎(23%) ‎[32] 。综上所述，Smad3可能是自身免疫病治疗的潜在可行的靶点。

4. Smad3对Th17分化的作用

在CD3/CD28共刺激条件下，naïve CD4+ T细胞在IL-6和TGF-β存在下，分化产生Th17细胞。IL-6驱动STAT3磷酸化易位到细胞核中，诱导T17细胞转录因子RORα和RORγt的表达 ‎[33] ‎[34] 。TGF-β通过抑制IL-6诱导的SOCS3表达，从而延长STAT3活化。STAT3和RORγt协同诱导Th17细胞特征基因IL-17A，IL-17F，IL-22和IL-23R的转录。IL-23能稳定Th17细胞谱系和诱导GM-CSF的产生，使这些细胞具有致病性 ‎[35] 。

Smad2和Smad3同属于经典的TGF-β下游胞内信号分子，但是对Th17细胞分化的作用两者相反，Smad2正向调节Th17细胞分化 ‎[15] ，而Smad3负向调节Th17细胞分化。较Treg细胞相比Th17细胞Smad3显著低表达 ‎[36] ，敲除Smad3能够促进Th17细胞分化 ‎[13] 。Smad3激活缺陷的Th17细胞，IFN和IL-17表达显著增加，致病性增强 ‎[16] 。Smad3过渡激活的T细胞，在初始刺激后分化成Th17细胞受阻 ‎[14] ，MAP3K2和MAP3K3所介导的Smad3接头区域磷酸化能抑制Th17细胞的体外分化，突变Smad3接头区域磷酸化位点能显著促进Th17细胞分化 ‎[37] 。磷酸酶PP2A能选择性降低Smad3磷酸化，这对于Th17细胞分化至关重要，当敲除/抑制PP2A，Smad3的C端磷酸化显著增加，导致Il17a基因的转录减少，Th17细胞分化显著抑制 ‎[14] 。随着研究的深入，Smad3抑制Th17细胞分化的作用机制已有相关论述，有报道表明C端未磷酸化的Smad3能与STAT3相互作用并招募PIAS3介导STAT3的转录活性抑制，造成Th17分化显著抑制 ‎[11] 。也有研究表明，Smad3能直接与RORγt结合，并抑制其转录活性 ‎[13] 。除此之外，激活Smad3能通过抑制Tiam1的表达 ‎[38] ，促进Th17细胞表达Foxp3 ‎[39] ，抑制Th17细胞分化。

5. Smad3对Th17细胞转分化的作用

从一种细胞类型转化到另一种细胞类型的过程被称为转分化，此过程伴随着谱系基因表达的改变和细胞功能的变化，这种转分化的潜力通常被称为可塑性。T细胞的可塑性是一种细胞应对微环境刺激，而适应性的改变发育程序的内在能力。Th17细胞存在广泛的可塑性，目前已有相关报道表明，Th17细胞不仅可转分化为经典的Treg ‎[40] 和Th1 ‎[41] 细胞，还可转分化为TR1细胞(一型调节性T细胞) ‎[42] ，后者是一种新的具有免疫抑制功能的CD4+ T细胞亚群。Th17细胞转分化为调节性细胞，有助于炎症反应的消退 ‎[42] ，其不稳定性和可塑性是是治疗类风湿性关节炎等自身免疫病的潜在靶点 ‎[43] ，Th17细胞的这种可塑性可以避免机体过度炎症和自身免疫性疾病的发生发展 ‎[44] 。

目前，治疗自身免疫性疾病的方法旨在针对Th17细胞的分化和功能，但鉴于IL-17A的抗感染和促黏膜愈合作用 ‎[45] ，以及IL-17A单抗对IBD临床试验失败无效的事实 ‎[46] ，基于Th17细胞的可塑性，调节其转分化有望成为自身免疫病治疗的新方向 ‎[47] 。Nanduri R等 ‎[31] 发现维生素D受体活化通过增加Smad3表达介导Th17细胞中IL-10的产生增加。Xu H等 ‎[48] 发现在Th17细胞中Smad3的激活能协同Smad4共定位于IL-10基因的启动子区域，诱导IL-10基因转录的增加，使炎性Th17细胞转变为抗炎表型，有利于炎症的消退和疾病的治疗。mTOR缺陷型naïve T细胞在Th17分化条件下，分化为Treg细胞，这与过度活化激活的Smad3相关 ‎[14] 。激活Smad3通过降低NF-κB的磷酸化促进Th17细胞转分化为Treg细胞，从而调节Th17/Treg细胞平衡 ‎[49] 。TGF-β通过Smad3诱导Th17细胞向TR1细胞的转分化 ‎[42] 。Th17细胞的可塑性是炎症性疾病的潜在治疗靶点，Samd3在其中扮演着关键角色。

6. 总结与展望

综上，Smad3密切参与Th17细胞的分化和转分化过程，并对Th17细胞所致的自身免疫病的发生发展具有积极的改善作用。但目前仍有很多尚未解决的问题，Th17细胞分化和转化详细的具体的开关和触发事件是什么？这些信号网络随环境和时间的具体变化是什么？以及Smad3具体的参与是什么？相信随着研究的深入，这些空白将会得到有效的填充和完善。越来越多的证据表明Samd3的激活在Th17细胞分化过程中显著受到抑制 ‎[50] ‎[51] ‎[52] ，促进Smad3的激活是包括UC在内的自身免疫病的有效治疗策略，其相关药物已经进入UC三期临床试验 ‎[53] ，虽然没能成功走出临床，我们认为可能的原因与Smad2的激活有关。因此，尽管Smad3在Th17分化和转分化以及自身免疫病治疗等相关研究中已经取得了可喜的进展，但该领域急切地需要靶向Smad3的相关研究的深入，机体的复杂性和TGF-β信号网络的多效性的背景下。从而为靶向Smad3治疗自身免疫病的药物开发提供良策。

文章引用

刘思远,戴 岳. Smad3对Th17细胞分化与转分化的调控作用与机制
The Role and Mechanism of Smad3 in the Regulation of Th17 Cell Differentiation and Transdifferentiation[J]. 药物资讯, 2023, 12(04): 309-316. https://doi.org/10.12677/PI.2023.124039

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    59. NOTES

    *通讯作者。

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