Angiopoietin-like 4 shapes the intrahepatic T-cell landscape via eIF2α signalingduring steatohepatitis in diet-induced NAFLD.
LOW, Z. S.; CHUA, D.; CHENG, H. S.; TEE, R.; SAHIB, W. R.; BALL, C.; SAHIB, N. B. E.; NG, S. S.; QU, J.; LIU, Y.; HONG, H.; CAI, C.; RAO, N. C. L.; WEE, A.; MUTHIAH, M. D.; BICHLER, Z.; MICKELSON, B.; LEE, J. Q.; NG, A. S.; YIP, Y. S.; VOS, M. I. G.; LIM, D. X. E.; CHITTEZHATH, M.; YALIGAR, J.; VERMA, S. K.; POPTANI, H.; GUAN, X. L.; VELAN, S. S.; ALI, Y.; LI, L.; TAN, N. S.; WAHLI, W.
Show abstract
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 eIF2 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 eIF2 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.
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