Notch1 induces Th1/Th2 imbalance in neonatal mice with <italic style="font-style: italic">Streptococcus pneumoniae</italic> infection

Yiying WANG; Ding JIAN; Lin ZHU; Hanzhi ZHANG; Yuanyuan LI; Shiyi CHEN; Guangli ZHANG; Zhengxiu LUO

doi:10.16016/j.2097-0927.202204021

您当前的位置：

首页 >

文章列表页 >

Notch1 induces Th1/Th2 imbalance in neonatal mice with Streptococcus pneumoniae infection

Basic Medicine | 更新时间：2026-01-09

- Notch1 induces Th1/Th2 imbalance in neonatal mice with Streptococcus pneumoniae infection
- Journal of Army Medical University Vol. 44, Issue 21, Pages: 2138-2145(2022)
- 作者机构：
  
  400014 重庆，重庆医科大学附属儿童医院呼吸科，国家儿童健康与疾病临床医学研究中心，儿童发育与疾病教育部重点实验室，儿科学重庆市重点实验室, 儿童感染免疫重庆市重点实验室
- 作者简介：
- 基金信息：
  
  the Natural Science Foundation of Chongqing(cstc2020jcyj-msxmX0677);the Basic Research Project of Key Laboratory of Child Development Disease of Ministry of Education(GBRP-202112)
- DOI：10.16016/j.2097-0927.202204021
  CLC： R378.12;R392.13;R563.1
- Received：02 April 2022，
  
  Revised：2022-06-23，
  
  Published：15 November 2022
- 稿件说明：
移动端阅览
Yiying WANG, Ding JIAN, Lin ZHU, et al. Notch1 induces Th1/Th2 imbalance in neonatal mice with Streptococcus pneumoniae infection[J]. Journal of Army Medical University, 2022, 44(21): 2138-2145.
DOI：

Yiying WANG, Ding JIAN, Lin ZHU, et al. Notch1 induces Th1/Th2 imbalance in neonatal mice with Streptococcus pneumoniae infection[J]. Journal of Army Medical University, 2022, 44(21): 2138-2145. DOI： 10.16016/j.2097-0927.202204021.

摘要

目的

研究Notch1信号通路在新生期小鼠肺炎链球菌感染诱导Th1/Th2失衡中的作用。

方法

12只1周龄Balb/c新生小鼠分

为3组(

=4)：新生期肺炎链球菌肺炎(

Streptococcus pneumoniae

pneumonia，S.pp)组、新生期肺炎链球菌肺炎Notch1抑制组[S.pp+DAPT(γ分泌酶抑制剂)

]

和对照组。S.pp组、S.pp+DAPT组小鼠鼻腔滴注10 μL含有1×10

cfu肺炎链球菌的悬液，对照组同期滴注等量PBS。小鼠感染肺炎链球菌后第7天，S.pp+DAPT组鼻腔滴注0.3 mg/kg的Notch1抑制剂DAPT，S.pp组和对照组鼻腔滴注等量PBS。小鼠发育至6周(成年)，检测气道反应性，收集支气管肺泡灌洗液(bronchoalveolar lavage fluid，BALF)行细胞分类计数，肺组织HE染色病理切片观察组织病理变化；Western blot检测肺组织Notch1蛋白水平；RT-PCR检测肺组织

T-bet

、

GATA

3 mRNA水平；流式细胞术检测肺组织Th1、Th2细胞水平并分析Th1/Th2比率。

结果

S.pp+DAPT组Notch1蛋白表达显著低于S.pp组(0.23±0.09

1.94±0.78，

0.01)。S.pp+DAPT组BALF细胞总数、中性粒细胞、单核细胞、淋巴细胞计数均明显低于S.pp组(

0.01)；肺组织中细支气管周围炎症(0.55±0.17

1.52±0.27

0.01)、血管周围炎症(0.05±0.10

0.88±0.25

0.01)、肺间质炎症评分(0.18±0.35

1.57±0.25

0.01)、肺部

GATA

3 mRNA表达(19.11±9.79

177.56±65.95

0.01)、Th2细胞水平[(0.16±0.02)%

(0.28±0.04)%

0.01

]

也显著低于S.pp组；而

T-bet

mRNA表达、Th1细胞水平与S.pp组比较差异无统计学意义(

0.05)，Th1/Th2比值较S.pp组明显增加(14.67±2.60

7.89±0.82

0.01)。S.pp+DAPT组小鼠吸入3.125~50 mg/mL浓度乙酰甲胆碱激发后，气道反应性较S.pp组显著降低(

0.01)。

结论

新生期肺炎链球菌肺炎可能通过激活Notch1信号诱导Th1/Th2失衡，促进气道高反应性及气道炎症形成。

Abstract

Objective

To investigate the role of Notch1 signaling pathway in Th1/Th2 imbalance induced by neonatal

Streptococcus pneumoniae

pneumonia (S.pp) infection.

