C-C motif chemokine receptor 2 inhibition reduces liver fibrosis by restoring the immune cell landscape

by Selleckchem | Aug 08 2023

The accumulation of extracellular matrix (ECM) proteins in the liver leads to liver fibrosis and end-stage liver cirrhosis. C-C motif chemokine receptor 2 (CCR2) is an attractive target for treating liver fibrosis. However, limited investigations have been conducted to explore the mechanism by which CCR2 inhibition reduces ECM accumulation and liver fibrosis, which is the focus of this study. Liver injury and liver fibrosis were induced by carbon tetrachloride (CCl4) in wild-type mice and Ccr2 knockout (Ccr2-/-) mice. CCR2 was upregulated in murine and human fibrotic livers. Pharmacological CCR2 inhibition with cenicriviroc (CVC) reduced ECM accumulation and liver fibrosis in prevention and treatment administration. In single-cell RNA sequencing (scRNA-seq), CVC was demonstrated to alleviate liver fibrosis by restoring the macrophage and neutrophil landscape. CVC administration and CCR2 deletion can also inhibit the hepatic accumulation of inflammatory FSCN1+ macrophages and HERC6+ neutrophils. Pathway analysis indicated that the STAT1, NFκB, and ERK signaling pathways might be involved in the antifibrotic effects of CVC. Consistently, Ccr2 knockout decreased phosphorylated STAT1, NFκB, and ERK in the liver. In vitro, CVC could transcriptionally suppress crucial profibrotic genes (Xaf1, Slfn4, Slfn8, Ifi213, and Il1β) in macrophages by inactivating the STAT1/NFκB/ERK signaling pathways. In conclusion, this study depicts a novel mechanism by which CVC alleviates ECM accumulation in liver fibrosis by restoring the immune cell landscape. CVC can inhibit profibrotic gene transcription via inactivating the CCR2-STAT1/NFκB/ERK signaling pathways.

Comments:

The study you mentioned focuses on investigating the mechanism by which CCR2 inhibition reduces extracellular matrix (ECM) accumulation and liver fibrosis. Liver fibrosis occurs when there is an excessive accumulation of ECM proteins in the liver, leading to end-stage liver cirrhosis. The researchers used carbon tetrachloride (CCl4) to induce liver injury and fibrosis in both wild-type mice and mice lacking the Ccr2 gene (Ccr2-/-). They found that CCR2 was upregulated in both murine and human fibrotic livers.

To explore the therapeutic potential of CCR2 inhibition, the researchers used a pharmacological inhibitor called cenicriviroc (CVC). They administered CVC to the mice either as a preventive measure or as a treatment. They observed that CVC reduced ECM accumulation and liver fibrosis in both cases.

To gain insights into the cellular changes associated with CVC treatment, the researchers performed single-cell RNA sequencing (scRNA-seq). They found that CVC treatment restored the macrophage and neutrophil landscape in the liver, contributing to the alleviation of liver fibrosis. Additionally, CVC administration and Ccr2 deletion inhibited the accumulation of inflammatory macrophages expressing FSCN1 and neutrophils expressing HERC6 in the liver.

Pathway analysis suggested that the STAT1, NFκB, and ERK signaling pathways might be involved in the antifibrotic effects of CVC. Consistently, Ccr2 deletion decreased the activation of STAT1, NFκB, and ERK in the liver. In in vitro experiments, the researchers found that CVC could suppress the transcription of crucial profibrotic genes (Xaf1, Slfn4, Slfn8, Ifi213, and Il1β) in macrophages by inactivating the STAT1/NFκB/ERK signaling pathways.

In summary, this study provides insights into a novel mechanism by which CVC alleviates ECM accumulation in liver fibrosis. It accomplishes this by restoring the immune cell landscape in the liver and inhibiting the transcription of profibrotic genes through inactivation of the CCR2-STAT1/NFκB/ERK signaling pathways. These findings contribute to a better understanding of the potential therapeutic role of CCR2 inhibition in liver fibrosis.