Iron-rich Kupffer cells exhibit phenotypic changes during the development of liver fibrosis in NASH
Yohei Kanamori,
Miyako Tanaka,
Michiko Itoh,
Kozue Ochi,
Ayaka Ito,
Isao Hidaka,
Isao Sakaida,
Yoshihiro Ogawa,
Takayoshi Suganami
Affiliations
Yohei Kanamori
Department of Molecular Medicine and Metabolism, Research Institute of Environmental Medicine, Nagoya University, Nagoya 464-8601, Japan; Department of Immunometabolism, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan
Miyako Tanaka
Department of Molecular Medicine and Metabolism, Research Institute of Environmental Medicine, Nagoya University, Nagoya 464-8601, Japan; Department of Immunometabolism, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan; Corresponding author
Michiko Itoh
Department of Molecular Medicine and Metabolism, Research Institute of Environmental Medicine, Nagoya University, Nagoya 464-8601, Japan; Kanagawa Institute of Industrial Science and Technology, Ebina 243-0435, Japan; Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, Tokyo 101-0062, Japan
Kozue Ochi
Department of Molecular Medicine and Metabolism, Research Institute of Environmental Medicine, Nagoya University, Nagoya 464-8601, Japan; Department of Immunometabolism, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan
Ayaka Ito
Department of Molecular Medicine and Metabolism, Research Institute of Environmental Medicine, Nagoya University, Nagoya 464-8601, Japan; Department of Immunometabolism, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan
Isao Hidaka
Department of Gastroenterology and Hepatology, Yamaguchi University Graduate School of Medicine, Yamaguchi 755-8505, Japan
Isao Sakaida
Department of Gastroenterology and Hepatology, Yamaguchi University Graduate School of Medicine, Yamaguchi 755-8505, Japan
Yoshihiro Ogawa
Department of Molecular Medicine and Metabolism, Research Institute of Environmental Medicine, Nagoya University, Nagoya 464-8601, Japan; Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan
Takayoshi Suganami
Department of Molecular Medicine and Metabolism, Research Institute of Environmental Medicine, Nagoya University, Nagoya 464-8601, Japan; Department of Immunometabolism, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan; Corresponding author
Summary: Although recent evidence suggests the involvement of iron accumulation in the pathogenesis of nonalcoholic steatohepatitis (NASH), the underlying mechanisms remain poorly understood. Previously, we reported a unique histological structure termed “crown-like structure (CLS),” where liver-resident macrophages (Kupffer cells) surround dead hepatocytes, scavenge their debris, and induce inflammation and fibrosis in NASH. In this study, using magnetic column separation, we show that iron-rich Kupffer cells exhibit proinflammatory and profibrotic phenotypic changes during the development of NASH, at least partly, through activation of MiT/TFE transcription factors. Activation of MiT/TFE transcription factors is observed in Kupffer cells forming CLSs in murine and human NASH. Iron chelation effectively attenuates liver fibrosis in a murine NASH model. This study provides insight into the pathophysiologic role of iron in NASH. Our data also shed light on a unique macrophage subset rich in iron that contributes to CLS formation and serves as a driver of liver fibrosis.