Methods

Twelve Balb/c neonatal mice (1 week old) were randomly divided into neonatal S.pp group

neonatal S.pp with Notch1 inhibition treatment group (S.pp+DAPT

a γ-secretase inhibitor) and mock-infected control group (control gro

up) (

=4). The S.pp group and the S.pp+DAPT group were infected with 1×10

CFU of

S. pneumoniae

in 10 μL of PBS intranasally

while the control group received equivalent PBS. In 7 d after infection

the S.pp+DAPT groups were given 0.3 mg/kg DAPT by nasal instillation

and the S.pp and the control groups were instilled equivalent PBS. In 5 weeks after infection

airway hyperresponsiveness (AHR) was evaluated by invasive body plethysmography system. Differential cell counts in bronchoalveolar lavage fluid (BALF) were analyzed. HE staining was used to observe the histopathological changes of the lung tissue. Western blotting was used to detect the protein expression of Notch1 protein

and RT-PCR to measure the mRNA levels of

T-bet

and

GATA

3. And the percentages of Th1 and Th2 cells in the lung tissue were determined by flow cytometry and Th1/Th2 ratio was calculated.

Results

Notch1 expression was significantly lower in the S.pp+ DAPT group than the S.pp group (0.23±0.09

1.94±0.78

0.01). The total cell count and counts of neutrophils

monocytes and lymphocytes in the BALF from the S.pp+DAPT group were remarkably lower than those in the S.pp group (

0.01). The S.pp+DAPT mice had obviously lower histologic scores of pulmonary peribronchiolitis

pulmonary perivasculitis and pulmonary alveolitis in lung tissue than the S.pp group (0.55±0.17

1.52±0.27

0.01; 0.05±0.10

0.88±0.25

0.01; 0.18±0.35

1.57±0.25

0.01). The mRNA level of

GATA

3 and percentage of Th2 cells were significantly lower in the S.pp+DAPT group than the S.pp group [19.11±9.79

177.56±65.95

0.01; (0.16±0.02)%

(0.28±0.04)%

0.01

]

. While the mRNA level

T-bet

and percentage of Th1 cells were similar between the 2 groups. The S.pp+DAPT group had significantly higher Th1/Th2 when compared with the S.pp group (14.67±2.60

7.89±0.82

0.01). The AHR in the S.pp+DAPT group mice was significantly decreased when inhaled different concentrations of acetylcholine (3.125~50 mg/mL) as compared with the S.pp group (

0.01).

Conclusion

Neonatal S.pp may induce Th1/Th2 imbalance by activating Notch1 signal

and thus promote airway hyperreactivity and airway inflammation.

关键词

Keywords

references

KATZ S E, WILLIAMS D J. Pediatric community-acquired pneumonia in the United States: changing epidemiology, diagnostic and therapeutic challenges, and areas for future research[J]. Infect Dis Clin North Am, 2018, 32(1): 47-63. DOI: 10.1016/j.idc.2017.11.002.

VISSING N H, CHAWES B L K, BISGAARD H. Increased risk of pneumonia and bronchiolitis after bacterial colonization of the airways as neonates[J]. Am J Respir Crit Care Med, 2013, 188(10): 1246-1252. DOI: 10.1164/rccm.201302-0215OC.

田琴琴, 刘茹, 陈云秀, 等. 新生期肺炎链球菌肺炎对成年期肺组织免疫状态及气道高反应的影响[J]. 免疫学杂志, 2015, 31(12): 1051-1055. DOI: 10.13431/j.cnki.immunol.j.20150221.

TIAN Q Q, LIU R, CHEN Y X, et al . The impact of neonatal pneumococcal pneumonia on adult lung immune status and airway hyperresponsiveness in mice[J ] . Immunol J, 2015, 31(12): 1051-1055. DOI: 10.13431/j.cnki.immunol.j.20150221.

