模式识别受体CD36对NKT细胞的调控及其在刀豆蛋白A诱导的免疫性肝损伤中的作用研究

The transmembrane glycoprotein CD36 is a pattern-recognition receptor with multiple ligands and diverse cellular functions, contributing to physiological function as well as inflammatory responses. However, its expression/role in immune system and whether it is involved in immune-mediated liver injury is unknown. Our previous studies have found that CD36 expression by hepatic NKT cells was markedly increased following Concanavalin A (ConA) challenge; CD36 deficiency protected mice from ConA-induced fulminant liver injury; Moreover, decreased IFN-γ production by hepatic NKT cells in CD36-deficient mice was detected. So, we suspect that CD36 may aggravates acute liver injury in autoimmune hepatitis by promoting the function of NKT cells. Based on previous findings, our project aims to investigate the role of CD36 in NKT-cell function. We will study whether the reduction of NKT-cell function is associated with decreased ConA-induced liver injury in CD36-deficient mice. We will also examine the molecular mechanisms involved in the regulation of NKT-cell function by CD36. Our research may contribute to a better understanding of the regulation of NKT-cell function by CD36 and provide new insights into therapeutic approaches for immune-mediated liver injury.

模式识别受体CD36是一个多配体、多功能的跨膜糖蛋白，参与机体多种生理活动和炎症应答；关于其在免疫细胞上的表达、功能及是否参与免疫性肝损伤，目前报道较少。我们前期研究发现：（1）刀豆蛋白A（Concanavalin A，ConA）刺激显著上调小鼠肝脏NKT细胞CD36分子表达。（2）CD36敲除可保护ConA诱导的急性肝损伤。（3）CD36敲除鼠NKT细胞分泌IFN-γ减少。基于NKT细胞介导ConA诱导的肝损伤发生，我们提出：CD36通过促进NKT细胞功能参与ConA诱导的急性肝损伤。为证实该假说，本课题拟通过体内和体外实验验证CD36敲除鼠对ConA诱导的肝损伤不敏感与其NKT细胞功能低下有关；基于原代细胞和NKT细胞系，应用流式分析，RNA干扰，免疫印迹等技术揭示CD36敲除诱导NKT细胞功能低下的分子机制，为免疫性肝损伤的防治提供新靶点。

模式识别受体CD36是一个多配体、多功能的跨膜糖蛋白，参与机体多种生理活动和炎症应答；关于其在免疫细胞上的表达、功能及是否参与免疫性肝损伤，目前报道较少。在本研究项目中，我们详细分析了CD36敲除对脾脏和肝脏NK细胞、NKT细胞、T细胞和B细胞群体分布的影响以及刀豆蛋白A （Concanavalin A，ConA）刺激是否改变肝脏淋巴细胞CD36表达，研究发现CD36敲除可导致小鼠对ConA诱导的急性肝损伤不敏感。与对照鼠相比，CD36敲除鼠在ConA刺激后血清炎症因子水平较低，CD36敲除鼠来源的NKT细胞和CD4+T细胞IFN-γ和TNF-α表达较低。进一步机制研究发现CD36敲除鼠在ConA刺激后IL-12表达水平较低，而注射IL-12则能逆转CD36敲除鼠对ConA诱导的肝损伤不敏感，并能提高CD36敲除鼠NKT细胞和CD4+T细胞IFN-γ和TNF-α表达水平，这表明CD36敲除鼠对ConA诱导的肝损伤不敏感与其IL-12表达下降有关。由以上可知，模式识别受体CD36通过调节免疫细胞功能参与免疫性肝损伤，CD36的免疫调节机制可为免疫性肝损伤的预防和治疗提供新的干预靶点。