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

Mucosal Immunol
Authors
Keywords
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.

Year of Publication
2018
Journal
Mucosal Immunol
Volume
11
Issue
3
Pages
703-715
Date Published
2018 05
ISSN
1935-3456
DOI
10.1038/mi.2017.91
PubMed ID
29139475
PubMed Central ID
PMC5953762
Links
Grant list
R01 AI084880 / AI / NIAID NIH HHS / United States
R01 DK097485 / DK / NIDDK NIH HHS / United States
RC1 DK086502 / DK / NIDDK NIH HHS / United States
U01 DK062432 / DK / NIDDK NIH HHS / United States