Angiopoietin-like 4 shapes the intrahepatic T-cell landscape via eIF2α signaling during steatohepatitis in diet-induced NAFLD
Author:
Low Zun Siong, Chua DamienORCID, Cheng Hong Sheng, Tee Rachel, Tan Wei Ren, Ball Christopher, Sahib Norliza Binte Esmail, Ng Ser Sue, Qu Jing, Liu Yingzi, Hong Haiyu, Cai Chaonong, Rao Nandini C. L., Wee Aileen, Muthiah Mark D., Bichler Zoë, Mickelson Barbara, Lee Jia Qi, Kong Mei Suen, Tay Vanessa S.Y., Yan Zhuang, Chen Jiapeng, Ng Aik Seng, Yip Yun Sheng, Vos Marcus Ivan Gerard, Lim Debbie Xiu En, Chittezhath Manesh, Yaligar Jadegoud, Verma Sanjay Kumar, Poptani Harish, Guan Xue Li, Velan S. Sendhil, Ali Yusuf, Li Liang, Tan Nguan SoonORCID, Wahli Walter
Abstract
ABSTRACTAdaptive 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.
Publisher
Cold Spring Harbor Laboratory
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