Inhibition of intrahepatic monocyte recruitment by Cenicriviroc and extracellular matrix degradation by MMP1 synergistically attenuate liver inflammation and fibrogenesis in vivo

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 CCl₄-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.

CCR2/CCR5 antagonist; Liver fibrosis; Liver inflammation; Matrix metalloproteinase 1; Monocyte recruitment.