Maraviroc Prevents HCC Development by Suppressing Macrophages and the Liver Progenitor Cell Response in a Murine Chronic Liver Disease Model

Abstract

Maraviroc (MVC), a CCR5 antagonist, reduces liver fibrosis, injury and tumour burden in mice fed a hepatocarcinogenic diet, suggesting it has potential as a cancer therapeutic. We investigated the effect of MVC on liver progenitor cells (LPCs) and macrophages as both have a role in hepatocarcinogenesis. Mice were fed the hepatocarcinogenic choline-deficient, ethionine-supplemented diet (CDE) ± MVC, and immunohistochemistry, RNA and protein expression were used to determine LPC and macrophage abundance, migration and related molecular mechanisms. MVC reduced LPC numbers in CDE mice by 54%, with a smaller reduction seen in macrophages. Transcript and protein abundance of LPC-associated markers correlated with this reduction. The CDE diet activated phosphorylation of AKT and STAT3 and was inhibited by MVC. LPCs did not express Ccr5 in our model; in contrast, macrophages expressed high levels of this receptor, suggesting the effect of MVC is mediated by targeting macrophages. MVC reduced CD45+ cells and macrophage migration in liver and blocked the CDE-induced transition of liver macrophages from an M1- to M2-tumour-associated macrophage (TAM) phenotype. These findings suggest MVC has potential as a re-purposed therapeutic agent for treating chronic liver diseases where M2-TAM and LPC numbers are increased, and the incidence of HCC is enhanced.

Cysteine–Cysteine Motif Chemokine Receptor 5 Expression in Letrozole-Induced Polycystic Ovary Syndrome Mice

“…Further, the autosomal recessive deficiencies of CCR5 underlie resistance to HIV-1 [ 22 ]. Maraviroc, a CCR5 antagonist, reduces liver fibrosis and injury, chronic liver disease, and tumor burden in mice fed a hepatocarcinogenic diet [ 23 ]. Another recent study demonstrated that CCR5 expression in adipose tissue and peripheral blood mononuclear cells was significantly higher in women with PCOS compared with women in the control group [ 24 ].…”

Polysaccharides and Their Derivatives as Potential Antiviral Molecules

“…Antiviral drugs may have an inhibitory effect on the entire replication cycle. They can be classified according to the stage to which they are targeted: cell entry inhibitors [52][53][54][55][56][57], replicant inhibitors [40,[58][59][60][61][62][63][64] and assembly, maturation, and release inhibitors [65][66][67][68][69]. Within a therapeutic class, antiviral agents can have different effects.…”

“…There are different types of inhibitors. Maraviroc inhibits HIV entry by binding selectively and specifically to the CCR5 receptor on the CD4 cell surface [52]. Enfuvirtide is a synthetic peptide that blocks the HIV envelope from fusing with the CD4 cell membrane [53].…”

CCR5 deficiency normalizes TIMP levels, working memory, and gamma oscillation power in APOE4 targeted replacement mice

“…CCL5 has also been linked to excess ECM deposition (Passman et al ., 2021; Bonnard et al ., 2022). Brain ECM exists in diffuse and condensed forms and both types can restrict neuroplasticity (Miyata & Kitagawa, 2017).…”

“…In the present study, our aim was to explore the possibility that CCL5 and other potential ECM effectors that limit pyramidal arbor, gamma power and SWR abundance may be elevated in APOE4 human and TR mice. We also investigated the possibility that reductions in CCR5, a molecule linked to excess ECM deposition in other end organs as well as reduced plasticity in the brain (Passman et al ., 2021; Bonnard et al ., 2022; Shen et al ., 2022), might rescue biochemical, neurophysiological and/or behavioral alterations associated with this allele.…”