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; Masaru Ishii

doi:10.1038/s41586-024-07372-6

Periportal macrophages protect against commensal-driven liver inflammation

Nature. 2024 Apr 24. doi: 10.1038/s41586-024-07372-6. Online ahead of print.

Authors

Yu Miyamoto^{1

2

3}, Junichi Kikuta^{1

2

3

4}, Takahiro Matsui^{1

5}, Tetsuo Hasegawa¹, Kentaro Fujii^{1

2

3}, Daisuke Okuzaki^{2

6}, Yu-Chen Liu^{2

6}, Takuya Yoshioka⁷, Shigeto Seno⁸, Daisuke Motooka^{2

6}, Yutaka Uchida^{1

2

3

4}, Erika Yamashita^{1

2

3}, Shogo Kobayashi⁹, Hidetoshi Eguchi⁹, Eiichi Morii⁵, Karl Tryggvason¹⁰, Takashi Shichita¹¹, Hisako Kayama^{2

12}, Koji Atarashi¹³, Jun Kunisawa⁷, Kenya Honda¹³, Kiyoshi Takeda^{2

12}, Masaru Ishii^{14

15

16

17}

Affiliations

¹ Department of Immunology and Cell Biology, Graduate School of Medicine and Frontier Biosciences, Osaka University, Osaka, Japan.
² WPI-Immunology Frontier Research Center, Osaka University, Osaka, Japan.
³ Life-omics Research Division, Institute for Open and Transdisciplinary Research Initiative, Osaka University, Osaka, Japan.
⁴ Laboratory of Bioimaging and Drug Discovery, National Institutes of Biomedical Innovation, Health and Nutrition, Osaka, Japan.
⁵ Department of Pathology, Graduate School of Medicine, Osaka University, Osaka, Japan.
⁶ Genome Information Research Center, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan.
⁷ Laboratory of Vaccine Materials, Center for Vaccine and Adjuvant Research, National Institutes of Biomedical Innovation, Health and Nutrition, Osaka, Japan.
⁸ Department of Bioinformatic Engineering, Graduate School of Information Science and Technology, Osaka University, Osaka, Japan.
⁹ Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan.
¹⁰ Cardiovascular and Metabolic Disorders Program, Duke-NUS, Duke-NUS Medical School, Singapore, Singapore.
¹¹ Laboratory for Neuroinflammation and Repair, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan.
¹² Department of Microbiology and Immunology, Graduate School of Medicine, Osaka University, Osaka, Japan.
¹³ Department of Microbiology and Immunology, School of Medicine, Keio University, Tokyo, Japan.
¹⁴ Department of Immunology and Cell Biology, Graduate School of Medicine and Frontier Biosciences, Osaka University, Osaka, Japan. mishii@icb.med.osaka-u.ac.jp.
¹⁵ WPI-Immunology Frontier Research Center, Osaka University, Osaka, Japan. mishii@icb.med.osaka-u.ac.jp.
¹⁶ Life-omics Research Division, Institute for Open and Transdisciplinary Research Initiative, Osaka University, Osaka, Japan. mishii@icb.med.osaka-u.ac.jp.
¹⁷ Laboratory of Bioimaging and Drug Discovery, National Institutes of Biomedical Innovation, Health and Nutrition, Osaka, Japan. mishii@icb.med.osaka-u.ac.jp.

PMID: 38658756
DOI: 10.1038/s41586-024-07372-6

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 zones^1-5. 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.