IFN-β/OAS1通过受体和非受体依赖途径参与SS-ILD的机制研究

I型干扰素(IFN-I)活化在干燥综合征相关肺间质病变(SS-ILD)作用已有报道，但抗IFN-I抗体治疗SS效果不佳，且IFN-I参与SS-ILD具体机制不明确。前期研究发现SS-ILD小鼠肺部IFN-I成员IFN-β及其诱导基因2’5’-寡腺苷酸合成酶1(OAS1)增多且与肺部炎性细胞浸润及活动程度相关。因此，我们提出科学假说:IFN-β与肺部上皮细胞表面受体结合后诱导OAS1，后者通过受体结合和受体非依赖途径促进巨噬细胞分泌促炎性分子和趋化因子，导致肺部炎性细胞浸润并发展成SS-ILD。为验证这一假说，我们拟应用基因敲除小鼠，确认IFN-β/OAS1参与SS-ILD；通过阻断IFN-β诱导OAS1通路或者特异性清除肺部巨噬细胞等，阐明OAS1受体依赖和非依赖途径参与SS-ILD分子机制。研究成果不仅揭示IFN-β/OAS1参与SS-ILD新机制，而且为临床治疗SS-ILD提供新靶点。

Previous studies have suggested activation of type I interferon (IFN-I) as a key player in the pathogenesis of Sjögren’s syndrome-associated interstitial lung disease (SS-ILD). However, no significant beneficial effects of anti-IFN-I antibody on the SS were observed. The mechanism responsible for the IFN-I in the SS-ILD remains unclear. Our preliminary studies have showed that elevated IFN-β and one of the IFN-induced genes (2’-5’ oligoadenylate synthetase, OAS1) were found in the lung and positively correlated with disease activity of SS-ILD. Based on these evidences, we hypothesized that IFN-β induced OAS1 expression by binding its receptors on the epithelial cells of lung. OAS1 promotes the production of proinflammatory cytokines and chemokines by macrophages through receptor-dependent and independent mechanisms. Finally the inflammatory cells infiltrate into lung and SS-ILD was developed. Therefore, the aim of the present study is to determine the role of IFN-β/OAS1 in the pathogenesis of SS-ILD through applying specific gene deficiency mice. Mechanically, whether OAS1 promotes the production of proinflammatory cytokines and chemokines by macrophages through receptor-dependent or independent mechanisms in SS-ILD is also to be explored by blocking IFN-β/OAS1 pathway or deletion of macrophages in lung. The findings of the present study will reveal the novel mechanism of the effects of IFN-β/OAS1 in SS-ILD. The results will also provide new therapeutic targets for treatment of SS-ILD.