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. 2021 May 20;41(5):716–721. [Article in Chinese] doi: 10.12122/j.issn.1673-4254.2021.05.12

芳香烃受体通过介导Th17/Treg分化调控蟑螂过敏原诱导的哮喘

Aryl hydrocarbon receptor modulates airway inflammation in mice with cockroach allergen-induced asthma by regulating Th17/Treg differentiation

Ting XU 1,*, Zhuang CUI 2, Junjie WANG 3, Yuan FENG 1, Ren XIE 1, Danqing LI 1, Jing PENG 1, Rong HUANG 1, Taoping LI 1,*
PMCID: PMC8214952  PMID: 34134959

Abstract

目的

探讨芳香烃受体（AhR）是否能够通过介导肺内Th17/Treg细胞的分化来调控蟑螂过敏原（CRE）诱导的哮喘。

方法

通过蟑螂过敏原激发和致敏，建立哮喘小鼠模型。部分哮喘小鼠给予AhR激动剂（TCDD）(10 μg/kg)或AhR拮抗剂（CH223191）（10 mg/kg）刺激。实验小鼠分为4组：对照组、哮喘组（CRE）、AhR激活组（CRE+TCDD）及AhR拮抗组（CRE+ TCDD+CH223191）。通过RT-PCR检测哮喘小鼠肺内AhR及其下游Cyp1a1和Cyp1b1基因的表达；免疫组化染色观察哮喘小鼠肺内炎症变化；酶联免疫吸附试验（ELISA）监测炎症细胞因子的表达；采用流式细胞术检测肺及纵膈淋巴结中Treg的表达。

结果

TCDD和CH223191能够调控哮喘小鼠肺内AhR及其下游基因Cyp1a1和Cyp1b1的表达（P < 0.002）；AhR激活后肺内炎症细胞及粘液分泌较CRE组减少，促炎因子IL-4、IL-13和Th17A表达减少（P < 0.001），而抑炎因子IL-10、IL-22和TGFβ1表达增加（P < 0.001），而拮抗AhR后逆转了这一现象，且与CRE组无统计学差异（P>0.05）；AhR激活后肺及纵膈淋巴结中Treg细胞及其转录因子FOXP3表达明显增加（P < 0.001），Th17细胞转录因子RORγt基因表达水平明显降低（P < 0.001），而拮抗AhR后，与激活组相比，肺及纵膈淋巴结中CD4+CD25+Foxp3+Treg细胞及其转录因子FOXP3表达减少（P < 0.001），RORγt基因表达水平增加（P < 0.001）；与CRE组相比，差别无统计学意义（P>0.05）。

结论

AhR通过介导Th17/Treg细胞分化来调控哮喘小鼠肺部炎症。

Keywords: 芳香烃受体, 蟑螂过敏原, 哮喘, Th17, 调节T细胞

哮喘是一种严重的慢性炎症性疾病，以气道高反应性，黏液分泌增加和气流可逆性受限为特征[1]。目前我国哮喘患病率约为1%，儿童可高达3%，且目前呈上升趋势，给国家、家庭带来严重的经济负担[2]。过敏性哮喘多发于市中心的居住人群中，最主要的原因可能是由于长期暴露于过敏原中，尤其早期暴露于蟑螂过敏原中(CRE)[3-4]。哮喘发病机制复杂，迄今尚未完全清楚，近年来研究发现Th17和调节性T细胞(Treg)的免疫失衡是哮喘发病机制的重要环节之一[5-8]。

