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.
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DOI：
10.1186/s12931-020-01583-x
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发表时间：
2021-02-08
影响因子：
5.8
通讯作者：
Ding F
中科院分区：
文献类型：
--
作者：
Wang Y;Liao K;Liu B;Niu C;Zou W;Yang L;Wang T;Tian D;Luo Z;Dai J;Li Q;Liu E;Gong C;Fu Z;Li Y;Ding F
糖皮质激素诱导的肿瘤坏死因子受体家族相关蛋白配体（GITRL）在肿瘤、自身免疫和炎症中起重要作用。然而，尚不知道GITRL调节过敏性哮喘的发病机制。在这项研究中，我们调查是否调控GITRL表达的树突状细胞（DC）可以预防哮喘，并阐明其作用机制。在体内，在腺相关病毒（AAV）-shGITRL小鼠中评估GITRL在调节屋尘螨（HDM）诱导的哮喘中的作用。在体外，在HDM刺激下在LV-shGITRL骨髓树突状细胞（BMDC）中评估DC表达GITRL的作用。用GITRL蛋白刺激脾细胞，观察GITRL的直接作用。检测调节GITRL对CD 4 + T细胞分化的影响。进一步检测哮喘患儿外周血中GITRL mRNA的表达。在HDM攻击的小鼠中，GITRL显著增加。在GITRL敲除小鼠中，变应原诱导的气道炎症、血清总IgE水平和气道高反应性（AHR）降低。在体外，HDM刺激后BMDCs上的GITRL表达增加。此外，敲低DC上的GITRL部分恢复了Th 1/Th 2和Th 17/Treg细胞的平衡。此外，体外GITRL刺激抑制Treg细胞分化，促进Th 2和Th 17细胞分化。同样，哮喘儿童外周血中GITRL mRNA表达增加。本研究确定了DC表达的GITRL作为哮喘中CD 4 + T细胞应答的正性调节剂的新作用，这暗示GITRL抑制剂可能是哮喘的潜在免疫治疗。
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. 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. 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. 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.
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DOI：
10.1016/j.jaci.2016.06.003
发表时间：
2016-09
期刊：
The Journal of allergy and clinical immunology
影响因子：
--
作者：
Noval Rivas M;Chatila TA
通讯作者：
Chatila TA
影响因子：
82.9
作者：
Collison, Adam;Hatchwell, Luke;Mattes, Joerg
通讯作者：
Mattes, Joerg
GITR信号传导通过在哮喘的小鼠模型中增强Th2细胞活性来增强气道高反应性。
影响因子：
5.8
作者：
Motta AC;Vissers JL;Gras R;Van Esch BC;Van Oosterhout AJ;Nawijn MC
通讯作者：
Nawijn MC
影响因子：
2.2
作者：
Lutz, MB;Kukutsch, N;Schuler, G
通讯作者：
Schuler, G
影响因子：
32.4
作者：
Chang, Yu-Han;Wang, Kuan Chung;Watts, Tania H.
通讯作者：
Watts, Tania H.