DOK3 maintains intestinal homeostasis by suppressing JAK2/STAT3 signaling and S100a8/9 production in neutrophils

Abstract How pathogenesis of inflammatory bowel disease (IBD) depends on the complex interplay of host genetics, microbiome and the immune system is not fully understood. Here, we showed that Downstream of Kinase 3 (DOK3), an adapter protein involved in immune signaling, confers protection of mice f...

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Autores principales:	Jia Tong Loh, Koon-Guan Lee, Alison P. Lee, Joey Kay Hui Teo, Hsueh Lee Lim, Susana Soo-Yeon Kim, Andy Hee-Meng Tan, Kong-Peng Lam
Formato:	article
Lenguaje:	EN
Publicado:	Nature Publishing Group 2021
Materias:	Cytology QH573-671
Acceso en línea:	https://doaj.org/article/9e614d935ff7407392251563afe5b819
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spelling	oai:doaj.org-article:9e614d935ff7407392251563afe5b8192021-11-07T12:05:36ZDOK3 maintains intestinal homeostasis by suppressing JAK2/STAT3 signaling and S100a8/9 production in neutrophils10.1038/s41419-021-04357-52041-4889https://doaj.org/article/9e614d935ff7407392251563afe5b8192021-11-01T00:00:00Zhttps://doi.org/10.1038/s41419-021-04357-5https://doaj.org/toc/2041-4889Abstract How pathogenesis of inflammatory bowel disease (IBD) depends on the complex interplay of host genetics, microbiome and the immune system is not fully understood. Here, we showed that Downstream of Kinase 3 (DOK3), an adapter protein involved in immune signaling, confers protection of mice from dextran sodium sulfate (DSS)-induced colitis. DOK3-deficiency promotes gut microbial dysbiosis and enhanced colitis susceptibility, which can be reversed by the transfer of normal microbiota from wild-type mice. Mechanistically, DOK3 exerts its protective effect by suppressing JAK2/STAT3 signaling in colonic neutrophils to limit their S100a8/9 production, thereby maintaining gut microbial ecology and colon homeostasis. Hence, our findings reveal that the immune system and microbiome function in a feed-forward manner, whereby DOK3 maintains colonic neutrophils in a quiescent state to establish a gut microbiome essential for intestinal homeostasis and protection from IBD.Jia Tong LohKoon-Guan LeeAlison P. LeeJoey Kay Hui TeoHsueh Lee LimSusana Soo-Yeon KimAndy Hee-Meng TanKong-Peng LamNature Publishing GrouparticleCytologyQH573-671ENCell Death and Disease, Vol 12, Iss 11, Pp 1-10 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Cytology QH573-671
spellingShingle	Cytology QH573-671 Jia Tong Loh Koon-Guan Lee Alison P. Lee Joey Kay Hui Teo Hsueh Lee Lim Susana Soo-Yeon Kim Andy Hee-Meng Tan Kong-Peng Lam DOK3 maintains intestinal homeostasis by suppressing JAK2/STAT3 signaling and S100a8/9 production in neutrophils
description	Abstract How pathogenesis of inflammatory bowel disease (IBD) depends on the complex interplay of host genetics, microbiome and the immune system is not fully understood. Here, we showed that Downstream of Kinase 3 (DOK3), an adapter protein involved in immune signaling, confers protection of mice from dextran sodium sulfate (DSS)-induced colitis. DOK3-deficiency promotes gut microbial dysbiosis and enhanced colitis susceptibility, which can be reversed by the transfer of normal microbiota from wild-type mice. Mechanistically, DOK3 exerts its protective effect by suppressing JAK2/STAT3 signaling in colonic neutrophils to limit their S100a8/9 production, thereby maintaining gut microbial ecology and colon homeostasis. Hence, our findings reveal that the immune system and microbiome function in a feed-forward manner, whereby DOK3 maintains colonic neutrophils in a quiescent state to establish a gut microbiome essential for intestinal homeostasis and protection from IBD.
format	article
author	Jia Tong Loh Koon-Guan Lee Alison P. Lee Joey Kay Hui Teo Hsueh Lee Lim Susana Soo-Yeon Kim Andy Hee-Meng Tan Kong-Peng Lam
author_facet	Jia Tong Loh Koon-Guan Lee Alison P. Lee Joey Kay Hui Teo Hsueh Lee Lim Susana Soo-Yeon Kim Andy Hee-Meng Tan Kong-Peng Lam
author_sort	Jia Tong Loh
title	DOK3 maintains intestinal homeostasis by suppressing JAK2/STAT3 signaling and S100a8/9 production in neutrophils
title_short	DOK3 maintains intestinal homeostasis by suppressing JAK2/STAT3 signaling and S100a8/9 production in neutrophils
title_full	DOK3 maintains intestinal homeostasis by suppressing JAK2/STAT3 signaling and S100a8/9 production in neutrophils
title_fullStr	DOK3 maintains intestinal homeostasis by suppressing JAK2/STAT3 signaling and S100a8/9 production in neutrophils
title_full_unstemmed	DOK3 maintains intestinal homeostasis by suppressing JAK2/STAT3 signaling and S100a8/9 production in neutrophils
title_sort	dok3 maintains intestinal homeostasis by suppressing jak2/stat3 signaling and s100a8/9 production in neutrophils
publisher	Nature Publishing Group
publishDate	2021
url	https://doaj.org/article/9e614d935ff7407392251563afe5b819
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DOK3 maintains intestinal homeostasis by suppressing JAK2/STAT3 signaling and S100a8/9 production in neutrophils

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