芳香烃受体(AhR)是一种配体激活转录因子，是细胞信号转导通路中的内源性调控因子，能够感应外界环境刺激，参与调节细胞增殖和免疫反应[9]。四氯二苯并二恶英(TCDD)能够激活AhR导致靶基因转录改变(细胞色素P450 cyp1a1, cyp1b1)和一系列免疫效应[10-11]。我们前期研究发现AhR在抑制CRE诱导哮喘模型中发挥关键作用[12]，小鼠体内敲除AhR(AhR-/-)显著加重CRE诱导的哮喘肺部炎症，而激活AhR明显缓解CRE诱导的哮喘肺部炎症；此外，我们发现AhR可调控肺组织内巨噬细胞极化发挥抑炎作用[13]。近期有研究发现被配体激活的AhR能调节T细胞分化[11, 14]，但在哮喘发病过程中，AhR是否能调控肺内Th17/Treg的免疫失衡，目前仍无相关研究。因此，本研究探讨AhR是否能够通过介导肺内Th17/Treg细胞的分化来调控CRE诱导的哮喘，旨在为哮喘发病机制的探讨提供了新的理论依据，同时为后续进一步研究AhR与Th17/Treg免疫失衡间相关信号通路提供研究基础。

1. 材料和方法

1.1. 实验动物

从南方医科大学动物实验中心购买8周龄雄性C57BL/6J小鼠，所有小鼠均在无病原菌、温度保持在25 ℃、相对湿度为50%，每天12 h明暗循环的环境下饲养，每隔1 d监测小鼠健康状况。所开展的动物实验都得到南方医科大学动物伦理委员会的批准。

1.2. 建立CRE诱导的哮喘小鼠模型及TCDD刺激模型

依据之前CRE诱导哮喘模型文献[12-13]，在激发阶段，实验组小鼠从第0天到第4天连续5 d通过气管内给予20 μg CRE(溶于50 μL PBS中)；在刺激阶段，实验组小鼠在第10、11、12、13天连续气管内给予同等剂量CRE刺激。对照组(Control)小鼠通过相同方式给予同等剂量的PBS。为进一步研究AhR在气道炎症中的作用，在CRE激发及刺激阶段前1天及刺激后第9天，通过灌胃方式给予AhR激动剂TCDD(10 μg/kg)刺激，同时在第10~13天每天通过口腔给予AhR拮抗剂CH223191(10 mg/kg)刺激。在第14天哮喘模型造模完成(图 1A)。实验动物分为4组：对照组(Control, n= 5)、哮喘组(CRE, n=5)、AhR激活组(CRE+TCDD, n=5) 及AhR拮抗组(CRE+TCDD+CH223191, n=5)。

1.

1

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哮喘小鼠在不同条件刺激下AhR的表达

Pulmonary AhR expression in mouse models of cockroach allergen-induced asthma with different treatments. A-C: Real-time PCR analyses of the expressions of AhR, cyp1a1, and cyp1b1 mRNA in lung tissues. D, E: Expression of AhR in the airways of asthmatic mice detected by immunofluorescent staining. Lung sections were stained with AhR (green), and the cell nucleus was stained with DAPI (blue). **P < 0.01.

1.3. 免疫组化和免疫荧光染色

造模完成后获取肺组织，用10%中性甲醛缓冲液固定24 h，然后石蜡包埋5 μm切片或者冰冻切片。石蜡包埋用于H & E和PAS染色。冰冻包埋用于免疫荧光染色。免疫荧光染色将标本孵于一抗AhR(ab84833; Abcam)，4 ℃过夜，次日加带有荧光标记的二抗，常温下1 h，同时避光。用DAPI (Sigma-Aldrich)对细胞核进行染色，使用共聚焦显微镜对染色进行观察和摄片(Olympus DP71)。

1.4. 酶联免疫吸附试验(ELISA)

造模完成后通过气管插管，用0.8 mL冰冷HBSS灌洗肺两次，收取肺泡灌洗液(BALF)。根据ELISA操作手册(eBioscience)分析肺泡灌洗液中IL-4、IL-10、IL-13、IL-17A、IL-22 and TGFβ1的表达。另外通过心脏穿刺收集血液，分离血清，用ELISA方法分析血液中蟑螂过敏原特异性IgE和IgG1的表达。

