Hepatic macrophages but not dendritic cells contribute to liver fibrosis by promoting the survival of activated hepatic stellate cells in mice

Abstract

Although it is well established that hepatic macrophages play a crucial role in the development of liver fibrosis, the underlying mechanisms remain largely elusive. Moreover, it is not known whether other mononuclear phagocytes such as dendritic cells contribute to hepatic stellate cell (HSC) activation and liver fibrosis. Here we show for the first time that hepatic macrophages enhance myofibroblast survival in an NF-κB-dependent manner, and thereby promote liver fibrosis. Microarray and pathway analysis revealed no induction of HSC activation pathways by hepatic macrophages but a profound activation of the nuclear factor-kappa B (NF-κB) pathway in HSCs. Conversely, depletion of mononuclear phagocytes during fibrogenesis in vivo resulted in suppressed NF-κB activation in HSCs. Macrophage-induced activation of NF-κB in HSC in vitro and in vivo was mediated by IL-1 and TNF. Notably, IL-1 and TNF did not promote HSC activation but promoted survival of activated HSC in vitro and in vivo and thereby increased liver fibrosis, as demonstrated by neutralization in co-culture experiments, and genetic ablation of IL-1 and TNF receptor in vivo. Co-culture and in vivo ablation experiments revealed only a minor contribution to NF-κB activation in HSCs by dendritic cells, and no contribution of dendritic cells to liver fibrosis development, respectively. Conclusion Promotion of NF-κB-dependent myofibroblast survival by macrophages but not dendritic cells provides a novel link between inflammation and fibrosis.

Endocannabinoid System Contributes to Liver Injury and Inflammation by Activation of Bone Marrow–Derived Monocytes/Macrophages in a CB1-Dependent Manner

“…Therefore, copious amount of macrophages would be recruited from bone marrow (BM), aggregate in inflammatory sites, and play a crucial role in inflammation and fibrosis (16). Indeed, it has been reported that the inflammation and fibrosis of injured liver were ameliorated after the depletion of macrophages (19). We have also found that reducing the recruitment of BM-derived monocytes/macrophages (BMM) can attenuate hepatic inflammation and fibrosis (20).…”

“…The levels of ALT and AST were downregulated, indicating the blockade of CB1-protected hepatocytes from damage. Additionally, fibrosis was markedly attenuated, possibly due to the fact that blockade of CB1 reduced the levels of profibrogenic cytokines and growth factors such as TNF-a, IL-6, and TGF-b1, which can drive hepatic stellate cell activation or promote the survival of activated hepatic stellate cells (19,41). However, other studies have also shown that macrophages revealed distinct roles during liver injury (42) and their depletion exacerbated liver injury (43).…”

“…Studies have demonstrated that reducing macrophages would improve hepatic fibrosis (19). To confirm this, we stained macrophages with F4/80 Ab by immunofluorescence assay and then performed sirius red staining for collagen in the same liver sample.…”

Isolation of Human Monocytes by Double Gradient Centrifugation and Their Differentiation to Macrophages in Teflon-coated Cell Culture Bags

“…Next to their fundamental role in the recognition and clearance of invading pathogens [4][5][6] , macrophages have increasingly come into focus in atherosclerosis, fibrosis, obesity, and cancer [7][8][9][10] . A reproducible method for the generation of human macrophages is therefore crucial for an understanding of these pathologies.…”

Key role of liver sinusoidal endothelial cells in liver fibrosis

“…such as viral hepatitis and alcohol consumption, KCs can be induced into an activated state in which they secrete a wide variety of proinflammatory cytokines, such as IL-6, IL-10, IL-13, TNF-α, and TGF-β, further activating HSCs. Macrophages can play an indirect role in the development of liver fibrosis (37)(38)(39)(40) (41). However, the correlation between LSECs and macrophages in chronic liver diseases and the mechanism of their interaction remains unclear and needs to be examined further.…”