Intestinal Epithelial Cell-Specific Deletion of PLD2 Alleviates DSS-Induced Colitis by Regulating Occludin

Abstract Ulcerative colitis is a multi-factorial disease involving a dysregulated immune response. Disruptions to the intestinal epithelial barrier and translocation of bacteria, resulting in inflammation, are common in colitis. The mechanisms underlying epithelial barrier dysfunction or regulation...

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Autores principales:	Chaithanya Chelakkot, Jaewang Ghim, Nirmal Rajasekaran, Jong-Sun Choi, Jung-Hwan Kim, Myoung Ho Jang, Young Kee Shin, Pann-Ghill Suh, Sung Ho Ryu
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/e627bc7f4f0645b6bc20709220d51531
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spelling	oai:doaj.org-article:e627bc7f4f0645b6bc20709220d515312021-12-02T11:52:22ZIntestinal Epithelial Cell-Specific Deletion of PLD2 Alleviates DSS-Induced Colitis by Regulating Occludin10.1038/s41598-017-01797-y2045-2322https://doaj.org/article/e627bc7f4f0645b6bc20709220d515312017-05-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-01797-yhttps://doaj.org/toc/2045-2322Abstract Ulcerative colitis is a multi-factorial disease involving a dysregulated immune response. Disruptions to the intestinal epithelial barrier and translocation of bacteria, resulting in inflammation, are common in colitis. The mechanisms underlying epithelial barrier dysfunction or regulation of tight junction proteins during disease progression of colitis have not been clearly elucidated. Increase in phospholipase D (PLD) activity is associated with disease severity in colitis animal models. However, the role of PLD2 in the maintenance of intestinal barrier integrity remains elusive. We have generated intestinal-specific Pld2 knockout mice (Pld2 IEC-KO) to investigate the mechanism of intestinal epithelial PLD2 in colitis. We show that the knockout of Pld2 confers protection against dextran sodium sulphate (DSS)-induced colitis in mice. Treatment with DSS induced the expression of PLD2 and downregulated occludin in colon epithelial cells. PLD2 was shown to mediate phosphorylation of occludin and induce its proteasomal degradation in a c-Src kinase-dependent pathway. Additionally, we have shown that treatment with an inhibitor of PLD2 can rescue mice from DSS-induced colitis. To our knowledge, this is the first report showing that PLD2 is pivotal in the regulation of the integrity of epithelial tight junctions and occludin turn over, thereby implicating it in the pathogenesis of colitis.Chaithanya ChelakkotJaewang GhimNirmal RajasekaranJong-Sun ChoiJung-Hwan KimMyoung Ho JangYoung Kee ShinPann-Ghill SuhSung Ho RyuNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-15 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Chaithanya Chelakkot Jaewang Ghim Nirmal Rajasekaran Jong-Sun Choi Jung-Hwan Kim Myoung Ho Jang Young Kee Shin Pann-Ghill Suh Sung Ho Ryu Intestinal Epithelial Cell-Specific Deletion of PLD2 Alleviates DSS-Induced Colitis by Regulating Occludin
description	Abstract Ulcerative colitis is a multi-factorial disease involving a dysregulated immune response. Disruptions to the intestinal epithelial barrier and translocation of bacteria, resulting in inflammation, are common in colitis. The mechanisms underlying epithelial barrier dysfunction or regulation of tight junction proteins during disease progression of colitis have not been clearly elucidated. Increase in phospholipase D (PLD) activity is associated with disease severity in colitis animal models. However, the role of PLD2 in the maintenance of intestinal barrier integrity remains elusive. We have generated intestinal-specific Pld2 knockout mice (Pld2 IEC-KO) to investigate the mechanism of intestinal epithelial PLD2 in colitis. We show that the knockout of Pld2 confers protection against dextran sodium sulphate (DSS)-induced colitis in mice. Treatment with DSS induced the expression of PLD2 and downregulated occludin in colon epithelial cells. PLD2 was shown to mediate phosphorylation of occludin and induce its proteasomal degradation in a c-Src kinase-dependent pathway. Additionally, we have shown that treatment with an inhibitor of PLD2 can rescue mice from DSS-induced colitis. To our knowledge, this is the first report showing that PLD2 is pivotal in the regulation of the integrity of epithelial tight junctions and occludin turn over, thereby implicating it in the pathogenesis of colitis.
format	article
author	Chaithanya Chelakkot Jaewang Ghim Nirmal Rajasekaran Jong-Sun Choi Jung-Hwan Kim Myoung Ho Jang Young Kee Shin Pann-Ghill Suh Sung Ho Ryu
author_facet	Chaithanya Chelakkot Jaewang Ghim Nirmal Rajasekaran Jong-Sun Choi Jung-Hwan Kim Myoung Ho Jang Young Kee Shin Pann-Ghill Suh Sung Ho Ryu
author_sort	Chaithanya Chelakkot
title	Intestinal Epithelial Cell-Specific Deletion of PLD2 Alleviates DSS-Induced Colitis by Regulating Occludin
title_short	Intestinal Epithelial Cell-Specific Deletion of PLD2 Alleviates DSS-Induced Colitis by Regulating Occludin
title_full	Intestinal Epithelial Cell-Specific Deletion of PLD2 Alleviates DSS-Induced Colitis by Regulating Occludin
title_fullStr	Intestinal Epithelial Cell-Specific Deletion of PLD2 Alleviates DSS-Induced Colitis by Regulating Occludin
title_full_unstemmed	Intestinal Epithelial Cell-Specific Deletion of PLD2 Alleviates DSS-Induced Colitis by Regulating Occludin
title_sort	intestinal epithelial cell-specific deletion of pld2 alleviates dss-induced colitis by regulating occludin
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/e627bc7f4f0645b6bc20709220d51531
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Intestinal Epithelial Cell-Specific Deletion of PLD2 Alleviates DSS-Induced Colitis by Regulating Occludin

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