Chitinase 3-like-1 contributes to acetaminophen-induced liver injury by promoting hepatic platelet recruitment

作者：Zhao Shan, Leike Li, Constance L. Atkins, Meng Wang, Yankai Wen, Jong‐Min Jeong, Nicolas F. Moreno, Dechun Feng, Xun Gui, Ningyan Zhang, Chun Geun Lee, Jack A. Elias, William M. Lee, Bin Gao, Fong Lam, Zhiqiang An, Cynthia Ju · 发表于：eLife · 年份：2021 · DOI：10.7554/elife.68571 · 被引用次数：82 · 研究领域：Studies on Chitinases and Chitosanases、Drug-Induced Hepatotoxicity and Protection、Immune cells in cancer

Background: Hepatic platelet accumulation contributes to acetaminophen (APAP)-induced liver injury (AILI). However, little is known about the molecular pathways involved in platelet recruitment to the liver and whether targeting such pathways could attenuate AILI. Methods: Mice were fasted overnight before intraperitoneally ( i.p. ) injected with APAP at a dose of 210 mg/kg for male mice and 325 mg/kg for female mice. Platelets adherent to Kupffer cells were determined in both mice and patients overdosed with APAP. The impact of α-chitinase 3-like-1 (α-Chi3l1) on alleviation of AILI was determined in a therapeutic setting, and liver injury was analyzed. Results: The present study unveiled a critical role of Chi3l1 in hepatic platelet recruitment during AILI. Increased Chi3l1 and platelets in the liver were observed in patients and mice overdosed with APAP. Compared to wild-type (WT) mice, Chil1 -/- mice developed attenuated AILI with markedly reduced hepatic platelet accumulation. Mechanistic studies revealed that Chi3l1 signaled through CD44 on macrophages to induce podoplanin expression, which mediated platelet recruitment through C-type lectin-like receptor 2. Moreover, APAP treatment of Cd44 -/- mice resulted in much lower numbers of hepatic platelets and liver injury than WT mice, a phenotype similar to that in Chil1 -/- mice. Recombinant Chi3l1 could restore hepatic platelet accumulation and AILI in Chil1 -/- mice, but not in Cd44 -/- mice. Importantly, we generated ant...