Endogenous sulfur dioxide is a novel inhibitor of hypoxia-induced mast cell degranulation.
Endogenous sulfur dioxide is a novel inhibitor of hypoxia-induced mast cell degranulation.
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内源性二氧化硫是缺氧诱导的肥大细胞脱粒的新型抑制剂
DOI：
10.1016/j.jare.2020.08.017
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发表时间：
2021-03
影响因子：
10.7
通讯作者：
Huang Y
中科院分区：
文献类型：
--
作者：
Zhang L;Jin H;Song Y;Chen SY;Wang Y;Sun Y;Tang C;Du J;Huang Y
内源性二氧化硫是缺氧诱导肥大细胞脱颗粒的一种新型抑制剂。MCs中存在内源性SO2/AAT通路。肥大细胞来源的SO2通过激活AC和抑制PDE来上调cAMP水平，从而抑制MCs的脱颗粒。肥大细胞中存在内源性SO2/AAT通路。内源SO2是一种新型的低氧MC膜稳定剂。MC来源的SO2上调cAMP水平，从而抑制MC脱粒。肥大细胞（MC）脱颗粒是炎症反应和过敏发生的重要步骤；然而，稳定MC膜以减少其脱颗粒的机制尚不清楚。采用HPLC-FD法测定MC培养上清液中SO2的含量。检测关键酶天冬氨酸转氨酶1 （AAT1）和AAT2的蛋白和mRNA表达以及细胞内AAT活性。免疫荧光法和ELISA法检测MCs中cAMP水平。测定MC脱粒标志物β-己糖氨酸酶的释放率。检测大鼠肺组织中AAT1、cAMP的表达、MC的积累和脱粒情况。目的：探讨MCs中是否存在内源性二氧化硫（SO2）途径，以及该途径是否可以作为一种新的内源性MCs稳定剂。我们首先在MCs中发现了内源性SO2/AAT通路的存在。此外，当AAT1在MCs中被敲除时，MCs脱粒明显增加，并可被SO2供体拯救。机制上，AAT1敲除降低了MCs中环磷酸腺苷（cAMP）的含量，而SO2以剂量无关的方式阻止了这种降低。使用cAMP合成激动剂forskolin或cAMP降解抑制剂IBMX预处理可显著阻断AAT1敲低诱导的MC脱颗粒的增加。此外，在缺氧刺激的MCs中，AAT1蛋白的表达和SO2的产生明显下调，并激活MCs的脱颗粒，而AAT1的过表达则使其钝化。cAMP合成抑制剂SQ22536破坏了AAT1过表达对缺氧诱导的MC脱粒的抑制作用。缺氧环境下，大鼠肺组织中AAT1 mRNA和蛋白表达明显降低。在体内暴露于缺氧环境的大鼠肺组织中，补充SO2可提高cAMP水平，减少血管周围MC的积累和脱颗粒。SO2作为内源性MC稳定剂，在缺氧条件下通过上调cAMP通路发挥作用。
Endogenous sulfur dioxide is a novel inhibitor of hypoxia-induced mast cell degranulation. Endogenous SO2/AAT pathway exists in MCs. Mast cell-derived SO2 upregulates cAMP level through activation of AC and inhibition of PDE, thereby suppressing degranulation of MCs. Endogenous SO2/AAT pathway exists in mast cells (MCs). Endogenous SO2 is a novel MC membrane stabilizer under hypoxic circumstance. MC-derived SO2 upregulates cAMP level, thereby suppressing MC degranulation. Mast cell (MC) degranulation is an important step in the pathogenesis of inflammatory reactions and allergies; however, the mechanism of stabilizing MC membranes to reduce their degranulation is unclear. SO2 content in MC culture supernatant was measured by HPLC-FD. The protein and mRNA expressions of the key enzymes aspartate aminotransferase 1 (AAT1) and AAT2 and intracellular AAT activity were detected. The cAMP level in MCs was detected by immunofluorescence and ELISA. The release rate of MC degranulation marker β-hexosaminidase was measured. The expression of AAT1 and cAMP, the MC accumulation and degranulation in lung tissues were detected. To exam whether an endogenous sulfur dioxide (SO2) pathway exists in MCs and if it serves as a novel endogenous MC stabilizer. We firstly show the existence of the endogenous SO2/AAT pathway in MCs. Moreover, when AAT1 was knocked down in MCs, MC degranulation was significantly increased, and could be rescued by a SO2 donor. Mechanistically, AAT1 knockdown decreased the cyclic adenosine monophosphate (cAMP) content in MCs, while SO2 prevented this reduction in a dose-independent manner. Pretreatment with the cAMP-synthesizing agonist forskolin or the cAMP degradation inhibitor IBMX significantly blocked the increase in AAT1 knockdown-induced MC degranulation. Furthermore, in hypoxia-stimulated MCs, AAT1 protein expression and SO2 production were markedly down regulated, and MC degranulation was activated, which were blunted by AAT1 overexpression. The cAMP synthesis inhibitor SQ22536 disrupted the suppressive effect of AAT1 overexpression on hypoxia-induced MC degranulation. In a hypoxic environment, mRNA and protein expression of AAT1 was significantly reduced in lung tissues of rats. Supplementation of SO2 elevated the cAMP level and reduced perivascular MC accumulation and degranulation in lung tissues of rats exposed to a hypoxic environment in vivo. SO2 serves as an endogenous MC stabilizer via upregulating the cAMP pathway under hypoxic circumstance.
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