Osteopontin regulation of MerTK+ macrophages promotes Crohn’s disease intestinal fibrosis
Juanhan Liu,
Wenbin Gong,
Peizhao Liu,
Yangguang Li,
Haiyang Jiang,
Cunxia Wu,
Xiuwen Wu,
Yun Zhao,
Jianan Ren
Affiliations
Juanhan Liu
Department of General Surgery, Research Institute of General Surgery, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
Wenbin Gong
Department of General Surgery, School of Medicine, Southeast University, Nanjing, China
Peizhao Liu
Department of General Surgery, Research Institute of General Surgery, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
Yangguang Li
Department of General Surgery, Research Institute of General Surgery, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
Haiyang Jiang
Department of General Surgery, BenQ Medical Center, Nanjing Medical School, Nanjing, China
Cunxia Wu
Department of General Surgery, BenQ Medical Center, Nanjing Medical School, Nanjing, China
Xiuwen Wu
Department of General Surgery, Research Institute of General Surgery, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China; Corresponding author
Yun Zhao
Department of General Surgery, BenQ Medical Center, Nanjing Medical School, Nanjing, China; Corresponding author
Jianan Ren
Department of General Surgery, Research Institute of General Surgery, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China; Corresponding author
Summary: The pathogenesis of intestinal fibrosis in Crohn’s disease (CD) remains unclear. Mer receptor tyrosine kinase (MerTK) is an immunosuppressive protein specifically expressed in macrophages. Osteopontin (OPN), also known as secreted phosphoprotein 1, contributes to inflammation and wound repair. This study investigates the potential profibrotic pathway in MerTK+ macrophages in order to provide a possible therapeutic target for intestinal fibrosis. MerTK expression in the inflamed and stenotic bowels was evaluated. The MerTK/ERK/TGF-β1 pathway was overactivated in the fibrotic intestinal tissues of patients with CD. This pathway was induced by epithelial cell apoptosis, resulting in activated fibroblasts with increased TGF-β1 secretion. OPN upregulated TGF production by altering ERK1/2 phosphorylation, as evidenced by OPN or MerTK knockdown and OPN overexpression in vitro. MerTK inhibitor UNC2025 alleviated intestinal fibrosis in mouse colitis models, suggesting a potential therapeutic target for intestinal fibrosis in patients with CD.
