长链非编码RNA-BG通过抑制RORγt活性减弱支气管哮喘中Th17细胞激活

Asthma is the main form of the idiopathic inflammation of airway, however, the mechanism for the development of asthma is still not fully understood. Multiple genes regulating the IL-23/Th17 axis have been associated with asthma. Patients with asthma have elevated levels of IL-17 and IL-23 within the airway mucosa. IL-17R-deficient mice show reduced emigration of inflammatory cells into the airway and reduced severity of asthma.Therefore, understanding the silencing program for Th17 cells will help to elucidate the mechanism for the development of asthma. We have recently demonstrated that lncRNA-BG silences Th17 celldifferentiation by antagonizing RORγt-mediated IL-17 transcription, resulting in the control of murine asthma development. However, the molecular mechanisms for the regulation of Th17 cell development and the control of human Th17 cell differentiation by lncRNA-BG needs to be addressed. So, The hypothesis driving this proposal is that active drugs targeting RORγt may antagonize the activation of RORγt and lead to the development of new therapies for asthma.

支气管哮喘认为是由多种气道内炎症细胞共同参与的气道非特异性慢性炎症性疾病，目前其病因还不十分清楚，深化免疫应答和调节方面的研究对促进哮喘发病机制的理解和改善治疗策略具有重要的意义。研究证实IL-23/Th17轴多种基因在哮喘的发病中扮演了关键角色。IL-17受体缺失能明显减少气道组织中炎症细胞侵润，缓解哮喘炎症反应。我们前期的结果表明IncRNA-BG能通过RORγt调节IL-17的转录，从而抑制了哮喘炎症进展。但是IncRNA-BG对Th17细胞的发育的分子基础仍需要进一步阐明。本研究的目的是在了解IncRNA-BG调节Th17细胞发育的基础上，开发抑制RORγt活性的的药物作为新的治疗哮喘的方法。

支气管哮喘被认为是由多种气道内炎症细胞共同参与的气道非特异性慢性炎症性疾病，目前其病因还不十分清楚，深化免疫应答和调节方面的研究对促进哮喘发病机制的理解和改善治疗策略具有重要的意义。研究证实IL-23-Th17轴多种基因在哮喘的发病中扮演了关键角色。我们前期的结果表明长链非编码RNA-BG（数据库中已经命名为lncRNA-STAT4-AS1）能通过RORγt调节IL-23-Th17轴，从而抑制了哮喘炎症进展。但是其对Th17细胞发育的分子基础仍需要进一步阐明。通过哮喘，COPD患者和体外实验，我们证明lncRNA-STAT4-AS1与Th17分化呈显著负相关。lncRNA-STAT4-AS1敲除促进了Th17的分化，而lncRNA-STAT4-AS1的高表达抑制了Th17的分化。通过RNA pulldown, RIP和双荧光素酶报告分析发现，lncRNA-STAT4-AS1与RORγt蛋白结合后，可抑制RORγt蛋白与IL-17a启动子的结合。而且lncRNA-STAT4-AS1在细胞质中与RORγt结合,阻止RORγt进入细胞核。总体来说，lncRNA-STAT4-AS1直接作用于RORγt蛋白，抑制RORγt和IL-17基因启动子的相互结合，最终抑制Th17细胞的分化。lncRNA-STAT4-AS1可作为临床诊断和治疗气道高反应性疾病的靶标。