The gut microbiota-induced kynurenic acid recruits GPR35-positive macrophages to promote experimental encephalitis

Kentaro Miyamoto; Tomohisa Sujino; Yosuke Harada; Hiroshi Ashida; Yusuke Yoshimatsu; Yuki Yonemoto; Yasuhiro Nemoto; Michio Tomura; Hassan Melhem; Jan Hendrik Niess; Toshihiko Suzuki; Toru Suzuki; Shohei Suzuki; Yuzo Koda; Ryuichi Okamoto; Yohei Mikami; Toshiaki Teratani; Kenji Tanaka; Akihiko Yoshimura; Toshiro Sato; Takanori Kanai

doi:10.1016/j.celrep.2023.113005

The gut microbiota-induced kynurenic acid recruits GPR35-positive macrophages to promote experimental encephalitis

Kentaro Miyamoto, Tomohisa Sujino, Yosuke Harada, Hiroshi Ashida, Yusuke Yoshimatsu, Yuki Yonemoto, Yasuhiro Nemoto, Michio Tomura, Hassan Melhem, Jan Hendrik Niess, Toshihiko Suzuki, Toru Suzuki, Shohei Suzuki, Yuzo Koda, Ryuichi Okamoto, Yohei Mikami, Toshiaki Teratani, Kenji Tanaka, Akihiko Yoshimura, Toshiro SatoTakanori Kanai

Research Institute for Biomedical Sciences

Research output: Contribution to journal › Article › peer-review

24 Citations (Scopus)

Abstract

The intricate interplay between gut microbes and the onset of experimental autoimmune encephalomyelitis (EAE) remains poorly understood. Here, we uncover remarkable similarities between CD4⁺ T cells in the spinal cord and their counterparts in the small intestine. Furthermore, we unveil a synergistic relationship between the microbiota, particularly enriched with the tryptophan metabolism gene EC:1.13.11.11, and intestinal cells. This symbiotic collaboration results in the biosynthesis of kynurenic acid (KYNA), which modulates the recruitment and aggregation of GPR35-positive macrophages. Subsequently, a robust T helper 17 (Th17) immune response is activated, ultimately triggering the onset of EAE. Conversely, modulating the KYNA-mediated GPR35 signaling in Cx3cr1⁺ macrophages leads to a remarkable amelioration of EAE. These findings shed light on the crucial role of microbial-derived tryptophan metabolites in regulating immune responses within extraintestinal tissues.

Original language	English
Article number	113005
Journal	Cell Reports
Volume	42
Issue number	8
DOIs	https://doi.org/10.1016/j.celrep.2023.113005
Publication status	Published - 29 Aug 2023

Keywords

CD4 T cells
CP: Immunology
CP: Microbiology
GPR35
encephalomyelitis
gut microbes
immune system
kynurenic acid
macrophages
multiple sclerosis
spinal cord
tryptophan metabolites

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10.1016/j.celrep.2023.113005

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Miyamoto, K., Sujino, T., Harada, Y., Ashida, H., Yoshimatsu, Y., Yonemoto, Y., Nemoto, Y., Tomura, M., Melhem, H., Niess, J. H., Suzuki, T., Suzuki, T., Suzuki, S., Koda, Y., Okamoto, R., Mikami, Y., Teratani, T., Tanaka, K., Yoshimura, A., ... Kanai, T. (2023). The gut microbiota-induced kynurenic acid recruits GPR35-positive macrophages to promote experimental encephalitis. Cell Reports, 42(8), Article 113005. https://doi.org/10.1016/j.celrep.2023.113005

@article{7fb713d6eacb42b6869dc8cae509408b,

title = "The gut microbiota-induced kynurenic acid recruits GPR35-positive macrophages to promote experimental encephalitis",

abstract = "The intricate interplay between gut microbes and the onset of experimental autoimmune encephalomyelitis (EAE) remains poorly understood. Here, we uncover remarkable similarities between CD4+ T cells in the spinal cord and their counterparts in the small intestine. Furthermore, we unveil a synergistic relationship between the microbiota, particularly enriched with the tryptophan metabolism gene EC:1.13.11.11, and intestinal cells. This symbiotic collaboration results in the biosynthesis of kynurenic acid (KYNA), which modulates the recruitment and aggregation of GPR35-positive macrophages. Subsequently, a robust T helper 17 (Th17) immune response is activated, ultimately triggering the onset of EAE. Conversely, modulating the KYNA-mediated GPR35 signaling in Cx3cr1+ macrophages leads to a remarkable amelioration of EAE. These findings shed light on the crucial role of microbial-derived tryptophan metabolites in regulating immune responses within extraintestinal tissues.",

keywords = "CD4 T cells, CP: Immunology, CP: Microbiology, GPR35, encephalomyelitis, gut microbes, immune system, kynurenic acid, macrophages, multiple sclerosis, spinal cord, tryptophan metabolites",

