血红素加氧酶-1调控STAT3/SOCS3信号分子拮抗中性粒细胞性气道炎症

Non-eosinophilic asthma (NEA) is an important type of severe and steroid-resistant asthma mediated by Th17 cells, which produce IL-17A to recruit polymorphonuclear neutrophil (PMN) infiltrating airway. IL-6, which triggers STAT3 phosphorylation, is the key factor controlling the differentiation of Th17 cells, SOCS3 is its negative feedback regulator. Our previous studies showed that heme oxygenase-1 (HO-1) could suppress Th17 response to attenuate airway inflammation in NEA via enhancing IL-10, reducing IL-6 levels, and restoring the immune balance between Th17 and Treg cells. However, the molecular mechanism of HO-1 modulation is obscure. Recently, we found that the level of phosphorylated STAT3 (p-STAT3) in cells decreased at first but increased later in vitro differentiation of Th17 cells. However, the level of IL-10 increased, suggesting the effect of IL-10 in this study. Since IL-10 and IL-6 both regulate the same signaling mediators, STAT3/SOCS3. Therefore, we aim to further explore the mechanism of HO-1 by regulating STAT3/SOCS3 signal moleculars to control Th17 cells differentiation and to alleviate NEA.

非嗜酸性粒细胞性哮喘（NEA），系由Th17及其分泌的IL-17A趋化并维持中性粒细胞（PMN）浸润气道所致，临床表现为重症、难治性哮喘。IL-6是诱导STAT3磷酸化调控na?ve T细胞分化为Th17的关键因子，SOCS3是其负反馈分子。前期我们发现血红素加氧酶-1（HO-1）经上调IL-10并降低IL-6水平，调控Th17/Treg平衡，抑制Th17炎症反应，减轻NEA，但HO-1调抑Th17分化的分子机制尚不清楚。近期我们发现在IL-6诱导na?ve T细胞分化为Th17中，HO-1干预抑制Th17分化同时，细胞内p-STAT3水平呈先降后升现象，伴之IL-10表达及分泌增加，提示IL-10在其中的作用。鉴于STAT3/SOCS3共为IL-10和IL-6作用的下游分子，本项目拟在此工作基础上，进一步探讨HO-1调控STAT3/SOCS3分子抑制Th17分化分子机制及干预NEA靶点。

非嗜酸性粒细胞性哮喘（NEA）是由Th17细胞及其分泌的IL-17A趋化并维持的中性粒细胞（PMN）浸润气道所致，临床表现为重症、难治性哮喘。我们前期研究发现血红素加氧酶-1（HO-1）上调IL-10并降低IL-6水平，调控Th17/Treg平衡，抑制Th17炎症反应，减轻NEA。本研究我们以STAT3-RORγt/SOCS3信号通路为切入点，通过体内外多种干预方式，深入探讨HO-1调控Th17细胞分化的具体机制。研究发现，HO-1通过阻断IL-6-STAT3-RORγt/SOCS3信号通路，抑制STAT3和下游核转录因子RORγt以及负反馈调节蛋白SOCS3表达，降低Th17细胞分化，进而抑制Th17细胞介导的中性粒细胞性气道炎症。其中，HO-1通过与STAT3结合抑制其磷酸化，进而调控Th17细胞分化，提示STAT3是HO-1调控Th17细胞分化的靶蛋白。本研究阐明了HO-1抑制Th17细胞分化及其介导的中性粒细胞性气道炎症的分子机制，为重症、难治性哮喘的临床治疗提供了理论基础及潜在干预靶点。