Tryptophan metabolites regulate Th17/Treg differentiation to alleviate airway inflammation in asthmatic mice receiving allergen-specific immunotherapy

Wenting FAN; Shimin ZHONG; Qi HU; Jing ZENG; Wei LIAO; Jinyu WANG

doi:10.16016/j.1000-5404.201709229

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Tryptophan metabolites regulate Th17/Treg differentiation to alleviate airway inflammation in asthmatic mice receiving allergen-specific immunotherapy

Basic Medicine | 更新时间：2026-01-09

- Tryptophan metabolites regulate Th17/Treg differentiation to alleviate airway inflammation in asthmatic mice receiving allergen-specific immunotherapy
- Journal of Third Military Medical University Vol. 40, Issue 8, Pages: 658-665(2018)
- 作者机构：
  
  400038 重庆，陆军军医大学(第三军医大学)第一附属医院儿科
- 作者简介：
- 基金信息：
  
  the General Program of National Natural Science Foundation of China(81570022);the Research Fund of First Affiliated Hospital of Third Military Medical University(SWH2015LC11)
- DOI：10.16016/j.1000-5404.201709229
  CLC： R392-33;R392.32;R562.25
- Received：30 September 2017，
  
  Revised：2017-12-29，
  
  Published：30 April 2018
- 稿件说明：
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Wenting FAN, Shimin ZHONG, Qi HU, et al. Tryptophan metabolites regulate Th17/Treg differentiation to alleviate airway inflammation in asthmatic mice receiving allergen-specific immunotherapy[J]. Journal of Third Military Medical University, 2018, 40(8): 658-665.
DOI：

Wenting FAN, Shimin ZHONG, Qi HU, et al. Tryptophan metabolites regulate Th17/Treg differentiation to alleviate airway inflammation in asthmatic mice receiving allergen-specific immunotherapy[J]. Journal of Third Military Medical University, 2018, 40(8): 658-665. DOI： 10.16016/j.1000-5404.201709229.

摘要

目的

对色氨酸代谢物调控Th17/Treg分化在小鼠哮喘变应原特异性免疫治疗中的作用及机制进行研究。

方法

将30只BALB/c 鼠随机法分为5组：对照组、哮喘组、OVA-SIT组(OVA：鸡卵白蛋白；SIT：变应原特异性免疫治疗)、OVA-SIT+1-MT组(1-MT：IDO抑制剂，1-甲基色氨酸)，OVA-SIT+ 1-MT+KYN组(KYN：色氨酸代谢产物，犬尿氨酸)。哮喘组：第0、7 d予OVA致敏，第6周每天予1% OVA雾化激发，50 d予10% OVA加强激发；OVA-SIT组：第4周每天予大剂量OVA皮下注射，余同哮喘组；OVA-SIT+1-MT组：第4周每天在腹腔内注入1-MT，1 h后予大剂量OVA皮下注射h，余同哮喘组；OVA-SIT+1-MT+KYN组：第3周每天加入1-MT，第4周每天加入KYN，末次加入KYN后1 h予大剂量OVA行免疫治疗，余同哮喘组。末次激发6 h内检测气道高反应性；对支气管肺泡灌洗液(BALF)进行细胞计数分析；ELISA检测血清IgE及BALF中IL-5、IL-10、IL-17；流式细胞技术检测脾脏CD4

RORγt

T及CD4

Foxp3

T细胞分化情况。

结果

OVA-SIT+1-MT+KYN组较OVA-SIT+1-MT组酸性粒细胞浸润减少，炎症反应明显减轻。前者BALF中Il-5为

74.8~86.8(83.48±6.02)pg/mL，IL-17为33.8~46.5(38.72±4.61)pg/mL，CD4

RORγt

T细胞为2.45~2.82(2.60 ±0.14)%，CD4

Foxp3

T细胞为7.83~9.09(8.36±0.53)%；后者BALF中Il-5为240.3~285.1(259.65±16.27)pg/mL，IL-17为55.2~65.8(59.97±3.76)pg/mL，CD4

RORγt

T细胞为4.31~5.34(4.94±0.38)%，CD4

Foxp3

T细胞为5.93~6.59(6.33±0.28)%，因此OVA-SIT+1-MT+KYN组中Il-5、IL-17细胞因子以及脾脏中CD4

RORγt

T细胞均明显低于OVA-SIT+1-MT组，差异均有统计学意义(

0.01)，而前组脾脏中CD4

Foxp3

T细胞水平明显高于后者，差异有统计学意义(

0.01)。

结论

色氨酸代谢产物有助于特异性免疫治疗减轻气道炎症作用，其机制与通过调控Th17及Treg分化有关。

Abstract

Objective

To study the role of tryptophan metabolites in regulating Th17/Treg differentiation to alleviate airway inflammation in asthmatic mice receiving allergen-specific immunotherapy (SIT).

Methods

Thirty BALB/c mice were randomized equally into control group

asthma group

chicken ovalbumin (OVA)-SIT group

OVA-SIT+1-methyltryptophan (1-MT

an indoleamine 2

3 dioxygenase inhibitor) group

and OVA-SIT+1-MT+kynurenine (KYN

a tryptophan metabolite) group. Except for those in the control group

all the mice were sensitized with OVA on days 0 and 7 followed by daily challenge with 1% OVA in the 6th week and then with 10% OVA on day 50 to induce asthma; In OVA-SIT group

the mice were treated in the 4th week with daily subcutaneous injection of high-dose OVA

and in OVA-SIT+1-MT group

the mice received daily intraperitoneal injection of 1-MT 1 h before subcutaneous high-dose OVA injection; in OVA-SIT+1-MT+KYN group

the mice were treated with daily 1-MT injection in the third week and daily KYN injection in the 4th week

and high-dose OVA immunotherapy was administered at 1 h after the last KYN injection. Airway hyperresponsiveness of the mice was measured within 6 h after the last challenge. Serum le

vels of IgE and levels of IL-10

IL-5 and IL-17 in bronchoalveolar lavage fluid (BALF) were detected with ELISA

and flow cytometry was performed to analyze the differentiation of CD4

RORγt

and CD4

Foxp3

T cells in the spleen.

Results

Compared with those in OVA-SIT+1-MT group

the infiltration of acidic granulocytes and neutrophils decreased and the inflammatory response was significantly reduced in OVA-SIT+1-MT+KYN group. In OVA-SIT+1-MT group

the mean IL-5 level in BALF was (83.48±6.22) pg/mL

IL-17 level was (38.72±4.61) pg/mL

CD4

Foxp3

T cell percentage was (2.60±0.14)%

and CD4

Foxp3

T cell percentage was (8.36±0.53)%

as compared with the levels of (259.65± 16.27) pg/mL

(59.97±3.76) pg/mL

(4.94±0.38)%

and (6.33±0.28)% in OVA-SIT+1-MT+KYN group

respectively; IL-5 and IL-17 levels and spleen CD4

RORγt

T cell percentage was significantly lower (

0.01) while CD4

Foxp3

T cell percentage was significantly higher (

0.01) in OVA-SIT+1-MT+KYN group than in OVA-SIT+1-MT group.

Conclusion

Tryptophan metabolites contribute to the efficacy of specific immunotherapy in reducing airway inflammation in asthmatic mice

the mechanism of which may involve the regulation of Th17/Treg cell differentiation.

关键词

Keywords

references

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