IL-33介导IL-17A诱导的REG3A促进皮肤伤口愈合以及抵御金黄色葡萄球菌感染的功能机制

发布时间：2018-03-17 02:26

  本文选题：白介素17A　切入点：白介素33　出处：《华东师范大学》2014年硕士论文　论文类型：学位论文

【摘要】：皮肤是人体抵御外界环境刺激的第一道防线,具有保护机体的作用。当皮肤受到创伤时,伤口部位容易被微生物感染并引发炎症,影响伤口修复,严重的甚至会导致伤口溃烂或周边组织坏死。因此对伤口愈合及微生物感染调控机制的研究迫在眉睫。我们的前期研究发现白介素17A(IL-17A),能够诱导角质形成细胞中REG3A的表达,进而抑制分化基因来增强角质形成细胞的增殖能力,促进伤口愈合。但是对于IL-17A调节REG3A表达的具体分子机制仍未研究清楚。本研究利用IL-17A刺激角质形成细胞,通过基因沉默和抑制剂筛选的方式发现除了需要IL-17RA参与外,其接头分子Actl和下游信号分子p38 MAPK和P-catenin的激活也是诱导REG3A必需的。此外,在角质形成细胞中,IL-17A诱导REG3A的表达是依赖白介素33(IL-33)的。当把IL33基因沉默之后,IL-17A不能够诱导REG3A表达。IL-17A诱导表达的IL-33分泌到细胞外,通过与受体ST2结合激活JNK-AKT-STAT3信号通路来诱导REG3A的表达。小鼠在体实验也证明了IL-17A/IL-33/RegⅢ/γ能够促进皮肤伤口愈合。除了促进受损组织修复,REG3A还能够作为一种抗菌蛋白,抑制胃肠道中病原微生物的生长。人体的皮肤表面栖息大量的共生菌,与机体形成良好的互利关系。当平衡被打破时,正常菌群则会转变成条件致病菌,引发各种皮肤的感染性疾病。REG3A在皮肤感染方面的研究至今未有原创性报道。我们发现,REG3A、RegⅢγ和经IL-33刺激的角质形成细胞裂解液均能够抑制金黄色葡萄球菌的生长。小鼠在体实验进一步证明了IL-33诱导RegIIIy的表达进而抑制金黄色葡萄球菌对小鼠皮肤的感染,并且IL-17A参与调节金黄色葡萄球菌感染时IL-33和RegⅢγ的表达。综上所述,我们的研究首次发现了IL-17A调节角质形成细胞中IL-33和REG3A的信号机制,并且证明了IL-17A/IL-33/REG3A在促进伤口愈合和抵御金黄色葡萄球菌感染过程中发挥重要作用。本研究的开展为揭示皮肤创伤后角质形成细胞的生理作用提供了新的依据,也为临床治疗皮肤伤口及微生物感染提供新的理论基础。
[Abstract]:The skin is the body's first line of defense against external environmental stimuli. When the skin is traumatized, the wound is easily infected by microbes and causes inflammation, which affects wound repair. It is urgent to study the regulation mechanism of wound healing and microbial infection. Our previous studies have found that IL-17An can induce the expression of REG3A in keratinocytes. In order to enhance the proliferation ability of keratinocytes and promote wound healing, however, the specific molecular mechanism of IL-17A regulating REG3A expression has not been studied. In this study, IL-17A was used to stimulate keratinocytes. Through gene silencing and inhibitor screening, it was found that the activation of Actl and downstream signaling molecules p38 MAPK and P-catenin were also necessary to induce REG3A in addition to the involvement of IL-17RA. The expression of REG3A in keratinocytes induced by IL-17A is dependent on IL-33). When the IL33 gene is silenced, IL-17A can not induce the expression of REG3A. IL-17A induces the secretion of IL-33 induced by IL-17A into the cells. The expression of REG3A was induced by activating the JNK-AKT-STAT3 signaling pathway by binding to the receptor ST2. The in vivo experiments in mice also demonstrated that IL-17A/IL-33/Reg 鈪，

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