School of Pharmacy, Anhui Medical University, Hefei, China.
FEBS Open Bio. 2020 Jun;10(6):1044-1055. doi: 10.1002/2211-5463.12850. Epub 2020 Apr 28.
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 Ca 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 Ca -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.
肝星状细胞（HSCs）的激活与肝纤维化有关，肝纤维化是大多数慢性肝损伤形式的病理特征，并伴有细胞外基质（ECM）的异常沉积。在病理过程中，负责钙转运的酸感应离子通道 1a（ASIC1a）参与了 HSCs 的激活。先前已经确定，ASIC1a 与关节软骨细胞中的细胞焦亡有关。然而，ASIC1a 是否在肝纤维化过程中抑制细胞焦亡仍不清楚。在这里，我们确定在酸诱导模型中引入 ASIC1a 后，与细胞焦亡相关的斑点样蛋白、Gasdermin D、半胱天冬酶-1、核苷酸结合寡聚化结构域（NOD）样受体 3 和凋亡相关斑点样蛋白（ASC）的水平降低，而α-平滑肌肌动蛋白和胶原-I 的水平增加。ASIC1a 的抑制或沉默以及使用不含 Ca 的培养基能够促进激活的 HSCs 的细胞焦亡，从而减少其沉积。总之，我们的研究表明，ASIC1a 抑制 HSCs 的细胞焦亡，抑制 ASIC1a 可能能够促进细胞焦亡以缓解肝纤维化。
