دورية أكاديمية
Chitinase 3-like-1 contributes to acetaminophen-induced liver injury by promoting hepatic platelet recruitment
| العنوان: | Chitinase 3-like-1 contributes to acetaminophen-induced liver injury by promoting hepatic platelet recruitment |
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| المؤلفون: | Zhao Shan, Leike Li, Constance Lynn Atkins, Meng Wang, Yankai Wen, Jongmin Jeong, Nicolas F Moreno, Dechun Feng, Xun Gui, Ningyan Zhang, Chun Geun Lee, Jack A Elias, William M Lee, Bin Gao, Fong Wilson Lam, Zhiqiang An, Cynthia Ju |
| المصدر: | eLife, Vol 10 (2021) |
| بيانات النشر: | eLife Sciences Publications Ltd, 2021. |
| سنة النشر: | 2021 |
| المجموعة: | LCC:Medicine LCC:Science LCC:Biology (General) |
| مصطلحات موضوعية: | drug-induced liver injury, platelets, kupffer cells, chi3l1, acetaminophen, Medicine, Science, Biology (General), QH301-705.5 |
| الوصف: | 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. |
| نوع الوثيقة: | article |
| وصف الملف: | electronic resource |
| اللغة: | English |
| تدمد: | 2050-084X |
| Relation: | https://elifesciences.org/articles/68571; https://doaj.org/toc/2050-084X |
| DOI: | 10.7554/eLife.68571 |
| URL الوصول: | https://doaj.org/article/87bb9242be7e4ea1a0cab9c6806e6563 |
| رقم الأكسشن: | edsdoj.87bb9242be7e4ea1a0cab9c6806e6563 |
| قاعدة البيانات: | Directory of Open Access Journals |
Full Text Finder | تدمد: | 2050084X |
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| DOI: | 10.7554/eLife.68571 |