IL‐34 and macrophage colony‐stimulating factor are overexpressed in hepatitis C virus fibrosis and induce profibrotic macrophages that promote collagen synthesis by hepatic stellate cells

Abstract

Chronic hepatitis C virus (HCV) infection is characterized by progressive hepatic fibrosis, a process dependent on monocyte recruitment and accumulation into the liver. The mediators expressed in chronically injured liver that control the differentiation of human monocytes into profibrotic macrophages (Mu) remain poorly defined. We report that chronically HCV-infected patients with high fibrosis stages have higher serum levels of macrophage colony-stimulating factor (M-CSF) and interleukin (IL)234 than HCV-infected patients with lower fibrosis stages and healthy subjects. Immunohistochemistry reveals an intense expression of IL-34 and M-CSF by hepatocytes around liver lesions. In addition, HCV infection and inflammatory cytokines enhance the in vitro production of IL-34 and M-CSF by hepatocytes. We next analyzed the acquisition of profibrotic properties by Mu generated with M-CSF (M-CSF-Mu) or IL-34 (IL-34-Mu). M-CSF and IL-34 up-regulate the expression, by differentiating monocytes, of chemokine (C-C motif) ligand (CCL)2, CCL4, C-C chemokine receptor (CCR)1, and CCR5, which are involved in monocyte recruitment/Mu accumulation in liver lesions. M-CSF-Mu and IL-34-Mu also express the hepatic stellate cell (HSC) activators, platelet-derived growth factor, transforming growth factor beta, and galectin-3. IL-34-Mu and M-CSF-Mu induce type I collagen synthesis by HSCs, the main collagen-producing cells in liver fibrosis. IL-13, whose expression correlates with the fibrosis stage in HCV-infected patients, decreases the expression of the collagenase, matrix metalloproteinase 1, by IL-34-Mu and M-CSF-Mu, thereby enhancing collagen synthesis. By inhibiting the production of interferon-gamma (IFN-c) by activated natural killer cells, IL-34-Mu and M-CSF-Mu prevent the IFN-c-induced killing of HSCs. Conclusion: These results identify M-CSF and IL-34 as potent profibrotic factors in HCV liver fibrosis.

Blood-Stage Plasmodium Berghei ANKA Infection Promotes Hepatic Fibrosis by Enhancing Hedgehog Signaling in Mice

“…Hemozoin activates macrophages by stimulating inflammatory signaling pathways, including Toll-like receptor 4 activation and NF-kB signaling. The activated macrophages produce inflammatory cytokines, such as IL1b and TNF-a, which accelerate HSC activation, contributing to liver fibrosis [32,46,[55][56][57][58]. In the present study, we found that Kupffer cell activation, hemozoin accumulation, and upregulation of pro-inflammatory genes were apparent in malaria-infected livers (Fig.…”

PD-L1+MDSCs are increased in HCC patients and induced by soluble factor in the tumor microenvironment

“…On the other hand, other research groups reported that M-CSF was associated with hepatic fibrosis in chronic hepatitis C and non-alcoholic fatty liver disease patients3132. Moreover, they found that M-CSF could be produced from hepatocytes with persistent HCV infection31. In this study, there was a significant difference in the percentages of PD-L1 + MDSCs between patients with HCC and those with chronic hepatitis.…”

“…They demonstrated that the increase in MDSCs was only correlated with tumor progression, but not with hepatic fibrosis or the disease activity of chronic liver disease30. On the other hand, other research groups reported that M-CSF was associated with hepatic fibrosis in chronic hepatitis C and non-alcoholic fatty liver disease patients3132. Moreover, they found that M-CSF could be produced from hepatocytes with persistent HCV infection31.…”

IL-34 and M-CSF form a novel heteromeric cytokine and regulate the M-CSF receptor activation and localization

“…In addition to the already identified functions of IL-34 and M-CSF in exacerbated macrophage activation (bowel diseases, liver fibrosis, chronic skin inflammation, arthritis, etc. ), this new heteromeric cytokine M-CSF/IL-34 which may differentially regulates the activation/localization of M-CSFR strengthens the global therapeutic approaches for blocking all biological functions coming from these molecules [7,8,[45][46][47][48][49][50][51].…”