IL-21调控嗜酸性粒细胞性慢性鼻窦炎鼻黏膜中Treg细胞分化及焦亡的机制研究

嗜酸性粒细胞性慢性鼻窦炎(ECRS)发病机制不明且在治疗后易复发。我们前期发表文章证明Treg细胞可抑制鼻黏膜嗜酸性粒细胞浸润，但Treg细胞比例在ECRS鼻黏膜中降低的机制尚不明确。我们近期预实验显示IL-21在ECRS鼻黏膜高表达并与Treg细胞比例显著负相关。进一步结合高通量分析及细胞功能实验，我们发现：①IL-21可抑制Treg细胞体外分化并诱导其焦亡；②IL-21可激活Treg细胞Akt与MAPK信号通路；③抑制Akt通路可逆转IL-21对Foxp3负调控；④抑制MAPK通路可抵抗IL-21诱导的Treg细胞焦亡。据此，我们提出科学假设：IL-21激活Akt/MAPK信号通路而抑制Treg细胞分化并促其焦亡，导致鼻黏膜嗜酸性粒细胞浸润而诱发ECRS。本项目将采用体内、体外模型并结合临床样本深入揭示IL-21升高及其调控Treg细胞分化及焦亡的分子机制，为ECRS治疗提供科学依据。

As the pathogenesis of eosinophilic chronic sinusitis (ECRS) is largely unknown, the patients with ECRS exhibit high relapse rate. Our previous study had reported that Treg cells could inhibit the infiltration of eosinophils into the nasal mucosa. However, the mechanism in which Treg cells decreased in the nasal mucosa of ECRS remains unclearly. Our recent preliminary results showed that IL-21 was highly expressed in the nasal mucosa of ECRS, which was negatively correlated with the percentage of Treg cells. Combined with high-throughput analysis data and cellular function results, we further found that: ① IL-21 could inhibit the development of Treg cells in vitro and also could induce Treg cells pyroptosis; ② IL-21 activated the Akt and MAPK signaling pathways in Treg cells; ③ Inhibition of Akt pathway could reverse the negative regulation of IL-21 on Foxp3; ④ Inhibition of MAPK pathway could resist the pyroptosis of Treg cells induced by IL-21. Accordingly, we proposed that increased IL-21 inhibit Treg cells development and pyroptosis via activation of Akt / MAPK signaling pathways, which resulted in infiltration of eosinophils into nasal mucosa and induce ECRS. Therefore, we will further reveal the molecular mechanisms of IL-21 elevation and its regulation in the development and pyroptosis of Treg cells via in vivo and in vitro models, as well as the clinical samples analysis, which providing scientific evidence for ECRS treatment.