2. Academic Validation
  3. GITRL on dendritic cells aggravates house dust mite-induced airway inflammation and airway hyperresponsiveness by modulating CD4+ T cell differentiation

GITRL on dendritic cells aggravates house dust mite-induced airway inflammation and airway hyperresponsiveness by modulating CD4+ T cell differentiation

  • Respir Res. 2021 Feb 8;22(1):46. doi: 10.1186/s12931-020-01583-x.
Yaping Wang 1 2,  Kou Liao 1 2,  Bo Liu 2 3,  Chao Niu 1 2,  Wenjing Zou 1 2,  Lili Yang 1 2,  Ting Wang 1 2,  Daiyin Tian 1 2,  Zhengxiu Luo 1 2,  Jihong Dai 1 2,  Qubei Li 1 2,  Enmei Liu 1 2,  Caihui Gong 1 2,  Zhou Fu 1 2,  Ying Li  # 4 5,  Fengxia Ding  # 6 7
Affiliations

Affiliations

  • 1 Department of Respiratory Medicine, Children's Hospital of Chongqing Medical University, Yuzhong District, No. 136, Zhongshan 2nd Road, Chongqing, 400014, 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, People's Republic of China.
  • 3 Department of Cardiothoracic Surgery, Children's Hospital of Chongqing Medical University, Chongqing, People's Republic of China.
  • 4 Department of Respiratory Medicine, Children's Hospital of Chongqing Medical University, Yuzhong District, No. 136, Zhongshan 2nd Road, Chongqing, 400014, China. [email protected].
  • 5 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, People's Republic of China. [email protected].
  • 6 Department of Respiratory Medicine, Children's Hospital of Chongqing Medical University, Yuzhong District, No. 136, Zhongshan 2nd Road, Chongqing, 400014, China. [email protected].
  • 7 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, People's Republic of China. [email protected].
  • # Contributed equally.
PMID: 33557842 DOI: 10.1186/s12931-020-01583-x
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.

Keywords

Asthma; Dendritic cells; GITRL; Th1/Th2; Th17/Treg.

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