Activation of STAT6 in Intestinal Epithelial Cells Predisposes to Gut Inflammation

被引:0
|
作者
Westermann, Stefanie [1 ,2 ]
Radtke, Daniel [1 ,2 ]
Kramer, Lisa [1 ,2 ]
Wirtz, Stefan [2 ,3 ]
Voehringer, David [1 ,2 ]
机构
[1] Univ Hosp Erlangen, Dept Infect Biol, Erlangen, Germany
[2] Friedrich Alexander Univ Erlangen Nuremberg FAU, Erlangen, Germany
[3] Univ Hosp Erlangen, Dept Med 1, Erlangen, Germany
关键词
dextran sodium sulfate; gasdermin C; inflammatory bowel disease; LGR4; STAT6; ulcerative colitis; UNFOLDED PROTEIN RESPONSE; ULCERATIVE-COLITIS; TIGHT JUNCTIONS; EXPRESSION; RECOGNITION; CLAUDIN-2; IMMUNITY; IL-4; UC;
D O I
10.1002/eji.202451394
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
Ulcerative colitis (UC) is an inflammatory bowel disease (IBD) often associated with a Type 2 immune response. Although previous reports hint at a role for signal transducer and activator of transcription (STAT) 6 signaling in non-immune cells, the contribution of STAT6-activation particularly in intestinal epithelial cells (IECs) is still unknown. Dextran sodium sulfate (DSS)-induced colitis is a model for UC in mice that we applied here on animals with expression of a constitutively active version of STAT6 in IECs (VillinCre_STAT6vt mice). We report increased pathology and mortality due to enhanced and systemic inflammation in these mice. Bulk RNA sequencing of colonic tissue from na & iuml;ve VillinCre_STAT6vt mice showed differential expression of more than 140 genes compared to control mice. Gene set enrichment analysis revealed STAT6-regulated expression of the unfolded protein response, MTORC- and MYC-signaling, and protein secretion pathways. A comparison of gene expression in the colon of na & iuml;ve VillinCre_STAT6vt mice and a human single-cell RNA sequencing dataset of a patient cohort with IBD revealed overlapping changes in the epithelial and macrophage compartment compared to corresponding controls. In conclusion, we found that activation of STAT6 in the intestinal epithelium predisposes to exacerbated colitis and gut inflammation.
引用
收藏
页数:9
相关论文
共 50 条
  • [21] IFN-α activates Stat6 and leads to the formation of Stat2:: Stat6 complexes in B cells
    Gupta, S
    Jiang, M
    Pernis, AB
    JOURNAL OF IMMUNOLOGY, 1999, 163 (07): : 3834 - 3841
  • [22] Myeloid cells are primed for anti-inflammatory STAT6 signaling during inflammation
    Wermeling, Fredrik
    JOURNAL OF IMMUNOLOGY, 2015, 194
  • [23] Stat6 dependence of intestinal epithelial responses to IL-4 and nematode infection in mice.
    Madden, KB
    Whitman, L
    Urban, JF
    Finkelman, FD
    Katona, IM
    Shea-Donohue, T
    GASTROENTEROLOGY, 2000, 118 (04) : A816 - A816
  • [24] STAT6 activation in response to viral nucleic acids
    Maria Papatriantafyllou
    Nature Reviews Immunology, 2011, 11 (12) : 801 - 801
  • [25] Sirtuin 6 maintains epithelial STAT6 activity to support intestinal tuft cell development and type 2 immunity
    Xiwen Xiong
    Chenyan Yang
    Wei-Qi He
    Jiahui Yu
    Yue Xin
    Xinge Zhang
    Rong Huang
    Honghui Ma
    Shaofang Xu
    Zun Li
    Jie Ma
    Lin Xu
    Qunyi Wang
    Kaiqun Ren
    Xiaoli S. Wu
    Christopher R. Vakoc
    Jiateng Zhong
    Genshen Zhong
    Xiaofei Zhu
    Yu Song
    Hai-Bin Ruan
    Qingzhi Wang
    Nature Communications, 13
  • [26] Sirtuin 6 maintains epithelial STAT6 activity to support intestinal tuft cell development and type 2 immunity
    Xiong, Xiwen
    Yang, Chenyan
    He, Wei-Qi
    Yu, Jiahui
    Xin, Yue
    Zhang, Xinge
    Huang, Rong
    Ma, Honghui
    Xu, Shaofang
    Li, Zun
    Ma, Jie
    Xu, Lin
    Wang, Qunyi
    Ren, Kaiqun
    Wu, Xiaoli S.
    Vakoc, Christopher R.
    Zhong, Jiateng
    Zhong, Genshen
    Zhu, Xiaofei
    Song, Yu
    Ruan, Hai-Bin
    Wang, Qingzhi
    NATURE COMMUNICATIONS, 2022, 13 (01)
  • [27] GATA6 DEFICIENCY IN THE INTESTINAL EPITHELIAL CELLS EXACERBATES INTESTINAL INFLAMMATION
    Laudisi, F.
    Bevivino, G.
    Stolfi, C.
    Marafini, I.
    Troncone, E.
    Di Fusco, D.
    Di Grazia, A.
    Dinallo, V.
    Colantoni, A.
    Ortenzi, A.
    Monteleone, I.
    Monteleone, G.
    DIGESTIVE AND LIVER DISEASE, 2020, 52 : S35 - S36
  • [28] STAT6 phosphorylation inhibitors block eotaxin-3 secretion in bronchial epithelial cells
    Zhou, Li
    Kawate, Tomohiko
    Liu, Xiaorong
    Kim, Young Bae
    Zhao, Yajuan
    Feng, Guohong
    Banerji, Julian
    Nash, Huw
    Whitehurst, Charles
    Jindal, Satish
    Siddiqui, Arshad
    Seed, Brian
    Wolfe, Jia L.
    BIOORGANIC & MEDICINAL CHEMISTRY, 2012, 20 (02) : 750 - 758
  • [29] Acute inflammation primes myeloid effector cells for anti-inflammatory STAT6 signaling
    Wermeling, Fredrik
    Anthony, Robert M.
    Brombacher, Frank
    Ravetch, Jeffrey V.
    PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2013, 110 (33) : 13487 - 13491
  • [30] STAT6 Activation Confers upon T Helper Cells Resistance to Suppression by Regulatory T Cells
    Pillemer, Brendan B. L.
    Qi, Zengbiao
    Melgert, Barbro
    Oriss, Timothy B.
    Ray, Prabir
    Ray, Anuradha
    JOURNAL OF IMMUNOLOGY, 2009, 183 (01): : 155 - 163