Department of Anesthesiology , McGovern Medical School , University of Texas Health Science Center at Houston , Houston , Texas , USA.
School of Basic Medical Science , Anhui Medical University , Hefei , Anhui , China.
Hepatology. 2023 Feb 1;77(2):456-465. doi: 10.1002/hep.32609. Epub 2022 Jul 15.
A better understanding of the underlying mechanism of acetaminophen (APAP)-induced liver injury (AILI) remains an important endeavor to develop therapeutic approaches. Eosinophils have been detected in liver biopsies of patients with APAP overdose. We recently demonstrated a profound protective role of eosinophils against AILI; however, the molecular mechanism had not been elucidated.
In agreement with our previous data from experiments using genetic deletion of eosinophils, we found that depletion of eosinophils in wild-type (WT) mice by an anti-IL-15 antibody resulted in exacerbated AILI. Moreover, adoptive transfer of eosinophils significantly reduced liver injury and mortality rate in WT mice. Mechanistic studies using eosinophil-specific IL-4/IL-13 knockout mice demonstrated that these cytokines, through inhibiting interferon-γ, mediated the hepatoprotective function of eosinophils. Reverse phase protein array analyses and in vitro experiments using various inhibitors demonstrated that IL-33 stimulation of eosinophils activated p38 mitogen-activated protein kinase (MAPK), and in turn, cyclooxygenases (COX), which triggered NF-κB-mediated IL-4/IL-13 production. In vivo adoptive transfer experiments showed that in contrast to naive eosinophils, those pretreated with COX inhibitors failed to attenuate AILI.
The current study revealed that eosinophil-derived IL-4/IL-13 accounted for the hepatoprotective effect of eosinophils during AILI. The data demonstrated that the p38 MAPK/COX/NF-κB signaling cascade played a critical role in inducing IL-4/IL-13 production by eosinophils in response to IL-33.
深入了解对乙酰氨基酚（APAP）诱导的肝损伤（AILI）的潜在机制仍是开发治疗方法的重要努力。在 APAP 过量患者的肝活检中已检测到嗜酸性粒细胞。我们最近证明了嗜酸性粒细胞对 AILI 具有深远的保护作用；然而，其分子机制尚未阐明。
与我们之前使用基因敲除嗜酸性粒细胞进行的实验数据一致，我们发现，用抗白细胞介素-15 抗体耗尽野生型（WT）小鼠中的嗜酸性粒细胞会导致 AILI 加重。此外，嗜酸性粒细胞的过继转移显著降低了 WT 小鼠的肝损伤和死亡率。使用嗜酸性粒细胞特异性白细胞介素-4/白细胞介素-13 敲除小鼠进行的机制研究表明，这些细胞因子通过抑制干扰素-γ，介导了嗜酸性粒细胞的肝保护功能。使用各种抑制剂的反相蛋白阵列分析和体外实验表明，IL-33 刺激嗜酸性粒细胞激活丝裂原活化蛋白激酶（MAPK），继而激活环氧化酶（COX），触发 NF-κB 介导的白细胞介素-4/白细胞介素-13 产生。体内过继转移实验表明，与未处理的嗜酸性粒细胞相比，经 COX 抑制剂预处理的嗜酸性粒细胞无法减轻 AILI。
本研究揭示了嗜酸性粒细胞衍生的白细胞介素-4/白细胞介素-13 是嗜酸性粒细胞在 AILI 期间发挥肝保护作用的原因。数据表明，p38 MAPK/COX/NF-κB 信号通路在 IL-33 刺激嗜酸性粒细胞产生白细胞介素-4/白细胞介素-13 中起关键作用。