1.5. 定量聚合酶链反应(RT-PCR)

造模完成后，收集新鲜肺组织和肺纵膈淋巴结。新鲜肺组织切碎后，肺组织培养在加入10 mg/mL DNase I和1 mg/mL胶原酶D(Sigma-Aldrich)的DMEM培养液中裂解消化45 min，之后通过70 μm的尼龙过滤器获得单细胞悬液，通过红细胞裂解液裂解红细胞。收集的肺纵膈淋巴结通过3 mL注射器的活塞柄按压分离成单细胞悬液。进行实时定量PCR分析，根据RNeasy Plus Mini kit(Qiagen, Valencia, CA)操作流程从肺及肺纵膈淋巴结单细胞悬液中提取RNA。用SuperScript Ⅲ (Life Technologies)合成cDNA模板。在ABI Prism 7300检测系统(Applied Biosystems)上使用SYBRGreen(Applied Biosystems, Foster City, CA)进行RT-PCR。分析时使用参考对比标准化数据。实验中涉及引物具体见表 1。

1.

基因表达RT-PCR所需引物序列

Primer sequences for RT-PCR

Actin (F) AGAAAATCTGGCACCACACC
(R) CAGAGGCGTACAGGGATAGC
F: Forward primer; R: Revise primer.
AhR (F) GTCGTCTAAGGTGTCTGCTGGA
(R) CGCAAACAAAGCCAACTGAGGTG
CYP1a1 (F) GATTGAGCACTGTCAGGAGAAGC
(R) ATGAGGCTCCAGGAGATAGCAG
CYP1b1 (F) GCCACTATCACTGACATCTTCGG
(R) CACGACCTGATCCAATTCTGCC
FOXP3 (G) GCCCATCCAATAAACTGTGG
(S) GTATCCGCTTTCTCCTGCTG
RORγt (F) CCTCCTGCCACCTTGAGTAT
(R) TCTGGACCCTGTTCTGGTT
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1.6. 流式细胞学分析

收取肺泡灌洗液(BALF)，在1500转4 ℃条件下离心10min，经红细胞裂解液裂解红细胞后，通过流式细胞仪FACSCalibur cytometer(BD Biosciences)分析各种细胞所占比例。显示forward scatterlow/side scatter (SSC)low和表达CD3或者CD19可以鉴定为淋巴细胞；SSChigh和Gr-1+细胞可识别为粒细胞；SSChigh Siglec-F+ Mac-3+的细胞为巨噬细胞；SSChigh Siglec-F+Mac-3-细胞为嗜酸性粒细胞。对于分析Tregs，肺组织和肺纵膈淋巴结分离裂解为单细胞，细胞首先用anti-CD4-FITC (RM4-5, eBioscience) 和anti-CD25-PE (PC61.5, eBioscience)抗体染色，然后用FoxP3-APC(FJK-16s, eBioscience)细胞内染色，CD4+CD25+Foxp3+为Tregs。

1.7. 统计学方法

采用SPSS 21.0软件进行统计分析。数据以均数±标准差表示。先进行方差齐性和正态性检验，再使用单因素方差分析进行组间比较，方差齐用LSD检验，不齐用Dunnett T3检验，以P < 0.05为差异有统计学意义。

2. 结果

2.1. AhR激活促进哮喘小鼠肺内Cyp1a1和Cyp1b1的表达

研究发现，与CRE组相比，AhR激动剂组显著增加了CRE致敏的哮喘小鼠肺内AhR、Cyp1a1和Cyp1b1基因的表达(P=0.002)；AhR拮抗组与AhR激动组相比，明显降低了AhR、Cyp1a1和Cyp1b1基因的表达(P= 0.004)，但与CRE组相比无明显统计学差异(图 1A~C)。此外，我们通过免疫荧光染色进一步验证了AhR在肺内表达变化情况(P < 0.001，图 1D、E)。