YANG B H, LIU R, YANG T, et al . Neonatal Streptococcus pneumoniae infection may aggravate adulthood allergic airways disease in association with IL-17A[J ] . PLoS One,2015, 10(3): e0123010. DOI: 10.1371/journal.pone.0123010..

LARCHÉ M, ROBINSON D S, KAY A B. The role of T lymphocytes in the pathogenesis of asthma[J]. J Allergy Clin Immunol, 2003, 111(3): 450-463;quiz464. DOI: 10.1067/mai.2003.169.

ELIAS J A, ZHU Z, CHUPP G, et al . Airway remodeling in asthma[J ] . J Clin Invest, 1999, 104(8): 1001-1006. DOI: 10.1172/JCI8124.

RADTKE F, FASNACHT N, MACDONALD H R. Notch signaling in the immune system[J]. Immunity, 2010, 32(1): 14-27. DOI: 10.1016/j.immuni.2010.01.004.

AMSEN D, ANTOV A, JANKOVIC D, et al . Direct regulation of Gata3 expression determines the T helper differentiation potential of Notch[J ] . Immunity, 2007, 27(1): 89-99. DOI: 10.1016/j.immuni.2007.05.021.

PEI J X, TANG Z H, ZANG G Q, et al . Blockage of Notch1 signaling modulates the T-helper (Th)1/Th2 cell balance in chronic hepatitis B patients[J ] . Hepatol Res, 2010, 40(8): 799-805. DOI: 10.1111/j.1872-034X.2010.00680.x.

KANG J H, KIM B S, UHM T G, et al . Gamma-secretase inhibitor reduces allergic pulmonary inflammation by modulating Th1 and Th2 responses[J ] . Am J Respir Crit Care Med, 2009, 179(10): 875-882. DOI: 10.1164/rccm.200806-893OC.

HU C P, LI Z F, FENG J T, et al . Glucocorticoids modulate Th1 and Th2 responses in asthmatic mouse models by inhibition of Notch1 signaling[J ] . Int Arch Allergy Immunol, 2018, 175(1/2): 44-52. DOI: 10.1159/000485890.

杨婷, 罗征秀, 符州, 等. 新生期小鼠非致死性肺炎链球菌感染模型的建立[J]. 中国生物制品学杂志, 2012, 25(7): 905-908. DOI: 10.13200/j.cjb.2012.07.114.yangt.026.

YANG T, LUO Z X, FU Z, et al . Establishment of neonatal mouse model of non-lethal Streptococcus pneumonia infection[J ] . Chin J Biol, 2012, 25(7): 905-908. DOI: 10.13200/j.cjb.2012.07.114.yangt.026..

LIN J J, PARK P, LI H, et al . Streptococcus pneumoniae elaborates persistent and prolonged competent state during pneumonia-derived sepsis[J ] . Infect Immun, 2020, 88(4): e00919-e00919. DOI: 10.1128/IAI.00919-19..

孔潇, 彭欣, 李媛媛, 等. 新生期肺炎链球菌肺炎对小鼠肺组织结构和功能的影响[J]. 解放军医学杂志, 2021, 46(6): 574-579. DOI: 10.11855/j.issn.0577-7402.2021.06.07.

KONG X, PENG X, LI Y Y, et al . Effects of neonatal Streptococcus pneumoniae pneumonia on lung structure and function of mice[J ] . Med J Chin PLA, 2021, 46(6): 574-579. DOI: 10.11855/j.issn.0577-7402.2021.06.07..

ZHANG L Q, GAO H, YANG T, et al . Infant 7-valent pneumococcal conjugate vaccine immunization alters young adulthood CD4 + T cell subsets in allergic airway disease mouse model[J ] . Vaccine, 2014, 32(18): 2079-2085. DOI: 10.1016/j.vaccine.2014.02.013.

姜小丽, 杨宝辉, 杨婷, 等. 肺炎链球菌感染小鼠早期肺组织细胞因子变化研究[J]. 免疫学杂志, 2013, 29(6): 484-489. DOI: 10.13431/j.cnki.immunol.j.20130104.

