Fas信号对TLR信号介导的巨噬细胞炎症反应的调节作用及其机制研究

Toll-like receptors(TLRs) play key roles in the innate immune respons to defense invading microbial pathogens.The tightly regulation of TLR signaling gets lots of attention and some molecules are identified to be associated with regulation of TLR response. Fas is a classic death receptor, which can induc apoptosis triggered by FasL to maintain systematic homeostasis. However, under certain condition, Fas signal can exert non-apoptotic function. It is unclear that the roles of Fas signal in the innate immune response triggered by TLRs in macrophage. In our previous study, we found that macrophage resist to apoptosis induced by Fas signal, macrophage from Fas-deficient mice produced higher IL-6 triggered by TLR ligands and the lever of IL-6 produced by macrophage after ligation with anti-Fas activated antibody and stimulation with TLR ligands was lower. In addition, Fas signal impairs activation of TLR signaling in macrophage. These results suggested Fas signal can suppress inflammation response in macrophage triggered by TLRs. In this project, we will decipher the role of Fas signal in the regulation of TLR signaling and the underlying molecular mechanisms. Our study is promising to reveal a novel mechanism for negative regulation of TLR signaling mediated by Fas signal.

TLR信号在机体防御感染性疾病的天然免疫应答中发挥了重要作用。TLR信号的精细调控受到广泛关注。FasL/Fas信号通路是诱导细胞凋亡的主要机制之一。除诱导凋亡，Fas信号的活化还可介导其它重要的效应功能，如诱导肿瘤细胞的增殖、侵袭等。目前，Fas信号是否参与对巨噬细胞TLR信号的调节尚不清楚。本课题拟通过细菌感染模型、Fas缺陷小鼠等研究Fas信号对TLR信号介导的巨噬细胞炎症反应的调节作用及相关机制。我们前期实验结果表明在TLR配体刺激的Fas缺陷小鼠的腹腔巨噬细胞中，可检测到更高水平的IL-6；而正常小鼠的腹腔巨噬细胞在Fas活化抗体及TLR配体共同刺激下，IL-6分泌水平明显下降；Fas信号能抑制LPS引起的ERK、p38及IRF3通路活化。因此，我们推测Fas信号对TLR信号具有负向调控作用。本项目的研究可揭示Fas信号对TLR信号的调节作用，丰富天然免疫应答调控的机制。

TLR信号在机体防御感染性疾病的天然免疫应答中发挥了重要作用。TLR信号的精细调控受到广泛关注。FasL/Fas信号通路是诱导细胞凋亡的主要机制之一。除诱导凋亡，Fas信号的活化还可介导其它重要的效应功能，如诱导肿瘤细胞的增殖、侵袭等。目前，Fas信号是否参与对巨噬细胞TLR信号的调节及详细机制尚不清楚。本课题通过细菌感染模型、Fas缺陷小鼠（lpr）等研究了Fas信号对TLR信号介导的巨噬细胞炎症反应的调节作用及相关机制。我们研究发现，TLR配体刺激促进巨噬细胞Fas表达，野生及lpr小鼠巨噬细胞研究发现，Fas信号可以通过Fps-shp2/MAPK、IRF3、NF-κB信号抑制IL-6、TNF-a和IFN-β.体内实验也证实，小鼠巨噬细胞Fas信号参与了LPS刺激机体的炎症反应。本项目的研究初次证实Fas信号可以磷酸化Fas受体，通过SH2结构域招募并活化Fps从而进一步发挥对TLR信号的调节作用，揭示了Fas信号对TLR信号的调节作用，完善了Fas信号在组织稳态中的调节作用，丰富天然免疫应答调控的机制，有望为过度炎症反应提供治疗思路。