Myeloid TLR4 signaling promotes post-injury withdrawal resolution of murine liver fibrosis

Yoichi Takimoto; Po-Sung Chu; Nobuhiro Nakamoto; Yuya Hagihara; Yohei Mikami; Kentaro Miyamoto; Rei Morikawa; Toshiaki Teratani; Nobuhito Taniki; Sota Fujimori; Takahiro Suzuki; Yuzo Koda; Rino Ishihara; Masataka Ichikawa; Akira Honda; Takanori Kanai

doi:10.1016/j.isci.2023.106220

Myeloid TLR4 signaling promotes post-injury withdrawal resolution of murine liver fibrosis

iScience. 2023 Feb 16;26(3):106220. doi: 10.1016/j.isci.2023.106220. eCollection 2023 Mar 17.

Authors

Yoichi Takimoto¹, Po-Sung Chu¹, Nobuhiro Nakamoto¹, Yuya Hagihara¹, Yohei Mikami¹, Kentaro Miyamoto^{1

2}, Rei Morikawa¹, Toshiaki Teratani¹, Nobuhito Taniki¹, Sota Fujimori^{1

3}, Takahiro Suzuki^{1

2}, Yuzo Koda^{1

3}, Rino Ishihara¹, Masataka Ichikawa¹, Akira Honda⁴, Takanori Kanai¹

Affiliations

¹ Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.
² Miyarisan Pharmaceutical Co., Ltd, Kita-ku, Tokyo 114-0016, Japan.
³ Research Unit/Immunology and Inflammation, Sohyaku Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, Yokohama, Kanagawa 227-0033, Japan.
⁴ Division of Gastroenterology and Hepatology, Department of Internal Medicine, Tokyo Medical University Ibaraki Medical Center, Inashiki-gun, Ibaraki 300-0395, Japan.

Abstract

The fate of resolution of liver fibrosis after withdrawal of liver injury is still incompletely elucidated. Toll-like receptor 4 (TLR4) in tissue fibroblasts is pro-fibrogenic. After withdrawal of liver injury, we unexpectedly observed a significant delay of fibrosis resolution as TLR4 signaling was pharmacologically inhibited in vivo in two murine models. Single-cell transcriptome analysis of hepatic CD11b⁺ cells, main producers of matrix metalloproteinases (MMPs), revealed a prominent cluster of restorative Tlr4-expressing Ly6c2-low myeloid cells. Delayed resolution after gut sterilization suggested its microbiome-dependent nature. Enrichment of a metabolic pathway linking to a significant increase of bile salt hydrolase-possessing family Erysipelotrichaceae during resolution. Farnesoid X receptor-stimulating secondary bile acids including 7-oxo-lithocholic acids upregulated MMP12 and TLR4 in myeloid cells in vitro. Fecal material transplant in germ-free mice confirmed phenotypical correlations in vivo. These findings highlight a pro-fibrolytic role of myeloid TLR4 signaling after injury withdrawal and may provide targets for anti-fibrotic therapy.

Keywords: Immunity; Microbiome; Transcriptomics.