Journal of advanced research · 2025
Exosomes derived from M1-macrophage promote enteric neuronal injury via MMP8-TGF-β pathway.
СтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
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Chen Yuqiong, Song Kai, Zheng Yi, Lan Chaoting, Mu Yide, Ma Zuyi, Chen Gen, Zhu Yun, Huang Yongwei, Chen Jiazhang, Huang Shenwei, He Qiuming, Huang Lihua, Zuo Xiaoyu, Li Fenjie, Zeng Jixiao, Xia Huimin, Zhang Yan
Аннотация
INTRODUCTION: 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.
OBJECTIVE: This study aimed to explore the potential contribution of macrophage-derived exosomes to enteric neuronal injury and investigate the underlying mechanisms.
METHODS: We established a benzalkonium chloride (BAC)-induced enteric neuronal injury mouse model and assessed the effects of macrophage depletion on gastrointestinal motility and neuronal density. In vitro, enteric neurons were co-cultured with macrophages to examine the role of macrophage-derived exosomes in neuronal apoptosis. M1 macrophage-derived exosomes were isolated and characterized to elucidate potential mechanisms both in vitro and in vivo.
RESULTS: Macrophage depletion partially rescued gastrointestinal dysmotility and enteric neuronal injury in BAC-treated mice. In vitro studies confirmed that M1 macrophage-derived exosomes promoted neuronal apoptosis. We identified matrix metalloproteinase 8 (MMP8) as enriched in M1 macrophage-derived exosomes, promoting the activation of the TGF-β signaling pathway and inducing neuronal apoptosis. Exosomes derived from M1 macrophages exacerbated neuronal injury in BAC mice, while inhibiting MMP8 partially mitigated neuronal injury and restored intestinal function. Additionally, elevated serum exosomal MMP8 levels were identified as a potential marker for Hirschsprung's disease, a typical gastrointestinal motility disorder.
CONCLUSION: M1 macrophages induce enteric neuronal injury via exosomal MMP8-mediated TGF-β signaling, highlighting a potential therapeutic target for gastrointestinal motility disorders.
OBJECTIVE: This study aimed to explore the potential contribution of macrophage-derived exosomes to enteric neuronal injury and investigate the underlying mechanisms.
METHODS: We established a benzalkonium chloride (BAC)-induced enteric neuronal injury mouse model and assessed the effects of macrophage depletion on gastrointestinal motility and neuronal density. In vitro, enteric neurons were co-cultured with macrophages to examine the role of macrophage-derived exosomes in neuronal apoptosis. M1 macrophage-derived exosomes were isolated and characterized to elucidate potential mechanisms both in vitro and in vivo.
RESULTS: Macrophage depletion partially rescued gastrointestinal dysmotility and enteric neuronal injury in BAC-treated mice. In vitro studies confirmed that M1 macrophage-derived exosomes promoted neuronal apoptosis. We identified matrix metalloproteinase 8 (MMP8) as enriched in M1 macrophage-derived exosomes, promoting the activation of the TGF-β signaling pathway and inducing neuronal apoptosis. Exosomes derived from M1 macrophages exacerbated neuronal injury in BAC mice, while inhibiting MMP8 partially mitigated neuronal injury and restored intestinal function. Additionally, elevated serum exosomal MMP8 levels were identified as a potential marker for Hirschsprung's disease, a typical gastrointestinal motility disorder.
CONCLUSION: M1 macrophages induce enteric neuronal injury via exosomal MMP8-mediated TGF-β signaling, highlighting a potential therapeutic target for gastrointestinal motility disorders.