Microbiota-derived short chain fatty acid promotion of Amphiregulin expression by dendritic cells is regulated by GPR43 and Blimp-1

Biochem Biophys Res Commun. 2020 Dec 10;533(3):282-288. doi: 10.1016/j.bbrc.2020.09.027. Epub 2020 Sep 18.

Abstract

Dendritic cells (DC) are the most important antigen-presenting cells, which guide T cell activation and function, and dysregulated DC function might be one of the crucial causes of inflammatory bowel disease (IBD). It has been well-known that microbiota and their metabolites play an essential role in regulating the biology and function of DC, thus contributing to the pathogenesis of IBD. However, the underlying mechanisms remain largely unknown. Amphiregulin (AREG), a molecule of the epidermal growth factor (EGF) family, is primarily described as an epithelial cell-derived cytokine and recognized as a critical regulator of cell proliferation and tissue repair. Here, we found that DC expression of AREG depended on butyrate (a microbiota-derived short chained fatty acid), which required the interaction between butyrate and G-protein-coupled receptor 43 (GPR43). Furthermore, we found that butyrate-GPR43 interaction failed to induce AREG expression in DC deficient in B lymphocyte induced maturation protein 1 (Blimp-1). Notably, DC-derived AREG was indispensable for the protection against experimental colitis in mice. Additionally, AREG expression was significantly decreased in DC from IBD patients. Our data provide novel evidences to interpret how AREG expression is regulated in DC, and shed new light on the mechanisms whereby microbiota regulate DC function.

Keywords: Amphiregulin; Dendritic cells; Inflammation bowel disease; Microbiota; Short chained fatty acids.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amphiregulin / genetics*
  • Amphiregulin / immunology
  • Animals
  • B-Lymphocytes / immunology
  • B-Lymphocytes / microbiology
  • B-Lymphocytes / pathology
  • Butyrates / immunology*
  • Butyrates / metabolism
  • Butyrates / pharmacology
  • Case-Control Studies
  • Colitis, Ulcerative / chemically induced
  • Colitis, Ulcerative / genetics*
  • Colitis, Ulcerative / immunology
  • Colitis, Ulcerative / microbiology
  • Crohn Disease / genetics*
  • Crohn Disease / immunology
  • Crohn Disease / microbiology
  • Crohn Disease / pathology
  • Dendritic Cells / immunology*
  • Dendritic Cells / microbiology
  • Dendritic Cells / pathology
  • Female
  • Gastrointestinal Microbiome / immunology
  • Gene Expression Regulation
  • Humans
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Pancreatitis-Associated Proteins / deficiency
  • Pancreatitis-Associated Proteins / genetics
  • Pancreatitis-Associated Proteins / immunology
  • Positive Regulatory Domain I-Binding Factor 1 / genetics*
  • Positive Regulatory Domain I-Binding Factor 1 / immunology
  • Receptors, Cell Surface / genetics*
  • Receptors, Cell Surface / immunology
  • Receptors, G-Protein-Coupled / deficiency
  • Receptors, G-Protein-Coupled / genetics
  • Receptors, G-Protein-Coupled / immunology
  • Signal Transduction
  • Sodium Dodecyl Sulfate / administration & dosage
  • Zonula Occludens-1 Protein / genetics
  • Zonula Occludens-1 Protein / immunology

Substances

  • AREG protein, human
  • Amphiregulin
  • Butyrates
  • FFA2R protein, human
  • Ffar2 protein, mouse
  • Pancreatitis-Associated Proteins
  • Prdm1 protein, mouse
  • Receptors, Cell Surface
  • Receptors, G-Protein-Coupled
  • Reg3b protein, mouse
  • Reg3g protein, mouse
  • Tjp1 protein, mouse
  • Zonula Occludens-1 Protein
  • PRDM1 protein, human
  • Sodium Dodecyl Sulfate
  • Positive Regulatory Domain I-Binding Factor 1