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

eLife

Meng Wang¹  Cynthia Ju¹  Constance Lynn Atkins¹  Jongmin Jeong¹  Nicolas F Moreno¹  Yankai Wen¹  Zhao Shan²  William M Lee³  Fong Wilson Lam⁴  Bin Gao⁵  Dechun Feng⁵  Chun Geun Lee⁶  Jack A Elias⁷  Leike Li⁸  Zhiqiang An⁸  Ningyan Zhang⁸  Xun Gui⁸ 

[1] Department of Anesthesiology, UTHealth McGovern Medical School, Houston, United States;Department of Anesthesiology, UTHealth McGovern Medical School, Houston, United States;Center for Life Sciences, School of Life Sciences, Yunnan University, Kunming, China;Division of Digestive and Liver Diseases, Department of Internal Medicine, University of Texas Southwestern Med School, Dallas, United States;Division of Pediatric Critical Care Medicine, Baylor College of Medicine, Houston, United States;Center for Translation Research on Inflammatory Diseases, Michael E. DeBakey Veterans Affairs Medical Center, Houston, United States;Laboratory of Liver Disease, National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, United States;Molecular Microbiology and Immunology, Brown University, Providence, United States;Molecular Microbiology and Immunology, Brown University, Providence, United States;Division of Medicine and Biological Sciences, Warren Alpert School of Medicine, Brown University, Providence, United States;Texas Therapeutics Institute, UTHealth McGovern Medical School, Houston, United States;

关键词: drug-induced liver injury;    platelets;    kupffer cells;    chi3l1;    acetaminophen;    Mouse;   

DOI  :  10.7554/eLife.68571

来源: eLife Sciences Publications, Ltd

【 摘 要 】

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 anti-Chi3l1 monoclonal antibodies and demonstrated that they could effectively inhibit hepatic platelet accumulation and AILI.Conclusions:We uncovered the Chi3l1/CD44 axis as a critical pathway mediating APAP-induced hepatic platelet recruitment and tissue injury. We demonstrated the feasibility and potential of targeting Chi3l1 to treat AILI.Funding:ZS received funding from NSFC (32071129). FWL received funding from NIH (GM123261). ALFSG received funding from NIDDK (DK 058369). ZA received funding from CPRIT (RP150551 and RP190561) and the Welch Foundation (AU-0042–20030616). CJ received funding from NIH (DK122708, DK109574, DK121330, and DK122796) and support from a University of Texas System Translational STARs award. Portions of this work were supported with resources and the use of facilities of the Michael E. DeBakey VA Medical Center and funding from Department of Veterans Affairs I01 BX002551 (Equipment, Personnel, Supplies). The contents do not represent the views of the US Department of Veterans Affairs or the US Government.

【 授权许可】

CC BY