Department of Anesthesiology, UTHealth McGovern Medical School, Houston, United States.
Center for Life Sciences, School of Life Sciences, Yunnan University, Kunming, China.
Elife. 2021 Jun 10;10:e68571. doi: 10.7554/eLife.68571.
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.
Mice were fasted overnight before intraperitoneally () 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.
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, 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 mice resulted in much lower numbers of hepatic platelets and liver injury than WT mice, a phenotype similar to that in mice. Recombinant Chi3l1 could restore hepatic platelet accumulation and AILI in mice, but not in mice. Importantly, we generated anti-Chi3l1 monoclonal antibodies and demonstrated that they could effectively inhibit hepatic platelet accumulation and AILI.
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.
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.
肝血小板聚集有助于对乙酰氨基酚（APAP）诱导的肝损伤（AILI）。然而，目前对于血小板向肝脏募集的分子途径知之甚少，也不清楚是否可以通过靶向这些途径来减轻 AILI。
雄性小鼠给予 210mg/kg 对乙酰氨基酚，雌性小鼠给予 325mg/kg 对乙酰氨基酚，隔夜禁食后腹腔内注射。在小鼠和过量服用对乙酰氨基酚的患者中确定与库普弗细胞结合的血小板。在治疗环境中确定 α-几丁质酶 3 样-1（α-Chi3l1）对减轻 AILI 的影响，并分析肝损伤。
本研究揭示了 Chi3l1 在 AILI 期间肝内血小板募集中的关键作用。过量服用对乙酰氨基酚的患者和小鼠中观察到 Chi3l1 和血小板在肝脏中增加。与野生型（WT）小鼠相比，Chi3l1 缺陷型（Chi3l1 -/-）小鼠发生 AILI 时明显减轻，肝内血小板聚集明显减少。机制研究表明，Chi3l1 通过巨噬细胞上的 CD44 发出信号，诱导 podoplanin 表达，通过 C 型凝集素样受体 2 介导血小板募集。此外，与 WT 小鼠相比，APAP 处理的 Chi3l1 -/-小鼠的肝内血小板数量和肝损伤明显减少，表型与 Chi3l1 -/-小鼠相似。重组 Chi3l1 可恢复 Chi3l1 -/-小鼠的肝内血小板聚集和 AILI，但不能恢复 Chi3l1 -/-小鼠的聚集和 AILI。重要的是，我们生成了抗 Chi3l1 单克隆抗体，并证明它们可以有效抑制肝内血小板聚集和 AILI。
我们揭示了 Chi3l1/CD44 轴作为介导 APAP 诱导的肝内血小板募集和组织损伤的关键途径。我们证明了靶向 Chi3l1 治疗 AILI 的可行性和潜力。
ZS 获得国家自然科学基金（32071129）的资助。FWL 获得 NIH（GM123261）的资助。ALFSG 获得 NIDDK（DK 058369）的资助。ZA 获得 CPRIT（RP150551 和 RP190561）和 Welch 基金会（AU-0042-20030616）的资助。CJ 获得 NIH（DK122708、DK109574、DK121330 和 DK122796）的资助和德克萨斯大学系统转化 STARs 奖的支持。本工作的部分内容得到了 Michael E. DeBakey VA 医疗中心的资源和设施以及美国退伍军人事务部 I01 BX002551（设备、人员、用品）的支持。内容不代表美国退伍军人事务部或美国政府的观点。
