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Job Title
instructor
Academic Rank
Instructor
Department
Medicine
Authors
Jinzhi Duan1, Juan D. Matute1,2, Lukas W. Unger3,4, Thomas Hanley1, Alexandra Schnell1 , Xi Lin1, Niklas Krupka1, Paul Griebel1, Conner Lambden1, Brandon Sit1, Joep Grootjans1, Michal Pyzik1, Felix Sommer5, Sina Kaiser5, Maren Falk-Paulsen5, Helmut Grasberger6, John Y. Kao6, Tobias Fuhrer7, Hai Li8, Donggi Paik9, Yunjin Lee13, Samuel Refetoff10, Jonathan N. Glickman9, Adrienne W. Paton11, Lynn Bry1, James C. Paton11, Uwe Sauer7, Andrew J. Macpherson8, Philip Rosenstiel5, Vijay K. Kuchroo1, Matthew K. Waldor1, Jun R. Huh9, Arthur Kaser3, Richard S. Blumberg1
Principal Investigator
Richard S. Blumberg
Categories
Tags
Intestinal IL-17-producing T helper cells (Th17) are dependent on adherent microbes in the gut for their development. However, how microbial adherence to intestinal epithelial cells (IECs) promotes Th17 cell differentiation 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 conditions. 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.
In our bodies, there are special cells in the intestine called Th17 cells that help protect our gut. These cells need the help of tiny organisms called gut bacteria. We found that some gut bacteria can trigger an ‘alarm system’ in the cells lining our intestines. This alarm system, known as the unfolded protein response (UPR), helps Th17 cells grow.Surprisingly, when we made this alarm system more active in these intestinal cells or removed a specific protein called X-box binding protein 1 (Xbp1), it led to even more Th17 cells. This happened even when we removed all the bacteria from the intestines with antibiotics or when the intestines were germ-free.The alarm system in these intestinal cells works by producing substances like ‘reactive oxygen species’ (ROS) and ‘purine metabolites,’ which help Th17 cells grow. When we gave mice medications to reduce these substances, it decreased the number of Th17 cells. We also found a link between this alarm system and a group of genes important for Th17 cells, which were more active in people with inflammatory bowel disease.
