GITRL on dendritic cells aggravates house dust mite-induced airway inflammation and airway hyperresponsiveness by modulating CD4+ T cell differentiation.
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.
['Wang|Yaping|Y|', 'Liao|Kou|K|', 'Liu|Bo|B|', 'Niu|Chao|C|', 'Zou|Wenjing|W|', 'Yang|Lili|L|', 'Wang|Ting|T|', 'Tian|Daiyin|D|', 'Luo|Zhengxiu|Z|', 'Dai|Jihong|J|', 'Li|Qubei|Q|', 'Liu|Enmei|E|', 'Gong|Caihui|C|', 'Fu|Zhou|Z|', 'Li|Ying|Y|', 'Ding|Fengxia|F|']
D000818:Animals D001249:Asthma D015496:CD4-Positive T-Lymphocytes D002454:Cell Differentiation D002648:Child D018920:Coculture Techniques D003713:Dendritic Cells D005260:Female D006801:Humans D051379:Mice D008810:Mice, Inbred C57BL D039981:Pyroglyphidae D012130:Respiratory Hypersensitivity D048069:Tumor Necrosis Factors
GITRL Dendritic cells Asthma Th1/Th2 Th17/Treg