author = "Kentaro Miyamoto and Tomohisa Sujino and Yosuke Harada and Hiroshi Ashida and Yusuke Yoshimatsu and Yuki Yonemoto and Yasuhiro Nemoto and Michio Tomura and Hassan Melhem and Niess, \{Jan Hendrik\} and Toshihiko Suzuki and Toru Suzuki and Shohei Suzuki and Yuzo Koda and Ryuichi Okamoto and Yohei Mikami and Toshiaki Teratani and Kenji Tanaka and Akihiko Yoshimura and Toshiro Sato and Takanori Kanai",

note = "Publisher Copyright: {\textcopyright} 2023 The Author(s)",

year = "2023",

month = aug,

day = "29",

doi = "10.1016/j.celrep.2023.113005",

language = "English",

volume = "42",

journal = "Cell Reports",

issn = "2211-1247",

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Miyamoto, K, Sujino, T, Harada, Y, Ashida, H, Yoshimatsu, Y, Yonemoto, Y, Nemoto, Y, Tomura, M, Melhem, H, Niess, JH, Suzuki, T, Suzuki, T, Suzuki, S, Koda, Y, Okamoto, R, Mikami, Y, Teratani, T, Tanaka, K, Yoshimura, A, Sato, T & Kanai, T 2023, 'The gut microbiota-induced kynurenic acid recruits GPR35-positive macrophages to promote experimental encephalitis', Cell Reports, vol. 42, no. 8, 113005. https://doi.org/10.1016/j.celrep.2023.113005

TY - JOUR

T1 - The gut microbiota-induced kynurenic acid recruits GPR35-positive macrophages to promote experimental encephalitis

AU - Miyamoto, Kentaro

AU - Sujino, Tomohisa

AU - Harada, Yosuke

AU - Ashida, Hiroshi

AU - Yoshimatsu, Yusuke

AU - Yonemoto, Yuki

AU - Nemoto, Yasuhiro

AU - Tomura, Michio

AU - Melhem, Hassan

AU - Niess, Jan Hendrik

AU - Suzuki, Toshihiko

AU - Suzuki, Toru

AU - Suzuki, Shohei

AU - Koda, Yuzo

AU - Okamoto, Ryuichi

AU - Mikami, Yohei

AU - Teratani, Toshiaki

AU - Tanaka, Kenji

AU - Yoshimura, Akihiko

AU - Sato, Toshiro

AU - Kanai, Takanori

PY - 2023/8/29

Y1 - 2023/8/29

N2 - The intricate interplay between gut microbes and the onset of experimental autoimmune encephalomyelitis (EAE) remains poorly understood. Here, we uncover remarkable similarities between CD4+ T cells in the spinal cord and their counterparts in the small intestine. Furthermore, we unveil a synergistic relationship between the microbiota, particularly enriched with the tryptophan metabolism gene EC:1.13.11.11, and intestinal cells. This symbiotic collaboration results in the biosynthesis of kynurenic acid (KYNA), which modulates the recruitment and aggregation of GPR35-positive macrophages. Subsequently, a robust T helper 17 (Th17) immune response is activated, ultimately triggering the onset of EAE. Conversely, modulating the KYNA-mediated GPR35 signaling in Cx3cr1+ macrophages leads to a remarkable amelioration of EAE. These findings shed light on the crucial role of microbial-derived tryptophan metabolites in regulating immune responses within extraintestinal tissues.

AB - The intricate interplay between gut microbes and the onset of experimental autoimmune encephalomyelitis (EAE) remains poorly understood. Here, we uncover remarkable similarities between CD4+ T cells in the spinal cord and their counterparts in the small intestine. Furthermore, we unveil a synergistic relationship between the microbiota, particularly enriched with the tryptophan metabolism gene EC:1.13.11.11, and intestinal cells. This symbiotic collaboration results in the biosynthesis of kynurenic acid (KYNA), which modulates the recruitment and aggregation of GPR35-positive macrophages. Subsequently, a robust T helper 17 (Th17) immune response is activated, ultimately triggering the onset of EAE. Conversely, modulating the KYNA-mediated GPR35 signaling in Cx3cr1+ macrophages leads to a remarkable amelioration of EAE. These findings shed light on the crucial role of microbial-derived tryptophan metabolites in regulating immune responses within extraintestinal tissues.

KW - CD4 T cells

KW - CP: Immunology

KW - CP: Microbiology

KW - GPR35

KW - encephalomyelitis

KW - gut microbes

KW - immune system

KW - kynurenic acid

KW - macrophages

KW - multiple sclerosis

KW - spinal cord

KW - tryptophan metabolites

UR - https://www.scopus.com/pages/publications/85167807317

U2 - 10.1016/j.celrep.2023.113005

DO - 10.1016/j.celrep.2023.113005

M3 - Article

C2 - 37590143

AN - SCOPUS:85167807317

SN - 2211-1247

VL - 42

JO - Cell Reports

JF - Cell Reports

IS - 8

M1 - 113005

ER -

The gut microbiota-induced kynurenic acid recruits GPR35-positive macrophages to promote experimental encephalitis

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