活化的滑膜巨噬细胞与骨关节炎(OA)致病密切相关，但其激活机制不十分清楚。我们前期发现随着软骨基质丢失和软骨磨损，软骨细胞来源外泌体(ChC-Exo)可进入滑膜组织，促进致敏巨噬细胞IL-1β的释放，并抑制细胞自噬反应及升高mitoROS水平。ChC-Exo诱导的IL-1β释放可被mitoROS清除剂和NLRP3抑制剂所拮抗。自噬转录组芯片及外泌体RNA-seq等实验结果提示巨噬细胞自噬抑制可能与miR-449a-5p介导的自噬基因ATG4B表达下调有关。结合文献报道和前期实验结果，我们提出“ChC-Exo可作为滑膜巨噬细胞所识别的损伤相关分子模式，通过靶向ATG4B抑制巨噬细胞自噬反应，激活NLRP3炎症小体，促进IL-1β释放”这一假说。本项目拟通过体内和体外实验，阐明ChC-Exo调控巨噬细胞ATG4B表达及炎症小体激活的机制，揭示该通路在OA致病中的作用，为OA防治提供新的思路。

The activated synovial macrophages are closely involved in the progress of osteoarthritis, but the mechanisms about the activation of synovial macrophages are still not clear. Our previous study found that chondrocytes can produce exosomes, and these exosomes could mediate the crosstalk between chondrocytes and synovial macrophages when the cartilage is injured. The chondrocytes-derived exosomes(ChC-Exo) significantly inhibits autophagy, but increase the IL-1β release and cellular mitoROS level in LPS-primed macrophages. The data from the experiments including autophagy cDNA array and exosomes RNA-seq reveal that the miR-449a-5p in chondrocytes-derived exosomes may regulate the expression of autophagy-related gene ATG4B，which may be involved in ChC-Exo-mediated autophagy inhibition of macrophages. Combined with literature report and our previous results, we propose that ChC-Exo could be a model of damage related molecule pattern that identified by synovial macrophages. The ChC-Exo could inhibits autophagy via ATG4B, activate inflammasomes and promote the release of IL-1β. In this study, we will investigate mechanisms of ChC-Exo-regulated ATG4B expression and inflammasomes activation in macrophages and reveal the role and significance of this signal pathway in the pathogenesis of OA , which may provide some novel clues for OA control in clinic.