Endoplasmic reticulum stress in the intestinal epithelium initiates purine metabolite synthesis and promotes Th17 cell differentiation in the gut

被引：46

作者：

Duan, Jinzhi ^{[1
]}

Matute, Juan D. ^{[1
,2
]}

Unger, Lukas W. ^{[3
,4
,5
]}

Hanley, Thomas ^{[1
]}

Schnell, Alexandra ^{[8
]}

Lin, Xi

Krupka, Niklas ^{[1
]}

Griebel, Paul ^{[1
]}

Lambden, Conner ^{[8
]}

Sit, Brandon ^{[9
]}

Grootjans, Joep ^{[10
]}

Pyzik, Michal ^{[1
]}

Sommer, Felix ^{[11
]}

Kaiser, Sina ^{[11
]}

Falk-Paulsen, Maren ^{[11
]}

Grasberger, Helmut ^{[12
]}

Kao, John Y. ^{[12
]}

Fuhrer, Tobias ^{[13
]}

Li, Hai ^{[14
]}

Paik, Donggi ^{[15
]}

Lee, Yunjin ^{[15
]}

Refetoff, Samuel ^{[5
,16
]}

Glickman, Jonathan N. ^{[6
,7
,17
]}

Paton, Adrienne W. ^{[8
,18
]}

Bry, Lynn ^{[19
]}

Paton, James C. ^{[8
,18
]}

Sauer, Uwe ^{[13
]}

Macpherson, Andrew J. ^{[14
]}

Rosenstiel, Philip ^{[11
]}

Kuchroo, Vijay K. ^{[6
,7
,8
]}

Waldor, Matthew K. ^{[9
,20
]}

Huh, Jun R. ^{[15
]}

Kaser, Arthur ^{[3
,4
]}

Blumberg, Richard S. ^{[1
]}

机构：

[1] Harvard Med Sch, Brigham & Womens Hosp, Dept Med, Div Gastroenterol, Boston, MA 02115 USA

[2] Harvard Med Sch, Massachusetts Gen Hosp, Dept Pediat, Div Newborn Med, Boston, MA 02114 USA

[3] Univ Cambridge, Cambridge Inst Therapeut Immunol & Infect Dis CITI, Jeffrey Cheah Biomed Ctr, Dept Med, Cambridge CB2 0AW, England

[4] Univ Cambridge, Dept Med, Div Gastroenterol & Hepatol, Cambridge CB2 0AW, England

[5] Med Univ Vienna, Dept Gen Surg, Div Visceral Surg, A-1090 Vienna, Austria

[6] Harvard Med Sch, Evergrande Ctr Immunol Dis, Boston, MA 02115 USA

[7] Brigham & Womens Hosp, Boston, MA 02115 USA

[8] Harvard Univ, Broad Inst, Cambridge, MA 02142 USA

[9] Brigham & Womens Hosp, Div Infect Dis, Boston, MA 02115 USA

[10] Amsterdam UMC, Locat AMC, Dept Gastroenterol & Hepatol, Amsterdam Gastroenterol Endocrinol Metab, NL-1105 AZ Amsterdam, Netherlands

[11] Univ Kiel, Inst Clin Mol Biol, D-24105 Kiel, Germany

[12] Univ Michigan Med Sch, Dept Internal Med, Div Gastroenterol & Hepatol, Michigan Med, Ann Arbor, MI 48109 USA

[13] Swiss Fed Inst Technol, Inst Mol Syst Biol, Zurich, Switzerland

[14] Univ Bern, Bern Univ Hosp, Inselspital, Dept Visceral Surg & Med, Bern, Switzerland

[15] Harvard Med Sch, Blavatnik Inst, Dept Immunol, Boston, MA 02115 USA

[16] Univ Chicago, Dept Med Pediat & Comm Genet, Chicago, IL 60637 USA

[17] Harvard Med Sch, Beth Israel Deaconess Med Ctr, Dept Pathol, Boston, MA 02215 USA

[18] Univ Adelaide, Res Ctr Infect Dis, Dept Mol & Biomed Sci, Adelaide 5005, Australia

[19] Harvard Med Sch, Brigham & Womens Hosp, Massachusetts Host Microbiome Ctr, Dept Pathol, Boston, MA 02115 USA

[20] Howard Hughes Med Inst, Boston, MA 02115 USA

来源：

IMMUNITY | 2023年 / 56卷 / 05期

基金：

欧洲研究理事会; 英国惠康基金; 奥地利科学基金会; 欧盟地平线“2020”;

关键词：

CITROBACTER-RODENTIUM; ER STRESS; INFLAMMATION; T(H)17; INDUCTION; AUTOPHAGY; DEFICIENT; CYTOKINE; IMMUNITY; PATHWAYS;

D O I：

10.1016/j.immuni.2023.02.018

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

100102 ;

摘要：

Intestinal IL-17-producing T helper (Th17) cells are dependent on adherent microbes in the gut for their devel-opment. However, how microbial adherence to intestinal epithelial cells (IECs) promotes Th17 cell differen-tiation remains enigmatic. Here, we found that Th17 cell-inducing gut bacteria generated an unfolded protein response (UPR) in IECs. Furthermore, subtilase cytotoxin expression or genetic removal of X-box binding protein 1 (Xbp1) in IECs caused a UPR and increased Th17 cells, even in antibiotic-treated or germ-free con-ditions. Mechanistically, UPR activation in IECs enhanced their production of both reactive oxygen species (ROS) and purine metabolites. Treating mice with N-acetyl-cysteine or allopurinol to reduce ROS production and xanthine, respectively, decreased Th17 cells that were associated with an elevated UPR. Th17-related genes also correlated with ER stress and the UPR in humans with inflammatory bowel disease. Overall, we identify a mechanism of intestinal Th17 cell differentiation that emerges from an IEC-associated UPR.

引用

页码：1115 / +

页数：27

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