Intestinal epithelial cell-specific RARα depletion results in aberrant epithelial cell homeostasis and underdeveloped immune system

Mucosal Immunol. 2018 May;11(3):703-715. doi: 10.1038/mi.2017.91. Epub 2017 Nov 15.

Abstract

Retinoic acid (RA), a dietary vitamin A metabolite, is crucial in maintaining intestinal homeostasis. RA acts on intestinal leukocytes to modulate their lineage commitment and function. Although the role of RA has been characterized in immune cells, whether intestinal epithelial cells (IECs) rely on RA signaling to exert their immune-regulatory function has not been examined. Here we demonstrate that lack of RA receptor α (RARα) signaling in IECs results in deregulated epithelial lineage specification, leading to increased numbers of goblet cells and Paneth cells. Mechanistically, lack of RARα resulted in increased KLF4+ goblet cell precursors in the distal bowel, whereas RA treatment inhibited klf4 expression and goblet cell differentiation in zebrafish. These changes in secretory cells are associated with increased Reg3g, reduced luminal bacterial detection, and an underdeveloped intestinal immune system, as evidenced by an almost complete absence of lymphoid follicles and gut resident mononuclear phagocytes. This underdeveloped intestinal immune system shows a decreased ability to clear infection with Citrobacter rodentium. Collectively, our findings indicate that epithelial cell-intrinsic RARα signaling is critical to the global development of the intestinal immune system.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Differentiation
  • Cells, Cultured
  • Citrobacter rodentium / immunology*
  • Enterobacteriaceae Infections / immunology*
  • Goblet Cells / physiology*
  • Homeostasis
  • Intestinal Mucosa / physiology*
  • Kruppel-Like Transcription Factors / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mononuclear Phagocyte System*
  • Pancreatitis-Associated Proteins / genetics
  • Pancreatitis-Associated Proteins / metabolism
  • Retinoic Acid Receptor alpha / genetics
  • Retinoic Acid Receptor alpha / metabolism*
  • Signal Transduction
  • Tretinoin / metabolism*
  • Zebrafish

Substances

  • GKLF protein
  • Kruppel-Like Transcription Factors
  • Pancreatitis-Associated Proteins
  • Rara protein, mouse
  • Reg3g protein, mouse
  • Retinoic Acid Receptor alpha
  • Tretinoin