Blockade of GITRL/GITR signaling pathway attenuates house dust mite-induced allergic asthma in mice through inhibition of MAPKs and NF-κB signaling

Yaping Wang; Bo Liu; Chao Niu; Wenjing Zou; Lili Yang; Ting Wang; Daiyin Tian; Zhengxiu Luo; Jihong Dai; Qubei Li; Enmei Liu; Caihui Gong; Zhou Fu; Fengxia Ding

doi:10.1016/j.molimm.2021.07.005

Blockade of GITRL/GITR signaling pathway attenuates house dust mite-induced allergic asthma in mice through inhibition of MAPKs and NF-κB signaling

Mol Immunol. 2021 Sep:137:238-246. doi: 10.1016/j.molimm.2021.07.005. Epub 2021 Jul 20.

Authors

Yaping Wang¹, Bo Liu², Chao Niu¹, Wenjing Zou¹, Lili Yang¹, Ting Wang¹, Daiyin Tian¹, Zhengxiu Luo¹, Jihong Dai¹, Qubei Li¹, Enmei Liu¹, Caihui Gong¹, Zhou Fu¹, Fengxia Ding³

Affiliations

¹ Department of Respiratory Medicine, Children's Hospital of Chongqing Medical University, Chongqing, PR China; National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Chongqing Key Laboratory of Pediatrics, Children's Hospital of Chongqing Medical University, Chongqing, PR China.
² National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Chongqing Key Laboratory of Pediatrics, Children's Hospital of Chongqing Medical University, Chongqing, PR China; Department of Cardiothoracic Surgery, Children's Hospital of Chongqing Medical University, Chongqing, PR China.
³ Department of Respiratory Medicine, Children's Hospital of Chongqing Medical University, Chongqing, PR China; National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Chongqing Key Laboratory of Pediatrics, Children's Hospital of Chongqing Medical University, Chongqing, PR China. Electronic address: 482613@hospital.cqmu.edu.cn.

PMID: 34293591
DOI: 10.1016/j.molimm.2021.07.005

Abstract

GITRL/GITR signaling pathway plays an important role in allergy, inflammation, transplantation and autoimmunity. However, its role in asthma remains unclear. Thus, the present study aimed to investigate changes in this pathway and observe the therapeutic effect of its blocking on asthma. By using house dust mite-induced asthma model, changes of GITRL/GITR and its downstream molecules MAPKs (e.g., p38 MAPK, JNK and Erk) and NF-κB were observed. After that, GITRL in lung of mice was knocked down by recombinant adeno-associated virus to observe the impact on its downstream molecules and assess the therapeutic effect on asthma. These results showed that GITRL/GITR and its downstream molecules MAPKs/NF-κB were activated in asthmatic mice. This activation was suppressed after GITRL knockdown, and allergic airway inflammation and airway hyperresponsiveness were alleviated. These results demonstrate that GITRL/GITR-MAPKs/NF-κB signaling pathway participates in the pathogenesis of asthma. Blockade of GITRL/GITR signaling pathway exhibits protective effects in a mouse model of house dust mite-induced allergic asthma.

Keywords: Adeno-associated virus; Asthma; GITRL/GITR; MAPKs; NF-κB.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Asthma / immunology*
Dermatophagoides pteronyssinus / immunology
Disease Models, Animal
Female
Glucocorticoid-Induced TNFR-Related Protein / immunology*
Hypersensitivity / immunology*
Inflammation / immunology
Lung / immunology
Mice
Mice, Inbred C57BL
Mitogen-Activated Protein Kinases / immunology*
NF-kappa B / immunology*
Pyroglyphidae / immunology*
Respiratory Hypersensitivity / immunology
Signal Transduction / immunology
Tumor Necrosis Factors / immunology*

Substances

Glucocorticoid-Induced TNFR-Related Protein
NF-kappa B
Tnfrsf18 protein, mouse
Tnfsf18 protein, mouse
Tumor Necrosis Factors
Mitogen-Activated Protein Kinases