Author:
Wang Yaping,Liao Kou,Liu Bo,Niu Chao,Zou Wenjing,Yang Lili,Wang Ting,Tian Daiyin,Luo Zhengxiu,Dai Jihong,Li Qubei,Liu Enmei,Gong Caihui,Fu Zhou,Li Ying,Ding Fengxia
Abstract
Abstract
Background
Glucocorticoid-induced tumor necrosis factor receptor family-related protein ligand (GITRL) plays an important role in tumors, autoimmunity and inflammation. However, GITRL is not known to modulate the pathogenesis of allergic asthma. In this study, we investigated whether regulating GITRL expressed on dendritic cells (DCs) can prevent asthma and to elucidate its mechanism of action.
Methods
In vivo, the role of GITRL in modulating house dust mite (HDM)-induced asthma was assessed in adeno-associated virus (AAV)-shGITRL mice. In vitro, the role of GITRL expression by DCs was evaluated in LV-shGITRL bone marrow dendritic cells (BMDCs) under HDM stimulation. And the direct effect of GITRL was observed by stimulating splenocytes with GITRL protein. The effect of regulating GITRL on CD4+ T cell differentiation was detected. Further, GITRL mRNA in the peripheral blood of asthmatic children was tested.
Results
GITRL was significantly increased in HDM-challenged mice. In GITRL knockdown mice, allergen-induced airway inflammation, serum total IgE levels and airway hyperresponsiveness (AHR) were reduced. In vitro, GITRL expression on BMDCs was increased after HDM stimulation. Further, knocking down GITRL on DCs partially restored the balance of Th1/Th2 and Th17/Treg cells. Moreover, GITRL stimulation in vitro inhibited Treg cell differentiation and promoted Th2 and Th17 cell differentiation. Similarly, GITRL mRNA expression was increased in the peripheral blood from asthmatic children.
Conclusions
This study identified a novel role for GITRL expressed by DCs as a positive regulator of CD4+ T cells responses in asthma, which implicates that GITRL inhibitors may be a potential immunotherapy for asthma.
Funder
National Natural Science Foundation of China
Publisher
Springer Science and Business Media LLC
Reference46 articles.
1. Collaborators GBDCRD. Global, regional, and national deaths, prevalence, disability-adjusted life years, and years lived with disability for chronic obstructive pulmonary disease and asthma, 1990–2015: a systematic analysis for the Global Burden of Disease Study 2015. Lancet Respir Med. 2017;5:691–706.
2. Tortola L, Pawelski H, Sonar SS, Ampenberger F, Kurrer M, Kopf M. IL-21 promotes allergic airway inflammation by driving apoptosis of FoxP3(+) regulatory T cells. J Allergy Clin Immunol. 2019;143(2178–2189):e2175.
3. Lambrecht BN, Hammad H, Fahy JV. The cytokines of asthma. Immunity. 2019;50:975–91.
4. Tumes DJ, Papadopoulos M, Endo Y, Onodera A, Hirahara K, Nakayama T. Epigenetic regulation of T-helper cell differentiation, memory, and plasticity in allergic asthma. Immunol Rev. 2017;278:8–19.
5. Vroman H, Bergen IM, van Hulst JAC, van Nimwegen M, van Uden D, Schuijs MJ, Pillai SY, van Loo G, Hammad H, Lambrecht BN, et al. TNF-α-induced protein 3 levels in lung dendritic cells instruct T(H)2 or T(H)17 cell differentiation in eosinophilic or neutrophilic asthma. J Allergy Clin Immunol. 2018;141(1620–1633):e1612.
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