Sertoli细胞中TAM受体对TLR3信号通路的负调控：机理和意义

发布时间：2018-06-25 04:54

本文选题：Sertoli细胞 + TLR信号通路　；参考：《中国协和医科大学》2010年博士论文

【摘要】： TAM为受体酪氨酸激酶的一个亚家族,由三个成员组成,即Tyro 3, Axl和Mer,简称为TAM受体。Toll-like受体(Toll like receptors, TLRs)是一种模式识别受体,识别病原微生物进化中的保守分子。TLRs在介导天然免疫和获得性免疫中发挥着重要的作用。在机体内,外来的病原体能够激活TLRs诱导产生大量的炎症因子,这些炎症因子可以杀伤入侵的病原体。然而TLRs持续活化会形成慢性炎症环境,对机体产生破坏作用,因此TLR信号通路的激活必须受到严格的调控。在睾丸组织中,作为唯一与生精细胞相接触的细胞,Sertoli细胞表达较高水平的TLR3受体,它的活化可以诱导炎症因子的表达,进而对外侵病原体产生免疫防御作用。为防止睾丸组织持续产生慢性炎症反应,Sertoli细胞中TLR3受体的活化必须受到严格的调控。本实验研究了TAM受体负调控Sertoli细胞TLR3信号的作用与机理。结果发现,Sertoli细胞中同时表达Tyro3, Axl和Mer受体。敲除TAM三个受体的Sertoli细胞在受到Poly(I:C) (TLR3的特异性配体)刺激时,TLR3处于超激活状态,炎症因子(IL-1β, IL-6和TNFα)和Ⅰ型干扰素(IFNa及IFNβ)表达明显增多。Sertoli细胞中的TLR3激活后,会引起核因子κB(NF-κB)和干扰素调节因子3(IRF3)的活化,进而诱导该细胞分泌炎症因子(IL-1β, IL-6和TNFa)和Ⅰ型干扰素(IFNa及IFNβ)。Gas6是TAM受体的特异性配体,在正常Sertoli细胞中加入Gas6能够显著抑制Poly(I:C)诱导的炎症因子表达,而敲除TAM受体的Sertoli细胞中Gas6不能发挥这种抑制作用。深入研究发现,TAM激活后促使信号转导和转录活化因子1(STAT1)表达,STAT1又促进TLRs负调控因子——细胞因子信号抑制物1(SOCS1)和3(SOCS3)表达,SOCS1/3抑制TLR3信号通路。这些结果表明,Sertoli细胞中TAM受体参与了负调控TLR3信号通路,其机制是通过上调TLRs负调控因子表达水平实现的。进一步我们发现这一调控系统在体内具有重要的生理意义。本研究阐明了TAM受体负调控Sertoli细胞中TLR3的作用机理。它可以防止生精上皮对外来及自身抗原的过度免疫反应,在维持睾丸的免疫稳态中发挥着重要作用。
[Abstract]:Tam is a subfamily of receptor tyrosine kinase, which consists of three members: Tyro 3, Axl and Mer.TLRs are pattern recognition receptors. TLRs, a conserved molecule in the evolution of pathogenic microorganisms, play an important role in mediating innate and acquired immunity. In the body, foreign pathogens can activate TLRs to induce the production of a large number of inflammatory factors, which can kill the invading pathogens. However, the continuous activation of TLRs can form chronic inflammatory environment and damage the body, so the activation of TLR signaling pathway must be strictly regulated. In testicular tissue, Sertoli cells, the only cells in contact with spermatogenic cells, express a higher level of TLR3 receptor, its activation can induce the expression of inflammatory factors, and then invade the pathogen to produce immune defense. The activation of TLR3 receptor in Sertoli cells must be strictly regulated in order to prevent the persistent chronic inflammatory reaction in testicular tissue. The effect and mechanism of TLR3 signal regulated by TAM receptor in Sertoli cells were studied. It was found that Tyro3, Axl and Mer receptors were expressed in Sertoli cells. Sertoli cells knockout the three receptors of TAM were stimulated by Poly (I: C) (specific ligand of TLR3). The expression of inflammatory factors (IL-1 尾, IL-6 and TNF 伪) and interferon type I (IFNa and IFN 尾) in Sertoli cells was significantly increased after the activation of TLR3 in Sertoli cells. It causes activation of nuclear factor- 魏 B (NF- 魏 B) and interferon regulatory factor 3 (IRF3), which in turn induces the secretion of inflammatory cytokines (IL-1 尾, IL-6 and TNFa) and interferon type I (IFNa and IFN 尾) .Gas6, which are specific ligands of TAM receptor. Adding Gas6 to normal Sertoli cells could significantly inhibit the expression of inflammatory factors induced by Poly (I: C), but Gas6 could not play such an inhibitory role in Sertoli cells knockout TAM receptor. It was found that after activation of TAM, signal transduction and transcription activator 1 (STAT1) expression and STAT1 and TLRs negative regulatory factor-cytokine signal suppressor 1 (SOCS1) and cytokine signal inhibitor 3 (SOCS3) expression were enhanced. SOCS1 / 3 inhibited TLR3 signaling pathway. These results suggest that TAM receptor participates in the negative regulation of TLR3 signaling pathway in Sertoli cells, and its mechanism is by upregulating the expression of TLRs negative regulatory factors. Further, we found that this regulatory system has important physiological significance in vivo. In this study, the mechanism of TLR3 in Sertoli cells was elucidated by the negative regulation of TAM receptor. It can prevent the excessive immune response of spermatogenic epithelium to foreign and autoantigen, and play an important role in maintaining the immune homeostasis of testis.
【学位授予单位】：中国协和医科大学
【学位级别】：博士
【学位授予年份】：2010
【分类号】：R392

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