Microbiome ssRNA as an environmental cue to activate TLR13-dependent tissue-protective programs in CD5L hi hepatic macrophages
Year: 2023
Type: preprint
Abstract: Hepatic macrophages maintain liver homeostasis, but little is known about the signals that activate the hepatoprotective programs within macrophages. Here, we show that toll-like receptor 13 (TLR13), a sensor of bacterial 23S ribosomal RNA (rRNA), senses microbiome RNAs to drive tissue-protective responses in CD5L hi hepatic macrophages. Splenomegaly and hepatomegaly developed in the absence of the endosomal RNase, RNaseT2, via TLR13-dependent macrophage proliferation. Furthermore, TLR13 in hepatic Ly6C lo macrophages activated the transcription factors LXRα and MafB, leading to expression of tissue-clearance molecules, such as CD5L, C1qb, and Axl. Consequently, Rnaset2 −/− mice developed resistance to acute liver injury caused by challenges with acetaminophen and lipopolysaccharide + D-galactosamine. TLR13 responses in Rnaset2 −/− mice were impaired by antibiotics, suggesting that TLR13 were activated by microbiome rRNAs, which was detected in the sera and hepatic macrophages. Repeated administration of wild-type mice with the TLR13 ligand, rather than other TLR ligands, selectively increased the number of Kupffer cells, which expressed immunoregulatory and tissue-clearance genes as hepatic macrophages in Rnaset2 −/− mice did. Our results suggest that microbiome ssRNA serves as an environmental cue for initiating tissue-protective TLR13 responses in hepatic macrophages. Graphical Abstract In the absence of an endosomal RNase, RNase T2, microbiome RNAs circulating in the vasculature activate TLR13 in hepatic macrophages to drive hepatoprotective responses through expression of immunoregulatory and tissue-clearance molecules. Consequently, mice lacking RNase T2 are resistant against acute liver injuries caused by acetaminophen and LPS + D-galactosamine.
Authors: Ryota Sato, Kaiwen Liu, Takuma Shibata, Katsuaki Hoshino, Kiyoshi Yamaguchi, Toru Miyazaki, Ryosuke Hiranuma, Ryutaro Fukui, Yuji Motoi, Yuri Fukuda-Ohta, Yun Zhang, Tatjana Reuter, Yuko Ishida, Toshikazu Kondo, Tomoki Chiba, Hiroshi Asahara, Masato Taoka, Yoshio Yamauchi, Toshiaki Isobe, Tsuneyasu Kaisho, Yoichi Furukawa, Eicke Latz, Kensuke Miyake
Institutions: Institute of Medical Science, The University of Tokyo, The University of Tokyo, Kagawa University, RIKEN, RIKEN Center for Integrative Medical Sciences, Wakayama Medical University, University of Bonn, University Hospital Bonn, Tokyo Medical and Dental University, Scripps Research Institute, Tokyo Metropolitan University, German Rheumatism Research Centre
Language: English
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: green
Funders: Japan Agency for Medical Research and Development, Ministry of Education, Culture, Sports, Science and Technology, University of Tokyo, Mochida Memorial Foundation for Medical and Pharmaceutical Research, Daiichi Sankyo Foundation of Life Science, Japan Society for the Promotion of Science, Core Research for Evolutional Science and Technology, Daiichi Sankyo Europe
Awards: G1525927269, G2333543989, G2576085165, G3004704145, Exploration of TLR3 ligands and the regulatory mechanism of response through nucleases in HSV infection., G3048749161, Development of monosaccharides that regulate the functions of the plasmacytoid dendritic cells., G3111881881, G338994770, G3443099889, G3597619522, G3752555748, Elucidating the significance of amplified expression of endogenous retrotransposon in autoimmune/autoinflammatory diseases, Molecular bases enabling various BCR responses, Underlying mechanisms for immune disorders caused by proteasome dysfunctions, Studying molecular bases of alternative TLR responses, Functions of dendritic cell subsets in graft versus host diseases, Elucidation of the immune regulation by dendritic cell subsets, G503978824, Molecular mechanisms on antigen presenting cell function and generation, Immune regulation of graft versus host diseases by dendritic cell subsets, G6718509927, G697504518, G6980561039, Clarification of novel functions of the protein degradation system, Analysis of function of mTORC2 as fatty acid sensor in TLR3 response, Elucidation of the molecular mechanism involved in TLR7/8 response to ssRNA, G7879866177, Advanced Animal Model Support
OpenAlex ID: W4376616991