Sertoli细胞中TAM受体对TLR3信号通路的负调控：机理和意义
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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。
TAM receptors belong to a subfamily of receptor tyrosine kinases, which contain 3 members—Tyro3, Axl and Mer (TAM). They are essential regulators of mammalian spermatogenesis. Mice lacking all three receptors produce no mature sperm, owing to the progressive death of differentiatinggerm cells. Toll-like receptors (TLRs) are "pattern-recognition receptors" that recognize conserved, pathogen-code molecular structures and play crucial roles in mediating innate and adaptive immunity. Several TLRs are expressed in Sertoli cells and can trigger testicular innate responses after activation by ligands. TLR signaling pathway must be tightly controlled because unrestrained TLR activationgenerates a chronic inflammatory milieu that often leads to pathogenesis of the host. However, the regulation of TLR signaling in Sertoli cells remains to be clarified. Here, we demonstrate that TAM receptors negatively regulate TLR3 signaling in Sertoli cells.
All three TAM receptors are constitutively expressed in Sertoli cells. The activation of TLR3 triggers a TIR domain-containing adaptor inducing interferonβ(TRIF)-dependent pathway that activates the nuclear factorκB (NF-κB) and interferon regulatory factor 3 (IRF3), thereby resulting in the induction of inflammatory cytokines and type I interferons. We demonstrate that Sertoli cells from TAM triple mutant (TAM-/-) mice exhibit an excessive activation of TLR3 in response to its ligand Poly (I:C), resulting in the upregulation of inflammatory cytokines including IL-1β, IL-6, TNFa and type I interferons (IFNa and IFNβ). Gas6, a common ligand of TAM receptors, inhibits the TLR3-driven expression of cytokines in Sertoli cells. This TAM-mediated inhibition of TLR3 signaling in Sertoli cells is transduced through the upregulation of TLR signaling suppressors—suppressor of cytokine signaling 1 (SOCS1) and SOCS3 by Gas6. TAM signaling activates signal transducer and activator of transcription 1 (STAT1), thus upregulates SOCS1/3. Moreover, we provide evidence that TAM inhibition of inflammatory cytokine production by Sertoli cells have physiological significance in vivo.
Our results illuminate a negative regulatory mechanism of TLR3 signaling in Sertoli cells. This regulatory system should be important in controlling the testicular innate immune responses to pathogens.
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。
TAM receptors belong to a subfamily of receptor tyrosine kinases, which contain 3 members—Tyro3, Axl and Mer (TAM). They are essential regulators of mammalian spermatogenesis. Mice lacking all three receptors produce no mature sperm, owing to the progressive death of differentiatinggerm cells. Toll-like receptors (TLRs) are "pattern-recognition receptors" that recognize conserved, pathogen-code molecular structures and play crucial roles in mediating innate and adaptive immunity. Several TLRs are expressed in Sertoli cells and can trigger testicular innate responses after activation by ligands. TLR signaling pathway must be tightly controlled because unrestrained TLR activationgenerates a chronic inflammatory milieu that often leads to pathogenesis of the host. However, the regulation of TLR signaling in Sertoli cells remains to be clarified. Here, we demonstrate that TAM receptors negatively regulate TLR3 signaling in Sertoli cells.
All three TAM receptors are constitutively expressed in Sertoli cells. The activation of TLR3 triggers a TIR domain-containing adaptor inducing interferonβ(TRIF)-dependent pathway that activates the nuclear factorκB (NF-κB) and interferon regulatory factor 3 (IRF3), thereby resulting in the induction of inflammatory cytokines and type I interferons. We demonstrate that Sertoli cells from TAM triple mutant (TAM-/-) mice exhibit an excessive activation of TLR3 in response to its ligand Poly (I:C), resulting in the upregulation of inflammatory cytokines including IL-1β, IL-6, TNFa and type I interferons (IFNa and IFNβ). Gas6, a common ligand of TAM receptors, inhibits the TLR3-driven expression of cytokines in Sertoli cells. This TAM-mediated inhibition of TLR3 signaling in Sertoli cells is transduced through the upregulation of TLR signaling suppressors—suppressor of cytokine signaling 1 (SOCS1) and SOCS3 by Gas6. TAM signaling activates signal transducer and activator of transcription 1 (STAT1), thus upregulates SOCS1/3. Moreover, we provide evidence that TAM inhibition of inflammatory cytokine production by Sertoli cells have physiological significance in vivo.
Our results illuminate a negative regulatory mechanism of TLR3 signaling in Sertoli cells. This regulatory system should be important in controlling the testicular innate immune responses to pathogens.
引文
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