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.

doi:10.1101/2023.01.10.523354

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bioRxiv · 10.1101/2023.01.10.523354

Angiopoietin-like 4 shapes the intrahepatic T-cell landscape via eIF2α signalingduring steatohepatitis in diet-induced NAFLD.

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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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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.. 2023-01-12. Angiopoietin-like 4 shapes the intrahepatic T-cell landscape via eIF2α signalingduring steatohepatitis in diet-induced NAFLD.. https://doi.org/10.1101/2023.01.10.523354

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