| Autor: |
Zun Siong Low, Damien Chua, Hong Sheng Cheng, Rachel Tee, Wei Ren Tan, Christopher Ball, Norliza Binte Esmail Sahib, Ser Sue Ng, Jing Qu, Yingzi Liu, Haiyu Hong, Chaonong Cai, Nandini C. L. Rao, Aileen Wee, Mark D. Muthiah, Zoë Bichler, Barbara Mickelson, Jia Qi Lee, Mei Suen Kong, Vanessa S.Y. Tay, Zhuang Yan, Jiapeng Chen, Aik Seng Ng, Yun Sheng Yip, Marcus Ivan Gerard Vos, Debbie Xiu En Lim, Manesh Chittezhath, Jadegoud Yaligar, Sanjay Kumar Verma, Harish Poptani, Xue Li Guan, S. Sendhil Velan, Yusuf Ali, Liang Li, Nguan Soon Tan, Walter Wahli |
| Rok vydání: |
2023 |
| DOI: |
10.1101/2023.01.10.523354 |
| Popis: |
Adaptive T-cell immune response is essential in conferring protective immunity, a process requiring tight cellular homeostasis regulation. Pathological intrahepatic T-cell landscape has a role in NAFLD propagation; however, its activation remains unknown. To address this gap, we extensively characterized a novel diet-induced NAFLD murine model (LIDPAD) featuring key phenotypic and genetic attributes reflective of human NAFLD. Comparative transcriptomic-guided staging of human and murine NASH reinforced the robustness of LIDPAD in recapitulating critical transitory stages of human NAFLD. We found that angiopoietin-like 4 (Angptl4) shapes activation of the intrahepatic T-cell landscape through the modulation of eIF2α signaling during fibrosis. Single-immune cell analysis and hepatic transcriptomics during fibrosis, and kinase inhibitor screening confirmed that Angptl4 orchestrates the hyperactivation of intrahepatic adaptive immunity via eIF2α signaling. Consistently, immunoblocking of cAngplt4 reduces T-cell overactivation, delaying disease aggravation. Taken together, Angptl4 is a crucial determinant in shaping intrahepatic adaptive immunity during fibrosis in NAFLD. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
|