2.2. AhR激活减轻CRE诱导哮喘小鼠肺部炎症

H & E和PAS染色发现，AhR激活可明显减轻CRE引发的支气管周围炎症及粘液分泌，而拮抗AhR后支气管周围炎症及粘液分泌明显增多，但与CRE组相比，无明显统计学差异(图 2A)。我们进一步通过流式细胞仪分析肺泡灌洗液中细胞数量及细胞成分发现，与CRE组相比，AhR激活组总的炎症细胞数明显减少(P < 0.001，图 2B)，其中嗜酸性粒细胞减少最明显(P=0.01)，中性粒细胞数量增加(P=0.02，图 2C)；与AhR激活组相比，AhR拮抗组明显增加了炎症细胞总数，其中以嗜酸性细胞增多最明显(P < 0.001，图 2B、C)。而且，AhR激活明显降低了哮喘小鼠血清中CRE特异性IgE及IgG1，而拮抗AhR后抵消了这一变化(P=0.01，图 3A、B)。通过进一步分析小鼠BALF中炎症因子的变化情况，我们发现与CRE组相比，AhR激活组中IL-4、IL-13和IL-17A表达降低(P < 0.001)，IL-10、IL-22和TGFβ1表达增加(P < 0.001)；与AhR激活组相比，AhR拮抗组增加了促炎因子IL-4、IL-13和IL-17A的表达(P < 0.01，图 3C~E)，降低了抑炎因子IL-10、IL-22和TGFβ1的表达(P < 0.001，图 3F~H)。

2.

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AhR激活减轻哮喘小鼠肺部炎症

AhR activation alleviates airway inflammation in asthmatic mice. A: Paraffin-embedded lung tissues stained with HE (top panel) and periodic acid-Schiff (PAS; bottom panel)(Original magnification: ×20). B, C: Total cell counts and differential cell counts of BAL determined by flow cytometry. *P < 0.05, **P < 0.01.

3.

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激活AhR对哮喘小鼠肺部炎症因子表达的影响

Effect of AhR activation on expressions of cytokines in the BALs of asthmatic mice. A, B: ELISA for detecting serum levels of cockroach allergen-specific IgE and IgG1. C-H: Levels of cytokines in BALs. **P < 0.01.

2.3. AhR激活通过调控Th17/Treg分化来缓解哮喘小鼠肺部炎症

我们进一步探讨AhR是否通过调节T细胞的分化来改善哮喘炎症。IL-17A是由Th17细胞产生的一种细胞因子。Treg与Th17细胞在分化发育和功能上相互抑制。通过流式细胞仪检测肺及肺纵膈淋巴结中Treg的表达，我们发现与CRE组相比，AhR激活组中CD4+CD25+Foxp3+Treg在肺及肺纵膈淋巴结中均表达增加(P < 0.001)；而AhR拮抗组与AhR激活组相比，肺及肺纵膈淋巴结中CD4+CD25+Foxp3+Treg表达减少(P < 0.001)，与CRE组无明显统计学差异(图 4A~C)。我们进一步通过基因表达水平的检测来观察AhR对Th17/Treg细胞分化的影响。AhR激活组哮喘小鼠肺纵膈淋巴结中RORγt基因表达水平明显降低(P < 0.001，图 4D)，FOXP3表达明显增加(P < 0.001，图 4E)，而拮抗AhR后逆转了这一变化。

4.

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激活AhR能抑制Th17细胞分化增加Treg分化

AhR activation promotes Treg differentiation and inhibits Th17 differentiation. A: Tregs in lung lymphocytes determined by flow cytometry gating on CD4+CD25+Foxp3+ cells. B: Percentage of CD4+CD25+Foxp3+ cells in lymph nodes and lungs among all analyzed cells. C, D: RORγt and Foxp3 mRNA expressions in lymphocytes determined by real-time PCR. **P < 0.01.

