Iron regulatory protein 2 contributes to antimicrobial immunity by preserving lysosomal function in macrophages

• 成果类型: Article
• 署名作者: Cheng, Chen; Xing, Zhiyao; Zhang, Wenxin; Zheng, Lei; Zhao, Hongting; Zhang, Xiao; Ding, Yibing; Qiao, Tong; Li, Yi; Meyron-Holtz, Esther G.; Missirlis, Fanis; Fan, Zhiwen; Li, Kuanyu
• 署名单位: Nanjing University; Nanjing University; Nanjing University; Technion Israel Institute of Technology; CINVESTAV - Centro de Investigacion y de Estudios Avanzados del Instituto Politecnico Nacional; Nanjing University
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-12336
• DOI: 10.1073/pnas.2321929121
• 发表日期: 2024-07-30
• 关键词: liver-abscess; targeted deletion; gut microbiota; homeostasis; autophagy; mechanisms; DEFENSE; disease; tfeb

摘要

Colorectal cancer and Crohn's disease patients develop pyogenic liver abscesses due to failures of immune cells to fight off bacterial infections. Here, we show that mice lacking when the intestinal tissue was injured with dextran sodium sulfate treatment. Further studies demonstrated that Irp2 is required for lysosomal acidification and biogenesis, both of which are crucial for bacterial clearance. In Irp2- deficient liver tissue or macrophages, the nuclear location of transcription factor EB (Tfeb) was remarkably reduced, leading to and, independently, through inhibition of lactic acid production. These experimental findings were confirmed clinically in patients with Crohn's disease and through bioinformatic searches in databases from Crohn's disease or ulcerative colitis biopsies showing loss of and lysosomal function, preserving macrophage antimicrobial activity and protecting the liver against invading bacteria during intestinal inflammation.