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

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...

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Autores principales: Jijon, Humberto B., Suarez-Lopez, Lucia, Diaz, Oscar E., Das, Srustidhar, De Calisto, Jaime, Yaffe, Michael B., Pittet, Mikael J., Mora, J. Rodrigo, Belkaid, Yasmine, Xavier, Ramnik J., Villablanca, Eduardo J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5953762/
https://www.ncbi.nlm.nih.gov/pubmed/29139475
http://dx.doi.org/10.1038/mi.2017.91
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author Jijon, Humberto B.
Suarez-Lopez, Lucia
Diaz, Oscar E.
Das, Srustidhar
De Calisto, Jaime
Yaffe, Michael B.
Pittet, Mikael J.
Mora, J. Rodrigo
Belkaid, Yasmine
Xavier, Ramnik J.
Villablanca, Eduardo J.
author_facet Jijon, Humberto B.
Suarez-Lopez, Lucia
Diaz, Oscar E.
Das, Srustidhar
De Calisto, Jaime
Yaffe, Michael B.
Pittet, Mikael J.
Mora, J. Rodrigo
Belkaid, Yasmine
Xavier, Ramnik J.
Villablanca, Eduardo J.
author_sort Jijon, Humberto B.
collection PubMed
description 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 retinoic acid receptor alpha (RARα) signaling in IECs results in deregulated epithelial lineage specification, leading to increased numbers of goblet cells and Paneth cells. Mechanistically, lack or 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.
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spelling pubmed-59537622018-05-31 Intestinal epithelial cell-specific RARα depletion results in aberrant epithelial cell homeostasis and underdeveloped immune system Jijon, Humberto B. Suarez-Lopez, Lucia Diaz, Oscar E. Das, Srustidhar De Calisto, Jaime Yaffe, Michael B. Pittet, Mikael J. Mora, J. Rodrigo Belkaid, Yasmine Xavier, Ramnik J. Villablanca, Eduardo J. Mucosal Immunol Article 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 retinoic acid receptor alpha (RARα) signaling in IECs results in deregulated epithelial lineage specification, leading to increased numbers of goblet cells and Paneth cells. Mechanistically, lack or 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. 2017-11-15 2018-05 /pmc/articles/PMC5953762/ /pubmed/29139475 http://dx.doi.org/10.1038/mi.2017.91 Text en http://www.nature.com/authors/editorial_policies/license.html#terms Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms
spellingShingle Article
Jijon, Humberto B.
Suarez-Lopez, Lucia
Diaz, Oscar E.
Das, Srustidhar
De Calisto, Jaime
Yaffe, Michael B.
Pittet, Mikael J.
Mora, J. Rodrigo
Belkaid, Yasmine
Xavier, Ramnik J.
Villablanca, Eduardo J.
Intestinal epithelial cell-specific RARα depletion results in aberrant epithelial cell homeostasis and underdeveloped immune system
title Intestinal epithelial cell-specific RARα depletion results in aberrant epithelial cell homeostasis and underdeveloped immune system
title_full Intestinal epithelial cell-specific RARα depletion results in aberrant epithelial cell homeostasis and underdeveloped immune system
title_fullStr Intestinal epithelial cell-specific RARα depletion results in aberrant epithelial cell homeostasis and underdeveloped immune system
title_full_unstemmed Intestinal epithelial cell-specific RARα depletion results in aberrant epithelial cell homeostasis and underdeveloped immune system
title_short Intestinal epithelial cell-specific RARα depletion results in aberrant epithelial cell homeostasis and underdeveloped immune system
title_sort intestinal epithelial cell-specific rarα depletion results in aberrant epithelial cell homeostasis and underdeveloped immune system
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5953762/
https://www.ncbi.nlm.nih.gov/pubmed/29139475
http://dx.doi.org/10.1038/mi.2017.91
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