Personalized Diagnostics and Therapeutics, Department of Bioengineering Technologies, Faculty of Science and Technology, Technical Medical Centre, University of Twente, Carre 4419, Drienerlolaan 5, 7522 NB, Enschede, The Netherlands.
Sci Rep. 2024 Jul 23;14(1):16897. doi: 10.1038/s41598-024-67926-6.
The chemokine (CCL)-chemokine receptor (CCR2) interaction, importantly CCL2-CCR2, involved in the intrahepatic recruitment of monocytes upon liver injury promotes liver fibrosis. CCL2-CCR2 antagonism using Cenicriviroc (CVC) showed promising results in several preclinical studies. Unfortunately, CVC failed in phase III clinical trials due to lack of efficacy to treat liver fibrosis. Lack of efficacy could be attributed to the fact that macrophages are also involved in disease resolution by secreting matrix metalloproteinases (MMPs) to degrade extracellular matrix (ECM), thereby inhibiting hepatic stellate cells (HSCs) activation. HSCs are the key pathogenic cell types in liver fibrosis that secrete excessive amounts of ECM causing liver stiffening and liver dysfunction. Knowing the detrimental role of intrahepatic monocyte recruitment, ECM, and HSCs activation during liver injury, we hypothesize that combining CVC and MMP (MMP1) could reverse liver fibrosis. We evaluated the effects of CVC, MMP1 and CVC + MMP1 in vitro and in vivo in CCl-induced liver injury mouse model. We observed that CVC + MMP1 inhibited macrophage migration, and TGF-β induced collagen-I expression in fibroblasts in vitro. In vivo, MMP1 + CVC significantly inhibited normalized liver weights, and improved liver function without any adverse effects. Moreover, MMP1 + CVC inhibited monocyte infiltration and liver inflammation as confirmed by F4/80 and CD11b staining, and TNFα gene expression. MMP1 + CVC also ameliorated liver fibrogenesis via inhibiting HSCs activation as assessed by collagen-I staining and collagen-I and α-SMA mRNA expression. In conclusion, we demonstrated that a combination therapeutic approach by combining CVC and MMP1 to inhibit intrahepatic monocyte recruitment and increasing collagen degradation respectively ameliorate liver inflammation and fibrosis.
趋化因子（CCL）-趋化因子受体（CCR2）相互作用，特别是 CCL2-CCR2，参与肝损伤时单核细胞在肝内的募集，促进肝纤维化。趋化因子 CCL2-CCR2 拮抗剂 Cenicriviroc（CVC）在几项临床前研究中显示出良好的效果。不幸的是，由于缺乏治疗肝纤维化的疗效，CVC 在 III 期临床试验中失败。疗效不佳可能归因于以下事实：巨噬细胞也通过分泌基质金属蛋白酶（MMPs）降解细胞外基质（ECM）参与疾病的解决，从而抑制肝星状细胞（HSCs）的激活。HSCs 是肝纤维化的关键致病细胞类型，其过度分泌 ECM 导致肝僵硬和肝功能障碍。鉴于肝损伤时肝内单核细胞募集、ECM 和 HSCs 激活的有害作用，我们假设将 CVC 和 MMP（MMP1）联合使用可能逆转肝纤维化。我们评估了 CVC、MMP1 和 CVC+MMP1 在 CCl4 诱导的肝损伤小鼠模型中的体内和体外的作用。我们观察到 CVC+MMP1 抑制了体外巨噬细胞迁移和 TGF-β诱导的成纤维细胞中胶原-I 的表达。在体内，MMP1+CVC 显著抑制了正常化的肝重，并改善了肝功能，而没有任何不良反应。此外，MMP1+CVC 通过 F4/80 和 CD11b 染色和 TNFα 基因表达抑制单核细胞浸润和肝炎症得到证实。MMP1+CVC 还通过抑制 HSCs 激活来改善肝纤维化，如胶原-I 染色和胶原-I 和α-SMA mRNA 表达所示。总之，我们证明了通过联合 CVC 和 MMP1 抑制肝内单核细胞募集和增加胶原降解的联合治疗方法分别改善肝炎症和纤维化。
