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

doi:10.1016/j.isci.2020.102032

Iron-rich Kupffer cells exhibit phenotypic changes during the development of liver fibrosis in NASH

iScience. 2021 Jan 5;24(2):102032. doi: 10.1016/j.isci.2020.102032. eCollection 2021 Feb 19.

Authors

Yohei Kanamori^{1

2}, Miyako Tanaka^{1

2}, Michiko Itoh^{1

3

4}, Kozue Ochi^{1

2}, Ayaka Ito^{1

2}, Isao Hidaka⁵, Isao Sakaida⁵, Yoshihiro Ogawa^{1

6}, Takayoshi Suganami^{1

2}

Affiliations

¹ Department of Molecular Medicine and Metabolism, Research Institute of Environmental Medicine, Nagoya University, Nagoya 464-8601, Japan.
² Department of Immunometabolism, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan.
³ Kanagawa Institute of Industrial Science and Technology, Ebina 243-0435, Japan.
⁴ Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, Tokyo 101-0062, Japan.
⁵ Department of Gastroenterology and Hepatology, Yamaguchi University Graduate School of Medicine, Yamaguchi 755-8505, Japan.
⁶ Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.

Abstract

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.

Keywords: Biochemistry; Biological Sciences; Cell Biology.