白细胞介素22与载脂蛋白AI融合蛋白靶向治疗自身免疫性肝炎的作用及机制研究

Autoimmune Hepatitis (AIH) is a chronic progressive inflammatory liver disease triggered by body’s autoimmune response. The etiology and pathogenesis of AIH is complex, and the therapeutic strategy is still limited, thus it’s urgent to develop effective therapeutics for the treatment of AIH. Previous studies have found that interleukin 22 could promote liver cell regeneration and participate in liver tissue repairing. Our research also confirmed that interleukin 22 has therapeutic effect on AIH, but as interleukin 22 receptors are widely existed in most cells of different organs, interleukin 22 could induce systemic biological effects after intravenous administration, and is not suitable for the treatment of AIH. Apolipoprotein A-I could specifically bind to Scavenger receptor class B type I (SR-BI) on liver cells, so our proposed study will develop liver-targeted delivery of interleukin 22 through recombinant interleukin 22 and apolipoprotein A-I fusion protein for AIH therapy. Furthermore, the role and mechanisms of autophagy, inflammasomes, and oxidative stress in liver-targeted therapy of AIH by interleukin 22 fusion protein will also be elucidated in this investigation. This study will shed light on the novel therapy of AIH with liver-targeted interleukin 22 and apolipoprotein A-I fusion protein alone or in combination with autophagy inhibitors, anti-inflammatory agents, or antioxidants for the treatment of AIH in clinic.

自身免疫性肝炎是由机体自身免疫反应引起的慢性肝脏炎症疾病，病因复杂，发病机制尚不明确，缺乏有效的治疗手段。已有研究发现白细胞介素22能促进肝细胞再生，参与肝组织修复并保护肝细胞；我们前期研究证实白介素22能改善自身免疫性肝炎，但由于白细胞介素22受体的广泛存在，静脉给药后白细胞介素22能引起全身性的生物学效应，不利于自身免疫性肝炎的治疗。我们推测通过表达白细胞介素22与载脂蛋白AI融合蛋白，利用载脂蛋白AI与肝细胞上B族I型清道夫受体特异性结合可实现白介素22肝靶向递药，使其在肝脏部位发挥抗炎和免疫调节作用治疗自身免疫性肝炎，避免全身给药的不良反应；同时通过探讨细胞自噬、炎性小体及氧化压力在白介素22融合蛋白治疗自身免疫性肝炎中的作用机理，可为临床上应用白细胞介素22融合蛋白靶向治疗自身免疫性肝炎或者联合自噬干预药物、抗氧化药物及抗炎药物增强自身免疫性肝炎的治疗效果提供新的思路和实验依据。

白细胞介素22（Interleukin-22, IL-22）作为一种能有效抑制肝损伤和促进肝脏组织修复的细胞因子，具有巨大的临床应用前景。但是由于IL-22受体分布广泛，静脉注射常导致多种并发症的产生，并且其相对较小的分子量也导致其体内较短的半衰期。本研究首次将IL-22和载脂蛋白AI（Apolipoprotein AI, ApoA-I）融合，来增强IL-22的肝靶向性及延长半衰期，同时系统地研究了IL-22融合ApoA-I后的生物分布、体内安全性、对自身免疫性肝炎、药物性肝损伤和非酒精性脂肪性肝炎的治疗效果等情况。研究结果显示，IL-22融合ApoA-I后不仅可以提高IL-22的半衰期和肝靶向性，还可以在对自身免疫性肝炎、药物性肝损伤和非酒精性脂肪性肝炎小鼠体内产生显著的治疗效果。进一步实验结果表明，IL-22融合ApoA-I可以显著激活肝细胞的STAT3信号通路、抑制活性氧产生和线粒体功能紊乱。不仅如此，我们还在小鼠体内实验证明了炎性小体信号通路的激活在自身免疫性肝炎发生发展过程中发挥重要的促进作用。因此本课题的研究为临床应用IL-22-ApoA-I融合蛋白靶向治疗多种肝脏炎症，以及联合抗氧化剂或抗炎性小体药物增强自身免疫性肝炎的治疗效果提供了新的思路和实验依据。