Abstract
Placental growth factor (PlGF), a member of the vascular endothelial growth factor (VEGF) family, mediates wound healing and inflammatory responses, exerting an effect on liver fibrosis and angiogenesis; however, the precise mechanism remains unclear. The aims of this study are to identify the role of PlGF in liver inflammation and fibrosis induced by bile duct ligation (BDL) in mice and to reveal the underlying molecular mechanism. PlGF small interfering RNA (siRNA) or non-targeting control siRNA was injected by tail vein starting 2 days after BDL. Liver inflammation, fibrosis, angiogenesis, macrophage infiltration, and hepatic stellate cells (HSCs) activation were examined. Our results showed that PlGF was highly expressed in fibrotic livers and mainly distributed in activated HSCs and macrophages. Furthermore, PlGF silencing strongly reduced the severity of liver inflammation and fibrosis, and inhibited the activation of HSCs. Remarkably, PlGF silencing also attenuated BDL-induced hepatic angiogenesis, as evidenced by attenuated liver endothelial cell markers CD31 and von Willebrand factor immunostaining and genes or protein expression. Interestingly, these pathological ameliorations by PlGF silencing were due to a marked reduction in the numbers of intrahepatic F4/80+, CD68+, and Ly6C+ cell populations, which were reflected by a lower expression of these macrophage marker molecules in fibrotic livers. In addition, knockdown of PlGF by siRNA inhibited macrophages activation and substantially suppressed the expression of pro-inflammatory cytokines and chemokines in fibrotic livers. Mechanistically, evaluation of cultured RAW 264.7 cells revealed that VEGF receptor 1 (VEGFR1) mainly involved in mediating the role of PlGF in macrophages recruitment and activation, since using VEGFR1 neutralizing antibody blocking PlGF/VEGFR1 signaling axis significantly inhibited macrophages migration and inflammatory responses. Together, these findings indicate that PlGF plays an important role in liver inflammation, angiogenesis, and fibrosis by promoting hepatic macrophage recruitment and activation, and suggest that blockage of PlGF could be a promising novel therapy for chronic fibrotic liver diseases.
Highlights
Liver fibrosis is the final common pathway of chronic liver diseases of various etiologies, which develops as a result of the sustained wound-healing process triggered by liver injury and inflammation [1,2,3]
Our results demonstrated that the levels of Placental growth factor (PlGF) mRNA expression were gradually increased following bile duct ligation (BDL); which were significantly downregulated at their corresponding time points by PlGF small interfering RNA (siRNA) administration (Figure 1E)
We found that the levels of CXCL10, vascular cell adhesion molecular-1 (VCAM-1), and intercellular adhesion molecule 1 (ICAM-1) mRNA expression in livers were markedly enhanced in BDL mice received siNTC compared with SHAM mice, but these increase in livers were attenuated by PlGF siRNA treatment to BDL mice (Figure 7A)
Summary
Liver fibrosis is the final common pathway of chronic liver diseases of various etiologies, which develops as a result of the sustained wound-healing process triggered by liver injury and inflammation [1,2,3]. Hepatic macrophages can arise from proliferating resident macrophages and from circulating monocyte that originates in the bone marrow (BM), which are recruited to the injured liver [4,5,6] These cells have been classified either into “proinflammatory” M1 or “immunoregulatory” M2 macrophages, though such binary classifications cannot represent the complex in vivo environment for most macrophage subsets [6, 7, 12, 13]. Chemokines and adhesion play a pivotal role in the recruitment and differentiate of monocyte and macrophages to the sites of inflammation through receptors among the inflammatory mediators [7,8,9,10]; leading to the development and progression of liver injury, inflammation, and fibrosis [3,4,5,6,7,8,9,10,11,12]. Elucidating the complex regulatory mechanisms by which macrophages promote inflammation and fibrosis might lead to novel therapies to suppress liver inflammation and prevent the development fibrosis [4, 5, 12]
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