Pharmacological inhibition of the chemokine C-C motif chemokine ligand 2 (monocyte chemoattractant protein 1) accelerates liver fibrosis regression by suppressing Ly-6C⁺macrophage infiltration in mice

Abstract

Macrophages constitute a major proinflammatory component during chronic liver diseases and are considered a key factor in promoting hepatic fibrosis. However, there is increasing evidence that distinct monocyte and macrophage subsets exert critical functions in regression from organ fibrosis as well. Experimental mouse models of fibrosis regression have identified “restorative” macrophages as Ly‐6C (Ly6C, Gr1) low‐expressing, monocyte‐derived cells. We investigated molecular pathways balancing proinflammatory and restorative macrophages during fibrosis regression as well as pharmacologically augmenting beneficial macrophage functionality in fibrosis resolution. Therefore, we employed a Spiegelmer‐based inhibitor of the chemokine, C‐C motif chemokine ligand 2 (CCL2; monocyte chemoattractant protein 1), termed mNOX‐E36, in the regression phase of two murine models of toxic (CCl4) and metabolic (methionine‐choline–deficient diet) liver fibrosis. Although inflammation rapidly declined after cessation of injury, we observed a transient influx of Ly‐6C+ infiltrating monocytes (iMΦ), which are characterized by typical macrophage morphology, up‐regulated expression of CCR2, and the pro‐inflammatory cytokine, tumor necrosis factor (TNF), in injured liver. By inhibiting the early influx of Ly‐6C+ iMΦ by the CCL2 inhibitor, mNOX‐E36, the intrahepatic macrophage equilibration shifted toward the “restorative” Ly‐6C‐ subset of iMΦ. Consequently, fibrosis resolution was significantly accelerated upon mNOX‐E36 administration in both models. Blocking transient recruitment of infiltrating Ly‐6C+ monocytes, but not direct effects of the inhibitor on the remaining macrophages, resulted in reduced intrahepatic levels of proinflammatory cytokines. Conclusion: Transient CCL2‐dependent recruitment of infiltrating Ly‐6C+ monocytes during fibrosis regression counteracts scar resolution by perpetuating inflammatory reactions through release of proinflammatory cytokines such as TNF. Pharmacological inhibition of Ly‐6C+ monocyte recruitment using the CCL2‐inhibitor, mNOX‐E36, accelerates regression from toxic and metabolic liver fibrosis in two independent experimental models. (Hepatology 2014;59:1060–1072)

Identifying Molecular Factors That Contribute to Resolution of Liver Fibrosis

“…4,7,8 Work by a number of groups, including the study by Yang et al in this issue of Gastroenterology, has demonstrated that macrophages are crucial to the resolution of fibrosis. 4,7,[9][10][11] Indeed, the removal of the macrophage population at the onset of spontaneous fibrosis resolution in rodent models of liver injury prevents remodeling of fibrosis. Additionally, deletion of the macrophage population is associated with a critical drop in liver levels of key enzymes such as MMP13 and MMP12-identifying the macrophage as a crucial source of these enzymes in fibrosis resolution.…”

“…Intriguingly, in the carbon tetrachloride-induced model of liver injury, the macrophages crucial for resolution are the same population that is recruited during fibrogenesis, and that contribute to fibrosis. 9,10 Associated with the onset of fibrosis resolution, this same macrophage population undergoes a phenotypic switch in situ, expressing markers that define a distinct phenotype and up-regulate the expression of matrix-degrading enzymes (and survival and proliferative signals for hepatocytes and hepatic progenitor cells) after ingestion of debris. 6,10 Against this background, the work by Yang et al 4 provides another crucial insight to the molecular regulators of fibrosis resolution.…”

Non-alcoholic fatty liver disease: an emerging driving force in chronic kidney disease

“…Modify leukocyte migration into tissues and consequent inflammation, tissue remodelling and fibrosis 94,95 .…”

Hepatic Fibrosis and its Regression: The Pursuit of Treatment

“…They concluded that M1 macrophages are predominantly present in fibrotic septa during resolution of fibrosis and releases various fibrolytic factors [11]. RNA-aptamer-based inhibitor of CCL2, termed mNOX-E36 reduces the infiltration of Ly6chi macrophage in fibrotic mouse models and favouring the shift of intrahepatic macrophage towards pro-resolution Ly6clo counterparts [12]. Cenicriviroc, the dual CCR2/CCR5 inhibitor in NASH shows promising results in Phase IIB clinical trial (NCT02217475) with decreased in inflammation and fibrosis [13].…”