自噬
粒体自噬
炎症
医学
帕金
发病机制
免疫学
细胞凋亡
药理学
癌症研究
生物
内科学
疾病
生物化学
帕金森病
作者
Stefanie Marek‐Iannucci,Asli Beyza Ozdemir,Debbie Moreira,Alejandro Raúl Gratacós Gómez,Malcolm Lane,Rebecca A. Porritt,Youngho Lee,Kenichi Shimada,Masanori Abe,Aleksandr Stotland,David Zemmour,Sarah J. Parker,Elsa Sánchez-López,Jennifer E. Van Eyk,Roberta A. Gottlieb,Michael C. Fishbein,Michael Karin,Timothy R. Crother,Magali Noval Rivas,Moshe Arditi
出处
期刊:JCI insight
[American Society for Clinical Investigation]
日期:2021-09-22
卷期号:6 (18)
被引量:26
标识
DOI:10.1172/jci.insight.151981
摘要
Kawasaki disease (KD) is the leading cause of acquired heart disease among children. Murine and human data suggest that the NLRP3-IL-1β pathway is the main driver of KD pathophysiology. NLRP3 can be activated during defective autophagy/mitophagy. We used the Lactobacillus casei cell wall extract (LCWE) murine model of KD vasculitis to examine the role of autophagy/mitophagy on cardiovascular lesion development. LCWE-injected mice had impaired autophagy/mitophagy and increased levels of ROS in cardiovascular lesions, together with increased systemic 8-OHdG release. Enhanced autophagic flux significantly reduced cardiovascular lesions in LCWE-injected mice, whereas autophagy blockade increased inflammation. Vascular smooth muscle cell-specific deletion of Atg16l1 and global Parkin-/- significantly increased disease formation, supporting the importance of autophagy/mitophagy in this model. Ogg1-/- mice had significantly increased lesions with increased NLRP3 activity, whereas treatment with MitoQ reduced vascular tissue inflammation, ROS production, and systemic 8-OHdG release. Treatment with MN58b or Metformin (increasing AMPK and reducing ROS) resulted in decreased cardiovascular lesions. Our results demonstrate that impaired autophagy/mitophagy and ROS-dependent damage exacerbate the development of murine KD vasculitis. This pathway can be efficiently targeted to reduce disease severity. These findings enhance our understanding of KD pathogenesis and identify potentially novel therapeutic avenues for KD treatment.
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