Dataset Information

Sirtuin 6 maintains epithelial STAT6 activity to support intestinal tuft cell development and type 2 immunity.

ABSTRACT: Dynamic regulation of intestinal epithelial cell (IEC) differentiation is crucial for both homeostasis and the response to helminth infection. SIRT6 belongs to the NAD⁺-dependent deacetylases and has established diverse roles in aging, metabolism and disease. Here, we report that IEC Sirt6 deletion leads to impaired tuft cell development and type 2 immunity in response to helminth infection, thereby resulting in compromised worm expulsion. Conversely, after helminth infection, IEC SIRT6 transgenic mice exhibit enhanced epithelial remodeling process and more efficient worm clearance. Mechanistically, Sirt6 ablation causes elevated Socs3 expression, and subsequently attenuated tyrosine 641 phosphorylation of STAT6 in IECs. Notably, intestinal epithelial overexpression of constitutively activated STAT6 (STAT6vt) in mice is sufficient to induce the expansion of tuft and goblet cell linage. Furthermore, epithelial STAT6vt overexpression remarkedly reverses the defects in intestinal epithelial remodeling caused by Sirt6 ablation. Our results reveal a novel function of SIRT6 in regulating intestinal epithelial remodeling and mucosal type 2 immunity in response to helminth infection.

SUBMITTER: Xiong X

PROVIDER: S-EPMC9440928 | biostudies-literature | 2022 Sep

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Sirtuin 6 maintains epithelial STAT6 activity to support intestinal tuft cell development and type 2 immunity.

Xiong Xiwen X Yang Chenyan C He Wei-Qi WQ Yu Jiahui J Xin Yue Y Zhang Xinge X Huang Rong R Ma Honghui H Xu Shaofang S Li Zun Z Ma Jie J Xu Lin L Wang Qunyi Q Ren Kaiqun K Wu Xiaoli S XS Vakoc Christopher R CR Zhong Jiateng J Zhong Genshen G Zhu Xiaofei X Song Yu Y Ruan Hai-Bin HB Wang Qingzhi Q

Nature communications 20220903 1

Dynamic regulation of intestinal epithelial cell (IEC) differentiation is crucial for both homeostasis and the response to helminth infection. SIRT6 belongs to the NAD<sup>+</sup>-dependent deacetylases and has established diverse roles in aging, metabolism and disease. Here, we report that IEC Sirt6 deletion leads to impaired tuft cell development and type 2 immunity in response to helminth infection, thereby resulting in compromised worm expulsion. Conversely, after helminth infection, IEC SIR ...[more]

PMID: 36057627

Similar Datasets

Project description:Background & aimsIntestinal epithelial homeostasis is maintained by complex interactions among epithelial cells, commensal gut microorganisms, and immune cells. Disruption of this homeostasis is associated with disorders such as inflammatory bowel disease (IBD), but the mechanisms of this process are not clear. We investigated how Sirtuin 1 (SIRT1), a conserved mammalian NAD+-dependent protein deacetylase, senses environmental stress to alter intestinal integrity.MethodsWe performed studies of mice with disruption of Sirt1 specifically in the intestinal epithelium (SIRT1 iKO, villin-Cre+, Sirt1flox/flox mice) and control mice (villin-Cre-, Sirt1flox/flox) on a C57BL/6 background. Acute colitis was induced in some mice by addition of 2.5% dextran sodium sulfate to drinking water for 5-9 consecutive days. Some mice were given antibiotics via their drinking water for 4 weeks to deplete their microbiota. Some mice were fed with a cholestyramine-containing diet for 7 days to sequester their bile acids. Feces were collected and proportions of microbiota were analyzed by 16S rRNA amplicon sequencing and quantitative PCR. Intestines were collected from mice and gene expression profiles were compared by microarray and quantitative PCR analyses. We compared levels of specific mRNAs between colon tissues from age-matched patients with ulcerative colitis (n=10) vs without IBD (n=8, controls).ResultsMice with intestinal deletion of SIRT1 (SIRT1 iKO) had abnormal activation of Paneth cells starting at the age of 5-8 months, with increased activation of NF-κB, stress pathways, and spontaneous inflammation at 22-24 months of age, compared with control mice. SIRT1 iKO mice also had altered fecal microbiota starting at 4-6 months of age compared with control mice, in part because of altered bile acid metabolism. Moreover, SIRT1 iKO mice with defective gut microbiota developed more severe colitis than control mice. Intestinal tissues from patients with ulcerative colitis expressed significantly lower levels of SIRT1 mRNA than controls. Intestinal tissues from SIRT1 iKO mice given antibiotics, however, did not have signs of inflammation at 22-24 months of age, and did not develop more severe colitis than control mice at 4-6 months.ConclusionsIn analyses of intestinal tissues, colitis induction, and gut microbiota in mice with intestinal epithelial disruption of SIRT1, we found this protein to prevent intestinal inflammation by regulating the gut microbiota. SIRT1 might therefore be an important mediator of host-microbiome interactions. Agents designed to activate SIRT1 might be developed as treatments for IBDs.

Dataset Information

Sirtuin 6 maintains epithelial STAT6 activity to support intestinal tuft cell development and type 2 immunity.

Publications

Sirtuin 6 maintains epithelial STAT6 activity to support intestinal tuft cell development and type 2 immunity.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets