TRAF4-Beclin1介导的自噬减弱在强直性脊柱炎MSCs免疫抑制能力降低中的机制研究

Ankylosing spondylitis(AS) is a kind of autoimmune disease, which is characterized by chronic inflammation. Our previous work have determined that immune suppression ability of mesenchymal stem cells(MSCs) from patients with AS was significantly lower than those from healthy donors, which was relative to chronic inflammation in AS. We further demonstrated that autophagy in MSCs from AS patients was significantly lower than that in MSCs from healthy donors, which was an important reason for their lower immune suppression ability. Which mechanism do result in the weaken autophagy and the subsequent lower immune suppression abitlity of MSCs in AS? Further research suggested the expression of TRAF4, a key negative regulatory factor of Toll like receptors signal pathway, was up-regulated in MSCs from AS patients, which subsequently resulted in weakening autophagy through down-regulating the expression of Beclin1. According to these results above, we suggest that autophagy weakening mediated by TRAF4-Beclin1 is the key mechanism of down-regulated immunosuppression ability of MSCs in AS. We aim to continue this study by experiments in vivo and vitro to investigate in deep the precise mechanism of Beclin1 expression regulated by TRAF4 and weakening autophagy mediated by TRAF4-Beclin1 and their roles in the down-regulated immunosuppression ability of MSCs in AS. We intend to elucidate the etiopathogenesis of AS, which finally provide brand new theoretical basis and experiment foundation for clinical diagnosis and therapy.

强直性脊柱炎（AS）是一种以慢性炎症为特征的自身免疫性疾病，发病机制尚不清楚。我们前期已证实AS患者间充质干细胞（MSCs）免疫抑制能力较正常人显著降低，与AS患者体内慢性炎症密切相关；进而发现AS患者MSCs自噬水平明显减弱，是其免疫抑制能力降低的主要原因。但是何机制介导自噬减弱、进而导致免疫抑制能力降低？进一步预实验结果提示AS患者MSCs中Toll样受体（TLRs）信号通路负性调控分子TRAF4的表达明显增加，可能通过下调自噬启动分子Beclin1的表达以介导自噬减弱。据此，我们推测TRAF4-Beclin1介导的自噬减弱是AS患者MSCs免疫抑制能力降低的关键机制。本研究拟以此为切入点，通过体内外实验探讨TRAF4影响Beclin1表达、介导自噬减弱的具体机制及其在AS患者MSCs免疫抑制能力降低中的作用，为阐明AS的发病机制提供理论依据和实验基础，为临床诊断和治疗AS提供新思路。

强直性脊柱炎（AS）是一种以慢性炎症为特征的自身免疫性疾病，发病机制尚不清楚。我们前期已证实AS患者间充质干细胞（MSCs）免疫抑制能力较正常人显著降低，与AS患者体内慢性炎症密切相关；进而发现AS患者MSCs自噬水平明显减弱，是其免疫抑制能力降低的主要原因。但是何机制介导自噬减弱、进而导致免疫抑制能力降低？本课题组通过深入研究发现，AS患者MSCs （ASMSCs）中TRAF4表达的上调，通过影响Beclin1的表达及其磷酸化水平，可抑制MSCs受LPS诱导的自噬反应，从而参与强直性脊柱炎的发生发展，证实了TRAF4-Beclin1介导的自噬减弱是AS患者MSCs免疫抑制能力降低的关键机制。同时本课题组从AS患者MSCs对TLR3和TLR4的反应性，对破骨细胞分化的调控，外泌体的分泌等多方面多角度阐明了AS患者MSCs参与强直性脊柱炎发病的内在机制及病理过程，为探讨强直性脊柱炎的发生发展机制提供了线索，为临床早期诊断及治疗开拓新方向