Segal-Salto Michal, Barashi Neta, Katav Avi, Edelshtein Vicktoria, Aharon Arnon, Hashmueli Sharon, George Jacob, Maor Yaakov, Pinzani Massimo, Haberman Dan, Hall Andrew, Friedman Scott, Mor Adi
ChemomAb, Tel Aviv, Israel.
Heart Center, Kaplan Medical Center, Rehovot, Affiliated to the Hebrew University, Jerusalem, Israel.
JHEP Rep. 2020 Jan 2;2(1):100064. doi: 10.1016/j.jhepr.2019.100064. eCollection 2020 Feb.
BACKGROUND & AIMS: C-C motif chemokine ligand 24 (CCL24) is a chemokine that regulates inflammatory and fibrotic activities through its receptor, C-C motif chemokine receptor (CCR3). The aim of the study was to evaluate the involvement of the CCL24-CCR3 axis in liver fibrosis and inflammation and to assess the potential of its blockade, by a monoclonal anti-CCL24 antibody, as a therapeutic strategy for non-alcoholic steatohepatitis (NASH) and liver fibrosis.
Expression of CCL24 and CCR3 was evaluated in liver biopsies and blood samples. CCL24 involvement in NAFLD/NASH pathogenesis was assessed in knockout mouse using the methionine-choline deficient (MCD) diet experimental model. Antifibrotic and anti-inflammatory effects of CM-101 were tested in the MCD and STAM mouse models and in the thioacetamide (TAA) model in rats. Liver enzymes, liver morphology, histology and collagen deposition, as well as fibrosis- and inflammation-related protein expression were assessed. Activation of hepatic stellate cells (HSCs) was evaluated in the human LX2 cell line.
Patients with NASH and advanced NAFLD exhibited significant expression of both CCL24 and CCR3 in liver and blood samples. In the experimental MCD-diet model, knockout mice showed an attenuated liver damage response compared to wild-type mice, exhibiting reduced histological NAFLD activity scores and fibrosis, as well as lower levels of liver enzymes. Blocking CCL24 using CM-101 robustly reduced liver damage in 3 experimental animal models (MCD, STAM and TAA), as demonstrated by attenuation of liver fibrosis and NAFLD activity score. Furthermore, blocking CCL24 by CM-101 significantly inhibited CCL24-induced HSC motility, α-SMA expression and pro-collagen I secretion.
Our results reveal that blocking CCL24 significantly attenuates liver fibrosis and inflammation and may have a potential therapeutic effect in patients with NASH and/or liver fibrosis.
CCL24 is a chemokine that regulates inflammation and fibrosis. It was found to be significantly expressed in patients with non-alcoholic steatohepatitis, in whom it regulates profibrotic processes in the liver. Herein, we show that blockade of CCL24 using a monoclonal antibody robustly attenuated liver fibrosis and inflammation in animal models, thus suggesting a potential therapeutic role for an anti-CCL24 agent.
C-C基序趋化因子配体24（CCL24）是一种趋化因子，通过其受体C-C基序趋化因子受体（CCR3）调节炎症和纤维化活动。本研究的目的是评估CCL24-CCR3轴在肝纤维化和炎症中的作用，并评估用单克隆抗CCL24抗体阻断该轴作为非酒精性脂肪性肝炎（NASH）和肝纤维化治疗策略的潜力。
在肝活检组织和血液样本中评估CCL24和CCR3的表达。使用蛋氨酸-胆碱缺乏（MCD）饮食实验模型，在基因敲除小鼠中评估CCL24在非酒精性脂肪性肝病/非酒精性脂肪性肝炎发病机制中的作用。在MCD和STAM小鼠模型以及大鼠硫代乙酰胺（TAA）模型中测试CM-101的抗纤维化和抗炎作用。评估肝酶、肝脏形态、组织学和胶原沉积，以及与纤维化和炎症相关的蛋白表达。在人LX2细胞系中评估肝星状细胞（HSC）的激活。
NASH和晚期非酒精性脂肪性肝病患者的肝脏和血液样本中CCL24和CCR3均有显著表达。在实验性MCD饮食模型中，与野生型小鼠相比，基因敲除小鼠的肝损伤反应减弱，组织学非酒精性脂肪性肝病活动评分和纤维化降低，肝酶水平也较低。使用CM-101阻断CCL24可显著降低3种实验动物模型（MCD、STAM和TAA）中的肝损伤，肝纤维化和非酒精性脂肪性肝病活动评分降低证明了这一点。此外，CM-101阻断CCL24可显著抑制CCL24诱导的肝星状细胞迁移、α-平滑肌肌动蛋白表达和I型前胶原分泌。
我们的结果表明，阻断CCL24可显著减轻肝纤维化和炎症，对NASH和/或肝纤维化患者可能具有潜在治疗作用。
CCL24是一种调节炎症和纤维化的趋化因子。在非酒精性脂肪性肝炎患者中发现其有显著表达，它在肝脏中调节促纤维化过程。在此，我们表明使用单克隆抗体阻断CCL24可显著减轻动物模型中的肝纤维化和炎症，因此提示抗CCL24药物具有潜在治疗作用。
