Potentiation of hepatic stellate cell activation by extracellular ATP is dependent on P2X7R-mediated NLRP3 inflammasome activation

Jiang, Shuang; Zhang, Yu; Jie, Zheng; Li, Xia; Yao, You-Li; Wu, Yan-Ling; Shen, Song; Sun, Peng; Nan, Jing; Lian, Li-Hua

doi:10.1016/j.phrs.2016.11.040

Cited by 92 publications

(67 citation statements)

References 60 publications

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“…(23) To date, there are only a few studies elucidating different stimuli that can trigger HSC activation and subsequent up-regulation of fibrotic markers along with activation of the NLRP3 inflammasome in both LX-2 cells, an immortalized human stellate cell line, and murine primary HSCs. (24)(25)(26) In particular, Watanabe et al (27) not only showed that HSC expressed all of the NLRP3 inflammasome components, but also that activation of the NLRP3 inflammasome using, monosodium urate crystals, leads to a phenotypic switch from a quiescent state to collagen-producing myofibroblasts. These changes were absent in HSCs derived from apoptosis-associated speck-like protein containing CARD-deficient mice.…”

Section: Discussionmentioning

confidence: 99%

NLR Family Pyrin Domain‐Containing 3 Inflammasome Activation in Hepatic Stellate Cells Induces Liver Fibrosis in Mice

et al. 2019

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The NLRP3 inflammasome plays an important role in liver fibrosis development. However, the mechanisms involved in NLRP3-induced fibrosis are unclear. Our aim was to test the hypothesis that the NLRP3 inflammasome in hepatic stellate cells (HSC) can directly regulate their activation and contribute to liver fibrosis. Primary HSC isolated from WT, Nlrp3 , or Nlrp3 knock-in crossed to inducible (estrogen receptor Cre - CreT) mice were incubated with LPS and ATP, or 4OH-tamoxifen, respectively. HSC-specific Nlrp3 -knock-in mice were generated by crossing transgenic mice expressing lecithin retinol acyltransferase (Lrat)-driven Cre and maintained on standard rodent chow for 6 months. Mice were then sacrificed; liver tissue and serum were harvested. Nlrp3 inflammasome activation along with HSC phenotype and fibrosis were assessed by RT-PCR, Western blot, FACS, ELISA, immunofluorescence and immunohistochemistry. Stimulated WT HSC displayed increased levels of NLRP3 inflammasome-induced ROS production and Cathepsin B activity, accompanied by an upregulation of mRNA and protein levels of fibrotic makers, an effect abrogated in Nlrp3 HSC. Nlrp3 CreT HSC also showed elevated mRNA and protein expression of fibrotic markers 24h after inflammasome activation induced with 4OH-tamoxifen. Protein and mRNA expression levels of fibrotic markers were also found to be increased in isolated HSC and whole liver tissue from Nlrp3 Lrat Cre mice compared to WT. Liver sections from 24 week-old Nlrp Lrat Cre mice showed fibrotic changes with increased αSMA and desmin positive cells and collagen deposition, independent of inflammatory infiltrates; these changes were also observed after LPS challenge in 8 week-old Nlrp Lrat Cre mice. Conclusion Our results highlight a direct role for the NLRP3 inflammasome in the activation of HSC directly triggering liver fibrosis. This article is protected by copyright. All rights reserved.

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Section: Discussionmentioning

confidence: 99%

NLR Family Pyrin Domain‐Containing 3 Inflammasome Activation in Hepatic Stellate Cells Induces Liver Fibrosis in Mice

et al. 2019

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“…Suppression of autophagy in hepatocytes by antagonism of IL-17A inhibits liver fibrosis by restoring the IL-10/STAT3 pathway in BDL and TAA-treated mice [295]. Potentiation of HSC activation by extracellular ATP is dependent on P2X7R-mediated NLRP3 inflammasome activation [296]. …”

Section: Mechanisms Of Hsc Activationmentioning

confidence: 99%

Hepatic stellate cells as key target in liver fibrosis

Higashi

Friedman

Hoshida

2017

Advanced Drug Delivery Reviews

1,078

894

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Progressive liver fibrosis, induced by chronic viral and metabolic disorders, leads to more than one million deaths annually via development of cirrhosis, although no antifibrotic therapy has been approved to date. Transdifferentiation (or “activation”) of hepatic stellate cells is the major cellular source of matrix protein-secreting myofibroblasts, the major driver of liver fibrogenesis. Paracrine signals from injured epithelial cells, fibrotic tissue microenvironment, immune and systemic metabolic dysregulation, enteric dysbiosis, and hepatitis viral products can directly or indirectly induce stellate cell activation. Dysregulated intracellular signaling, epigenetic changes, and cellular stress response represent candidate targets to deactivate stellate cells by inducing reversion to inactivated state, cellular senescence, apoptosis, and/or clearance by immune cells. Cell type- and target-specific pharmacological intervention to therapeutically induce the deactivation will enable more effective and less toxic precision antifibrotic therapies.

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“…Another report indicated that the activation of inflammatory bodies can lead to the death of hepatocytes, thereby further inducing liver inflammation and liver fibrosis [32]. There are a small number of inflammatory bodies in HSCs, and the inhibition of the formation of inflammatory bodies in HSCs can downregulate the content of collagen and α‐SMA, as well as the formation and deposition of the ECM, which are important for liver fibrosis [36]. However, further research is needed on whether or not their inhibition can result in their death.…”

Section: Discussionmentioning

confidence: 99%

ASIC1a inhibits cell pyroptosis induced by acid‐induced activation of rat hepatic stellate cells

Kong

Huang

et al. 2020

FEBS Open Bio

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The activation of hepatic stellate cells (HSCs) is associated with liver fibrosis, the pathological feature of most forms of chronic hepatic damage, and is accompanied by abnormal deposition of the extracellular matrix (ECM). During the pathological process, acid‐sensing ion channel 1a (ASIC1a), which is responsible for Ca2+ transportation, is involved in the activation of HSCs. It has previously been identified that ASIC1a is related to pyroptosis in articular chondrocytes. However, it remains unclear whether ASIC1a restrains pyroptosis during liver fibrosis. Here, we determined that the levels of pyroptosis‐associated speck‐like protein, gasdermin D, caspase‐1, nucleotide‐binding oligomerization domain (NOD)‐like receptor 3, and apoptosis‐associated speck‐like protein (ASC) decreased, while the level of α‐smooth muscle actin and collagen‐I increased upon introduction of ASIC1a into an acid‐induced model. Inhibition or silencing of ASIC1a and the use of Ca2+‐free medium were able to promote the pyroptosis of activated HSCs, which reduced their deposition. In summary, our study indicates that ASIC1a inhibits pyroptosis of HSCs and that inhibition of ASIC1a may be able to promote pyroptosis to relieve liver fibrosis.

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Potentiation of hepatic stellate cell activation by extracellular ATP is dependent on P2X7R-mediated NLRP3 inflammasome activation

Cited by 92 publications

References 60 publications

NLR Family Pyrin Domain‐Containing 3 Inflammasome Activation in Hepatic Stellate Cells Induces Liver Fibrosis in Mice

NLR Family Pyrin Domain‐Containing 3 Inflammasome Activation in Hepatic Stellate Cells Induces Liver Fibrosis in Mice

Hepatic stellate cells as key target in liver fibrosis

ASIC1a inhibits cell pyroptosis induced by acid‐induced activation of rat hepatic stellate cells

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