Exosomes derived from M1-macrophage promote enteric neuronal injury via MMP8-TGF-β pathway

作者：Yuqiong Chen, Kai Song, Yi Zheng, Chaoting Lan, Yue Mu, Zuyi Ma, Gen Chen, Yun Zhu, Yongwei Huang, Jiazhang Chen, Shenwei Huang, Qiuming He, Lihua Huang, Xiaoyu Zuo, Fenjie Li, Jixiao Zeng, Huimin Xia, Yan Zhang · 发表于：Journal of Advanced Research · 年份：2025 · DOI：10.1016/j.jare.2025.10.020 · 被引用次数：4 · 研究领域：Congenital gastrointestinal and neural anomalies、Gastrointestinal motility and disorders、Diverticular Disease and Complications

Schematic representation of proposed mechanisms. In BAC mouse, M1 macrophages significantly increase, and depletion of macrophages can partially rescue gastrointestinal motility disorders to a certain extent. In vitro co-culture of intestinal neurons and macrophages reveals that M1 macrophages can cause neuronal apoptosis through exosomes, in which matrix metalloproteinase 8 (MMP8) plays a crucial role. Exosomal MMP8 promotes the activation of the TGF-β signaling pathway, resulting in neuronal apoptosis. The inhibition of MMP–8 partially alleviates neuronal injury in BAC mice, and restore intestinal function. • • Neuroimmune mechanism, particularly the interaction between enteric neurons and macrophages, is a key factor responsible for gastrointestinal motility disorders • • Abnormal M1-macrophage activation triggers neuronal injury in BAC mice. • • M1-macrophages contribute to enteric neuronal injury via MMP8-carrying exosomes. • • Exosomal MMP8 activates TGF-β signaling pathway, resulting in neuronal apoptosis. • • MMP8 inhibition may serve as a potential target for gastrointestinal motility disorders. Enteric neuronal injury significantly contributes to gastrointestinal motility disorders. While macrophages are known to interact closely with enteric neurons and modulate intestinal homeostasis, their specific impact on enteric neuronal survival and injury remains poorly understood. This study aimed to explore the potential contribution of macrophage-derived exosomes to ente...