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

Abstract

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.

Identification and characterization of endogenous retroviruses upon SARS-CoV-2 infection

“…Interestingly, these four copies of ERVB2_1-I_MM-int were found in close proximity to Ifi208, Ifi213, Mlph, and Serpinb10 in the mouse genome (Supplementary Table 7). Notably, Ifi208 and Ifi213 are two interferon-stimulated genes (ISGs) that play essential roles in anti-viral immunity (40,41). Upon treatment with VSV and HSV-1, both Ifi208 and Ifi213 were significantly upregulated, indicating a potential interaction between ERVB2_1-I_MM-int and Ifi208 as well as Ifi213.…”

NUP85 alleviates lipid metabolism and inflammation by regulating PI3K/AKT signaling pathway in nonalcoholic fatty liver disease

“…NUP85 could combine with CCR2 protein by querying STING database 44 . CCR2 is the chemokine receptor, which regulates the mobilization of monocytes from bone marrow to the inflammatory sites 45 , 46 . Interestingly, the circulating precursor of macrophages could control the migration of bone marrow monocytes to the liver 47 .…”

Editorial: Community series in hepatic immune response underlying liver cirrhosis and portal hypertension, volume II

“…As the study of the immune response in liver disease has received increasing interest, potential novel anti-fibrotic or anti-cirrhotic therapies that target the hepatic immune microenvironment are being developed ( Zhang et al. ) ( 16 ). With the advance of regenerative medicine, mesenchymal stem cell (MSC) therapy has emerged as a promising treatment option for liver cirrhosis.…”