2. Academic Validation
  3. The pyruvate-GPR31 axis promotes transepithelial dendrite formation in human intestinal dendritic cells

The pyruvate-GPR31 axis promotes transepithelial dendrite formation in human intestinal dendritic cells

  • Proc Natl Acad Sci U S A. 2024 Oct 29;121(44):e2318767121. doi: 10.1073/pnas.2318767121.
Eri Oguro-Igashira 1 2 3,  Mari Murakami 1 2,  Ryota Mori 4,  Ryuichi Kuwahara 5,  Takako Kihara 6,  Masaharu Kohara 7,  Makoto Fujiwara 8,  Daisuke Motooka 2 9 10,  Daisuke Okuzaki 2 9 10 11 12,  Mitsuru Arase 1 2,  Hironobu Toyota 1,  Siyun Peng 1 2,  Takayuki Ogino 4,  Yasuji Kitabatake 8,  Eiichi Morii 7,  Seiichi Hirota 6,  Hiroki Ikeuchi 5,  Eiji Umemoto 13,  Atsushi Kumanogoh 3 10 11 12 14,  Kiyoshi Takeda 1 2 10 11
Affiliations

Affiliations

  • 1 Department of Microbiology and Immunology, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan.
  • 2 World Premier International Research Center Initiative (WPI) Immunology Frontier Research Center, Osaka University, Osaka 565-0871, Japan.
  • 3 Department of Respiratory Medicine and Clinical Immunology, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan.
  • 4 Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan.
  • 5 Department of Gastroenterological Surgery, Division of Inflammatory Bowel Disease Surgery, Hyogo Medical University, Hyogo 663-8501, Japan.
  • 6 Department of Surgical Pathology, Hyogo Medical University, Hyogo 663-8501, Japan.
  • 7 Department of Pathology, Osaka University Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan.
  • 8 Department of Pediatrics, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan.
  • 9 Department of Infection Metagenomics, Genome Information Research Center, Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan.
  • 10 Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiatives, Osaka University, Osaka 565-0871, Japan.
  • 11 Division of Microbiology and Immunology, Center for Infectious Disease Education and Research, Osaka University, Osaka 565-0871, Japan.
  • 12 Center for Advanced Modalities and Drug Delivery System, Osaka University, Osaka 565-0871, Japan.
  • 13 Laboratory of Microbiology and Immunology, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka 422-8526, Japan.
  • 14 Department of Immunopathology, World Premier International Research Center Initiative (WPI) Immunology Frontier Research Center, Osaka University, Osaka 565-0871, Japan.
PMID: 39432783 DOI: 10.1073/pnas.2318767121
Abstract

The intestinal lumen is rich in gut microbial metabolites that serve as signaling molecules for gut immune cells. G-protein-coupled receptors (GPCRs) sense metabolites and can act as key mediators that translate gut luminal signals into host immune responses. However, the impacts of gut microbe-GPCR interactions on human physiology have not been fully elucidated. Here, we show that GPR31, which is activated by the gut Bacterial metabolite pyruvate, is specifically expressed on type 1 conventional dendritic cells (cDC1s) in the lamina propria of the human intestine. Using human induced pluripotent stem cell-derived cDC1s and a monolayer human gut Organoid coculture system, we show that cDC1s extend their dendrites toward pyruvate on the luminal side, forming transepithelial dendrites (TED). Accordingly, GPR31 activation via pyruvate enhances the fundamental function of cDC1 by allowing efficient uptake of gut luminal antigens, such as dietary compounds and Bacterial particles through TED formation. Our results highlight the role of GPCRs in tuning the human gut immune system according to local metabolic cues.

Keywords

G protein-coupled receptors; GPR31; antigen recognition; dendritic cell; transepithelial dendrite formation.

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