IL-4和IL-13的siRNA 對異位性皮膚炎動物模型的影響

Abstract

異位性皮膚炎(atopic dermatitis，AD)是一種會反覆發作過敏引起的慢性疾病，主要是會造成皮膚的病變，如：發炎、搔癢、紅腫、脹痛等症狀。全球約有10～20%的孩童受此疾病所苦。在AD的發病機制中，第二型輔助Ｔ細胞（Th2 cells）扮演重要角色，分泌介白素4（interleukin 4）與介白素13（interleukin 13）會抑制表皮分化和抑制表皮脂質生成，再次破壞皮膚屏障，並刺激B細胞分泌免疫球蛋白E (IgE)使肥大細胞致敏化，最後釋出組織胺介質而導致AD。目前已有抗IgE單株抗體藥物omalizuma和抗IL-4, IL-13 dupilumab，不過生物製劑的費用較為昂貴，因此我們想研究利用RNA干擾(RNAi)技術來研究治療。本研究將針對發病機制中關鍵的細胞激素IL-4和IL-13作為治療軸心，利用RNAi的技術幫助降解IL-4/IL-13的mRNA。實驗結果顯示，使用慢病毒載體遞送siRNA能有效地降低炎症細胞浸潤和減少發炎細胞激素IL-4，IL-13的表現，並進一步通過水凝膠混合帶有IL-4和IL-13的siRNA慢病毒載體敷至AD小鼠皮膚抑制基因的表現，實驗結果表明表現有顯著差異。未來，我們將選用微針技術更有效率地將siRNA遞送至小鼠做進一步的探討。本研究為AD的治療提供了新的思路和方法，有望成為治療AD的有效手段。

The goal of this research is to explore therapeutic strategies for atopic dermatitis (AD), a chronic disease caused by repeated allergic reactions, affecting approximately 10-20% of children worldwide. AD involves Th2 cells that release IL-4 and IL-13, which inhibit epidermal differentiation and suppress epidermal lipid synthesis, resulting in the impairment of the skin’s protective barrier. Mast cells become more sensitive or reactive due to the release of IgE antibodies. Ultimately, the release of histamine mediators cause AD. Currently, monoclonal antibodies against IgE, such as omalizumab and anti-IL-4R dupilumab are available, but they are quite expensive. Therefore, we aimed to explore the feasibility of RNA interference (RNAi) technology as a potential alternative. The study focused on targeting IL-4 and IL-13 of AD via RNAi to degrade their mRNA. The experimental results demonstrated that the use of a lentiviral vector to deliver siRNA can effectively reduce inflammatory cell infiltration and decrease IL-4 and IL-13 inflammatory cytokines. Moreover, the application of hydrogel mixed with lentiviral vectors carrying siRNA targeting IL-4 and IL-13 was employed to treat AD in mice, resulting in significant differences in the experimental outcomes. In the future, the study aims to investigate further the efficient delivery of siRNA to mice using microneedle technology. This study provides novel ideas and methods to address AD and might become a promising strategy to treating this disease.