3. 讨论

哮喘是由多种细胞、细胞因子和炎性介质引起的变态反应性炎症性疾病，其发病机制复杂，迄今为止尚未完全清楚。经典理论认为Th1细胞和Th2细胞失衡是哮喘发病的关键机制[15-16]，近年来有学者提出Th17细胞和Treg细胞的免疫失衡也可能是哮喘发病的重要机制之一[5-8, 17]。Th17细胞和Treg细胞分化上相互关联，在功能上互相拮抗。Treg具有免疫调节作用，可通过抑制自身免疫T细胞的活化来维持自身的免疫耐受[18]。Foxp是调控Treg的标志性转录因子[19-21]。研究证明，Treg功能降低、数量下降是哮喘患者免疫紊乱的重要表现及哮喘发病的重要机制之一。Th17细胞是近年来发现的另一种CD4+T细胞的新亚型，RORγt是其特异性的转录因子[22-23]。有研究发现Th17细胞及其分泌的细胞因子IL-17表达增多，并发现IL-17与哮喘气道重塑有很大的相关性[24]。IL-17A是由Th17细胞产生的一种细胞因子，它通过释放促炎因子和中性粒细胞趋化因子，在支气管哮喘的发病中发挥发挥重要作用[25]。但在哮喘发病过程中，Th17/Treg免疫失衡调控机制仍不完全清楚。

AhR是一种能感受和应答环境刺激的多功能调节蛋白，在正常细胞反应和免疫调节中起重要作用[26-28]。当配体与AhR结合并使其发生活化，活化状态的配体-AhR复合物在Hsp90、ARA9和p23协助下转移至细胞核，与AhR核转位蛋白(ARNT)形成AhR/ARNT异源二聚体。活化的AhR/ARNT异源二聚体结合于相应的DNA序列，启动异型新生物质新陈代谢的基因以及内生物质的基因转录和翻译[29]。研究发现，AhR通过调控多种免疫细胞的分化、活化，参与了气道变应性疾病的一系列病理生理过程[30]。我们依据前期研究[12-13]，成功构建CRE诱导的哮喘模型。我们发现AhR激活减轻了CRE诱导的哮喘小鼠肺部炎症反应，表现为肺部炎症细胞减少，粘液分泌减少；同时AhR激活促进了抑炎因子IL-10、IL-22和TGFβ1的表达，抑制了促炎因子IL-4、IL-13和IL-17A的表达，而拮抗AhR后增加了哮喘小鼠肺部炎症，增加了促炎因子的表达，降低了抑炎因子的表达，与CRE组相比，表达无明显差异。我们进一步分析发现，AhR激活引起肺内及肺纵膈淋巴结中Treg细胞表达增加。AhR激活增强了Treg细胞转录因子Foxp 3的表达，减少了Th17细胞转录因子RORγt的表达，而拮抗AhR后使Treg细胞及其转录因子Foxp3表达减少，Th17细胞转录因子RORγt的表达增加。我们的实验结果表明，AhR的激活和拮抗能够调控小鼠肺内Th17及Treg细胞及其相应促炎和抑炎因子的表达。

因此，我们发现AhR能够通过调节Th17/Treg分化来减轻CRE诱导的哮喘小鼠肺部炎症反应。这一发现为哮喘疾病的防治提供新策略，同时为后续进一步探讨AhR与Th17/Treg免疫失衡间机制通路研究提供理论基础。

Biography

许婷，博士，主治医师，E-mail: xuting0359@163.com

Funding Statement

国家自然科学基金青年基金（81600013）；广东省自然科学基金（2019A1515011614）；广州市科技计划项目基础与应用基础项研究（202002030483）；广州市医药卫生科技项目（20171A011305）

Supported by Natural Science Foundation for the Youth (NSFY) of China (81600013)

Contributor Information

许 婷 (Ting XU), Email: xuting0359@163.com.

李 涛平 (Taoping LI), Email: ltpnet@126.com.

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