Hydrogen sulfide inhibits ATP-induced neuroinflammation and Aβ1-42 synthesis by suppressing the activation of STAT3 and cathepsin S
Hydrogen sulfide inhibits ATP-induced neuroinflammation and Aβ1-42 synthesis by suppressing the activation of STAT3 and cathepsin S
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DOI：
10.1016/j.bbi.2018.07.005
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发表时间：
2018-10-01
影响因子：
15.1
通讯作者：
Bian, Jin-Song
中科院分区：
文献类型：
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作者：
Cao, Lei;Cao, Xu;Bian, Jin-Song
神经炎症和β-淀粉样蛋白（1-42）（A β（1-42））的过度生成有助于阿尔茨海默病（AD）的发病机制。新出现的证据表明，硫化氢（H2S），一种内源性气体递质，在AD中产生治疗作用;然而，其潜在的机制在很大程度上仍然难以捉摸。在本研究中，我们研究了H2S对BV-2和原代培养的小胶质细胞中外源性ATP诱导的炎症和A β（1-42）产生的影响，并分析了介导这些影响的潜在机制。我们的研究结果表明，NaHS，H2S供体，抑制外源性ATP刺激的炎症反应，表现为减少促炎细胞因子，ROS和激活核因子-κ B（NF-κ B）途径。此外，NaHS还抑制由外源性ATP诱导的A β（1-42）的产生增加，这可能是由于其抑制外源性ATP促进的淀粉样前体蛋白（APP）的表达和β-和γ-分泌酶的激活。此后，我们发现外源性ATP诱导的炎症和A β（1-42）的产生需要激活信号转导和转录激活因子3（STAT 3）和组织蛋白酶S（Cat S），因为抑制这两种蛋白的活性会减弱外源性ATP的作用。有趣的是，NaHS抑制外源性ATP诱导的STAT 3磷酸化和Cat S的活化。此外，我们观察到NaHS导致Cat S在半胱氨酸-25处的过硫化。重要的是，半胱氨酸-25突变为丝氨酸减弱了由外源性ATP刺激的Cat S活性以及随后的炎症和A β（1-42）产生，表明其参与了H25介导的作用。总之，我们的数据提供了一个新的理解H2S介导的影响神经炎症和A β（1-42）的生产通过抑制STAT 3和Cat S的激活。
Neuroinflarnmation and excessive beta-amyloid(1-42) (A beta(1-42)) generation contribute to the pathogenesis of Alzheimer's disease (AD). Emerging evidence has demonstrated that hydrogen sulfide (H2S), an endogenous gasotransmitter, produces therapeutic effects in AD; however, the underlying mechanisms remain largely elusive. In the present study, we investigated the effects of H2S on exogenous ATP-induced inflammation and A beta(1-42) production in both BV-2 and primary cultured microglial cells and analyzed the potential mechanism(s) mediating these effects. Our results showed that NaHS, an H2S donor, inhibited exogenous ATP-stimulated inflammatory responses as manifested by the reduction of pro-inflammatory cytokines, ROS and activation of nuclear factor-kappa B (NF-kappa B) pathway. Furthermore, NaHS also suppressed the enhanced production of A beta(1-42) induced by exogenous ATP, which is probably due to its inhibitory effect on exogenous ATP-boosted expression of amyloid precursor protein (APP) and activation of beta- and gamma-secretase enzymes. Thereafter, we found that exogenous ATP-induced inflammation and A beta(1-42) production requires the activation of signal transducer and activator of transcription 3 (STAT3) and cathepsin S (Cat S) as inhibition of the activity of either proteins attenuated the effect of exogenous ATP. Intriguingly, NaHS suppressed exogenous ATP-induced phosphorylation of STAT3 and the activation of Cat S. In addition, we observed that NaHS led to the persulfidation of Cat S at cysteine-25. Importantly, mutation of cysteine-25 into serine attenuated the activity of Cat S stimulated by exogenous ATP and subsequent inflammation and A beta(1-42) production, indicating its involvement in H25-mediated effect. Taken together, our data provide a novel understanding of H2S-mediated effect on neuroinflammation and A beta(1-42) production by suppressing the activation of STAT3 and Cat S.