Monocyte chemoattractant protein-1 is not required for liver regeneration after partial hepatectomy

Abstract

BackgroundLiver regeneration following 70 % partial hepatectomy (PH) requires the coordinated expression of soluble mediators produced by macrophages. Monocyte chemoattractant protein-1 (MCP-1) is a potent stimulus of monocyte recruitment and macrophage activation. The goal of this study was to determine how MCP-1 contributes to liver regeneration.MethodsPH was performed on anesthetized C57Bl/6 (wild type) and MCP-1 knockout mice, and macrophage-produced cytokines and hepatocyte proliferation were measured.ResultsIn wild type mice, hepatic MCP-1 protein levels increased 4–6 h after PH, and elevated plasma MCP-1 levels were detected 12 h after PH. Hepatocyte proliferation was comparable in MCP-1 knockout and wild type mice, as was the expression of macrophage-derived cytokines, TNFα and IL-6, and levels of phosphorylated STAT3. The number of CCR2+ cells in the liver was similar in MCP-1 knockout and wild type mice, which suggests that other chemokines may recruit CCR2+ cells in the absence of MCP-1. Studies with CCR2 knockout mice revealed that hepatocyte proliferation was suppressed ~40 % compared to wild type mice 36 h after PH, but proliferation and liver-body-weight ratios were similar at 48 h.ConclusionThese findings suggest that MCP-1 is not required for PH-induced liver regeneration, yet the role of CCR2 warrants further study.

Dynamics of macrophage populations of the liver after subtotal hepatectomy in rats

“…The monocyte-derived macrophages are typically detected within the liver during recovery from acute toxic damage, e.g. induced by hepatotoxic substances (paracetamol, tetrachloromethane), accompanied by strong inflammatory response [ 16 ]. It is evident that Kupffer cells are not capable of full-fledged participation in inflammatory reactions.…”

“…Any morphogenetic tensions associated with the local macrophage incapability could be possibly solved by immigration of monocytes or monocyte-derived macrophages into residual liver tissue immediately after the resection, but such immigration has been never observed. It is probably prevented by low MCP-1 concentrations insufficient to attract macrophages of bone marrow origin [ 16 ]. Deficiency in cytokines and growth factors needed to stimulate hepatocyte proliferation is partly counterbalanced by their synthesis elsewhere.…”

Hepatic macrophages in liver homeostasis and diseases-diversity, plasticity and therapeutic opportunities

“…175,176 When hepatic infiltration of MoMϕs is impaired by BM irradiation, a CCR2 antagonist or CCR2 deletion, hepatocyte proliferation is attenuated after PHx. 175,177 The underlying mechanism of MoMϕ-induced hepatocyte proliferation involves IL-6, as transferring wild-type BM to IL-6-deficient mice restores normal hepatocyte proliferation after PHx. 178 The role of MoMϕs in HPC-induced liver regeneration has been reported as well.…”

Hallmarks of Aging in the Liver

“…In another study, aging was associated with a redistribution of KCs into the lymphoid collections that are frequently seen in old rodent livers [69]. Recruitment of KC may be mediated by increased secretion of MCP-1 by aging hepatocytes [71]; however, MCP-1 is not essential for KC activation [72]. In old rats, there was an increase in the RNA expression of the inflammatory cytokine IL-6 in KCs which suggests that KCs might be one source of elevated IL-6 that is characteristic of old age [61].…”