Periportal macrophages protect against commensal-driven liver inflammation

Yu Miyamoto, Junichi Kikuta, Takahiro Matsui, Tetsuo Hasegawa, Kentaro Fujii, Daisuke Okuzaki, Yu-chen Liu, Takuya Yoshioka, Shigeto Seno, Daisuke Motooka, Yutaka Uchida, Erika Yamashita, Shogo Kobayashi, Hidetoshi Eguchi, Eiichi Morii, Karl Tryggvason, Takashi Shichita, Hisako Kayama, Koji Atarashi, Jun Kunisawa, Kenya Honda, Kiyoshi Takeda and Masaru Ishii ()
Additional contact information
Yu Miyamoto: Osaka University
Junichi Kikuta: Osaka University
Takahiro Matsui: Osaka University
Tetsuo Hasegawa: Osaka University
Kentaro Fujii: Osaka University
Daisuke Okuzaki: Osaka University
Yu-chen Liu: Osaka University
Takuya Yoshioka: Health and Nutrition
Shigeto Seno: Osaka University
Daisuke Motooka: Osaka University
Yutaka Uchida: Osaka University
Erika Yamashita: Osaka University
Shogo Kobayashi: Osaka University
Hidetoshi Eguchi: Osaka University
Eiichi Morii: Osaka University
Karl Tryggvason: Duke-NUS Medical School
Takashi Shichita: Tokyo Medical and Dental University
Hisako Kayama: Osaka University
Koji Atarashi: Keio University
Jun Kunisawa: Health and Nutrition
Kenya Honda: Keio University
Kiyoshi Takeda: Osaka University
Masaru Ishii: Osaka University

Nature, 2024, vol. 629, issue 8013, 901-909

Abstract: Abstract The liver is the main gateway from the gut, and the unidirectional sinusoidal flow from portal to central veins constitutes heterogenous zones, including the periportal vein (PV) and the pericentral vein zones1–5. However, functional differences in the immune system in each zone remain poorly understood. Here intravital imaging revealed that inflammatory responses are suppressed in PV zones. Zone-specific single-cell transcriptomics detected a subset of immunosuppressive macrophages enriched in PV zones that express high levels of interleukin-10 and Marco, a scavenger receptor that sequesters pro-inflammatory pathogen-associated molecular patterns and damage-associated molecular patterns, and consequently suppress immune responses. Induction of Marco+ immunosuppressive macrophages depended on gut microbiota. In particular, a specific bacterial family, Odoribacteraceae, was identified to induce this macrophage subset through its postbiotic isoallolithocholic acid. Intestinal barrier leakage resulted in inflammation in PV zones, which was markedly augmented in Marco-deficient conditions. Chronic liver inflammatory diseases such as primary sclerosing cholangitis (PSC) and non-alcoholic steatohepatitis (NASH) showed decreased numbers of Marco+ macrophages. Functional ablation of Marco+ macrophages led to PSC-like inflammatory phenotypes related to colitis and exacerbated steatosis in NASH in animal experimental models. Collectively, commensal bacteria induce Marco+ immunosuppressive macrophages, which consequently limit excessive inflammation at the gateway of the liver. Failure of this self-limiting system promotes hepatic inflammatory disorders such as PSC and NASH.

Date: 2024
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DOI: 10.1038/s41586-024-07372-6

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