Cellular Interplay as a Consequence of Inflammatory Signals Leading to Liver Fibrosis Development

Abstract

Inflammation has been known to be an important driver of fibrogenesis in the liver and onset of hepatic fibrosis. It starts off as a process meant to protect the liver from further damage, but it can become the main promoter of liver fibrosis. There are many inflammation-related pathways activated during liver fibrosis that lead to hepatic stellate cells (HSCs) activation and collagen-deposition in the liver. Such events are mostly modulated upstream of HSCs and involve signals from hepatocytes and innate immune cells. One particular event is represented by cell death during liver injury that generates multiple inflammatory signals that further trigger sterile inflammation and enhancement of inflammatory response. The assembly of inflammasome that responds to danger-associated molecular patterns (DAMPs) stimulates the release of pro-inflammatory cytokines and at the same time, initiates programmed cell death called pyroptosis. This review focuses on cellular and molecular mechanisms responsible for initiation and progress of inflammation in the liver.

Sorafenib reduces steatosis‐induced fibrogenesis in a human 3D co‐culture model of non‐alcoholic fatty liver disease

“…Enhanced FA influx in the hepatocytes promotes the production of pro‐inflammatory cytokines (eg, IL‐6, IL‐8, and TNF‐α) that are strongly correlated with HSC activation and survival, 39 and the generation of lipotoxic metabolites that may ultimately culminate in oxidative stress and necrosis‐induced cell death 36 . In addition, damage‐associated molecular patterns and reactive oxygen species that are released following hepatocyte death or damage, as confirmed by the increased LDH levels in fatty spheroids observed in the present study, can stimulate receptors and downstream effectors in the HSCs leading to the epithelial‐to‐mesenchymal transition 36,40 . Furthermore, activated HSCs produce cytokines and growth factors such as IL‐6 and TGF‐β, which perpetuate their activation in an autocrine loop, followed by the production of ECM and the modulation of ECM‐turnover mediators including TIMPs and MMPs 41,42 …”

Pharmaceutical Efficacy of Gypenoside LXXV on Non-Alcoholic Steatohepatitis (NASH)

“…Non-alcoholic steatohepatitis (NASH) is a severe liver disease that begins with fat accumulation in the organ, resulting in chronic liver injury, necrosis, inflammation, and unbalanced lipid metabolism in the liver, which can lead to hepatic fibrosis, dysfunction, and even cirrhosis which ultimately leads to cancer [ 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 ]. Particularly, obesity and insulin resistance are considered main factors in the initiation and perpetuation of NASH [ 10 ] and play a key role in the pathogenesis of type 2 diabetes mellitus and non-alcoholic fatty liver disease (T2DM-NAFLD) [ 11 ].…”

Pro- and Anti-fibrogenic Functions of Gram-Negative Bacterial Lipopolysaccharide in the Liver

“…It is generally accepted that in almost all etiologies of fibrosis, factors derived from injured/dying hepatocytes including apoptotic bodies, danger-associated molecular patterns (DAMPs), reactive oxygen species (ROS) and hedgehog ligands are the initial stimuli for HSC activation (8,65,66). High mobility group box 1 (HMGB1), a prominent DAMP released by dying/damaged hepatocytes, is shown to induce activation of HSCs, and also to elicit profibrogenic signals in combination with transforming growth factor-beta 1 (TGFβ) (67). Upon phagocytosis of hepatocyte apoptotic bodies and stimulation with DAMPs, Kupffer cells synthesize and release multiple cytokines, ROS and growth factors such as platelet-derived growth factor (PDGF) that promote activation and proliferation of HSCs (8,68).…”

“…In this phase, TNFα produced by inflammatory macrophages, including Kupffer cells, stimulates survival signals in HSCs, whereas TGFβ1 induces activation as well as fibrogenic signals. Other cytokines prominently involved in HSC activation, proliferation and fibrosis are IL17, IL1α, and IL1β (67). Importantly, aHSCs themselves produce ROS, pro-inflammatory cytokines and chemokines, and express cell adhesion molecules to recruit circulating inflammatory and immune cells, and retain activated phenotype (8,9,(69)(70)(71).…”