Abstract
Macrophages are the master regulator of the dynamic fibrogenesis–fibrosis resolution paradigm. TNF-like ligand 1 aberrance (TL1A) was found to be able to induce intestinal inflammation and fibrosis. Furthermore, significantly increased TL1A had been detected in liver tissues and mononuclear cells of patients with primary biliary cirrhosis (PBC). This study was to investigate the effect of myeloid cells with constitutive TL1A expression on liver fibrogenesis. We found that TL1A expressions in liver tissues and macrophages were significantly increased in mice with liver fibrosis induced by injection of carbon tetrachloride (CCl4). TL1A overexpression in myeloid cells induced liver function injury, accelerated the necrosis and apoptosis of hepatocytes, recruited macrophages, and promoted activation of hepatic stellate cells (HSCs) and fibrosis. In vitro results of our study showed that TL1A overexpression in macrophages promoted secretion of platelet-derived growth factor-BB (PDGF-BB), tumor necrosis factor-α (TNF-α), and interleukin-1β (IL-1β). Culturing macrophages with TL1A overexpression could accelerate the activation and proliferation of primary HSCs. These results indicated that constitutive TL1A expression in myeloid cells exacerbated liver fibrosis, probably through macrophage recruitment and secretion of proinflammatory and profibrotic cytokines.
Highlights
Hepatic fibrosis is a common pathological consequence of chronic liver diseases, which is characterized by an extensive deposition of the extracellular matrix (ECM) mainly secreted by activated hepatic stellate cells (HSCs) [1]
Chu et al [4] found that C-C motif chemokine receptor 9-positive macrophages activated HSCs and promoted liver fibrosis, Lodder et al [5] demonstrated that macrophage autophagy protected against liver fibrosis in mice, and He et al [6] identified that myeloid-specific disruption of recombination signal-binding protein-Jkappa ameliorated hepatic fibrosis by attenuating inflammation
The results showed that tumor necrosis factor-α (TNF-α) and IL-1β were remarkably higher in serum, liver tissue, and conditioned medium (CM) obtained from TNF-like ligand 1 aberrance (TL1A)-transgenic mice (Tg) mice than WT mice (Figures 6(c) and 6(d))
Summary
Hepatic fibrosis is a common pathological consequence of chronic liver diseases, which is characterized by an extensive deposition of the extracellular matrix (ECM) mainly secreted by activated hepatic stellate cells (HSCs) [1]. HSC activation is the leading cause of liver fibrogenesis, and persistent chronic liver inflammation plays a vital role in HSC activation. In the stage of liver fibrogenesis, macrophages secrete proinflammatory and profibrotic cytokines which worsen hepatocellular damage and activate HSCs and release chemokines such as C–C chemokine ligand 2 (CCL2) which recruit monocytes/ macrophages in blood [3]. Chu et al [4] found that C-C motif chemokine receptor 9-positive macrophages activated HSCs and promoted liver fibrosis, Lodder et al [5] demonstrated that macrophage autophagy protected against liver fibrosis in mice, and He et al [6] identified that myeloid-specific disruption of recombination signal-binding protein-Jkappa ameliorated hepatic fibrosis by attenuating inflammation
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