JIANG X L, YANG B H, YANG T, et al . The dynamic change of cytokines in lung tissues of mice in the early phase of Streptococcus pneumoniae infection[J ] . Immunol J, 2013, 29(6): 484-489. DOI: 10.13431/j.cnki.immunol.j.20130104..

PEEBLES JR R S, SHELLER J R, COLLINS R D, et al . Respiratory syncytial virus infection does not increase allergen-induced type 2 cytokine production, yet increases airway hyperresponsiven ess in mice[J ] . J Med Virol, 2001, 63(2): 178-188. DOI: 10.1002/1096-9071(20000201)63:2178:AID-JMV1013 > 3.0.CO;2-O.

DENG Y, CHEN W, ZANG N, et al . The antiasthma effect of neonatal BCG vaccination does not depend on the Th17/Th1 but IL-17/IFN-γ balance in a BALB/c mouse asthma model[J ] . J Clin Immunol, 2011, 31(3): 419-429. DOI: 10.1007/s10875-010-9503-5.

LAMBRECHT B N, HAMMAD H, FAHY J V. The cytokines of asthma[J]. Immunity, 2019, 50(4): 975-991. DOI: 10.1016/j.immuni.2019.03.018.

ZHANG Y, ZHANG Y G, GU W P, et al . Th1/Th2 cell's function in immune system[J ] . Adv Exp Med Biol, 2014, 841: 45-65. DOI: 10.1007/978-94-017-9487-9_3.

QIN L, QIU K Z, HU C P, et al . Bronchial epithelial cells promote the differentiation of Th2 lymphocytes in airway microenvironment through jagged/Notch-1 signaling after RSV infection[J ] . Int Arch Allergy Immunol, 2019, 179(1): 43-52. DOI: 10.1159/000495581.

AMSEN D, BLANDER J M, LEE G R, et al . Instruction of distinct CD4 T helper cell fates by different Notch ligands on antigen-presenting cells[J ] . Cell, 2004, 117(4): 515-526. DOI: 10.1016/s0092-8674(04)00451-9.

CUI Z L, HAN F F, PENG X H, et al . YES-associated protein 1 promotes adenocarcinoma growth and metastasis through activation of the receptor tyrosine kinase Axl[J ] . Int J Immunopathol Pharmacol, 2012, 25(4): 989-1001. DOI: 10.1177/039463201202500416.

SUN J, KRAWCZYK C J, PEARCE E J. Suppression of Th2 cell development byNotch ligands Delta1 and Delta4[J]. J Immunol, 2008, 180(3): 1655-1661. DOI: 10.4049/jimmunol.180.3.1655.

AUDERSET F, SCHUSTER S, COUTAZ M, et al . Redundant Notch1 and Notch2 signaling is necessary for IFNγ secretion by T helper 1 cells during infection with Leishmania major [J ] . PLoS Pathog, 2012, 8(3): e1002560. DOI: 10.1371/journal.ppat.1002560..

GU W, XU W G, DING T, et al . Fringe controls naïve CD4 + T cells differentiation through modulating Notch signaling in asthmatic rat models[J ] . PLoS One, 2012, 7(10): e47288. DOI: 10.1371/journal.pone.0047288..

ZHANG Y, ZHANG Y G, GU W P, et al . TH1/TH2 cell differentiation and molecular signals[J ] . Adv Exp Med Biol, 2 014, 841: 15-44. DOI:10.1007/978-94-017-9487-9_2.

Views

下载量

CSCD

Alert me when the article has been cited

提交

Tools

Publicity Resources

Minocycline improves hippocampal neurogenetic defects in neonatal BTBR mice

Increased ratio of Th1/Th2 cells promotes pyroptosis of placental trophoblast cells in early-onset severe preeclampsia

Expression of Notch1 intracellular domain in astrocytic tumors and their clinical significance: an analysis based on 97 cases

Changes of IL-18 and Th1/Th2 in serum of lung cancer patients and their relationship with tumor staging

Related Author

范晓棠

龚洪

宁露

郑富杰

王刘永葳

骆燚

Yi WANG

Li LIU

Related Institution

Department of Clinical Laboratory, Forth Hospital of Shijiazhuang

⁰

Notch1 induces Th1/Th2 imbalance in neonatal mice with Streptococcus pneumoniae infection

DOI：10.16016/j.2097-0927.202204021

摘要

Abstract

关键词

Keywords

references