Faculty of Health and Medicine, School of Biomedical Sciences and Pharmacy, University of Newcastle, Callaghan, NSW, Australia.
Hunter Medical Research Institute, New Lambton Heights, NSW, Australia.
Clin Exp Allergy. 2020 May;50(5):609-624. doi: 10.1111/cea.13582. Epub 2020 Mar 2.
Glutathione S-transferases omega class 1 (GSTO1-1) is a unique member of the GST family regulating cellular redox metabolism and innate immunity through the promotion of LPS/TLR4/NLRP3 signalling in macrophages. House dust mite (HDM) triggers asthma by promoting type 2 responses and allergic inflammation via the TLR4 pathway. Although linked to asthma, the role of GSTO1-1 in facilitating type 2 responses and/or HDM-driven allergic inflammation is unknown.
To determine the role of GSTO1-1 in regulating HDM-induced allergic inflammation in a preclinical model of asthma.
Wild-type and GSTO1-1-deficient mice were sensitized and aeroallergen challenged with HDM to induce allergic inflammation and subsequently hallmark pathophysiological features characterized.
By contrast to HDM-challenged WT mice, exposed GSTO1-1-deficient mice had increased numbers of eosinophils and macrophages and elevated levels of eotaxin-1 and -2 in their lungs. M1 macrophage-associated factors, such as IL-1β and IL-6, were decreased in GSTO1-1-deficient mice. Conversely, M2 macrophage factors such as Arg-1 and Ym1 were up-regulated. HIF-1α expression was found to be higher in the absence of GSTO1-1 and correlated with the up-regulation of M2 macrophage markers. Furthermore, HIF-1α was shown to bind and activate the eotaxin-2 promotor. Hypoxic conditions induced significant increases in the levels of eotaxin-1 and -2 in GSTO1-deficient BMDMs, providing a potential link between inflammation-induced hypoxia and the regulation of M2 responses in the lung. Collectively, our results suggest that GSTO1-1 deficiency promotes M2-type responses and increased levels of nuclear HIF-1α, which regulates eotaxin (s)-induced eosinophilia and increased disease severity.
CONCLUSION & CLINICAL IMPLICATION: We propose that GSTO1-1 is a novel negative regulator of TLR4-regulated M2 responses acting as an anti-inflammatory pathway. The discovery of a novel HIF-1α-induced eotaxin pathway identifies an unknown connection between hypoxia and the regulation of the severity of allergic inflammation in asthma.
谷胱甘肽 S-转移酶 ω 类 1（GSTO1-1）是 GST 家族的一个独特成员，通过促进巨噬细胞中的 LPS/TLR4/NLRP3 信号转导来调节细胞氧化还原代谢和先天免疫。屋尘螨（HDM）通过 TLR4 途径促进 2 型反应和过敏炎症，引发哮喘。尽管 GSTO1-1 与哮喘有关，但它在促进 2 型反应和/或 HDM 驱动的过敏炎症中的作用尚不清楚。
确定 GSTO1-1 在哮喘的临床前模型中调节 HDM 诱导的过敏炎症中的作用。
用 HDM 对野生型和 GSTO1-1 缺陷型小鼠进行敏化和变应原挑战，以诱导过敏炎症，并随后对其特征性的病理生理特征进行表征。
与 HDM 处理的 WT 小鼠相比，暴露于 GSTO1-1 缺陷型小鼠的肺部嗜酸性粒细胞和巨噬细胞数量增加，并且 eotaxin-1 和 -2 的水平升高。M1 巨噬细胞相关因子，如 IL-1β 和 IL-6，在 GSTO1-1 缺陷型小鼠中减少。相反，M2 巨噬细胞因子，如 Arg-1 和 Ym1，则上调。发现 GSTO1-1 缺失时 HIF-1α 的表达更高，并与 M2 巨噬细胞标志物的上调相关。此外，HIF-1α 被证明可以结合并激活 eotaxin-2 启动子。缺氧条件诱导 GSTO1 缺陷型 BMDM 中 eotaxin-1 和 -2 的水平显著增加，为炎症诱导的缺氧与肺部 M2 反应的调节之间提供了潜在联系。总之，我们的结果表明 GSTO1-1 缺乏促进 M2 型反应和核 HIF-1α 的增加水平，其调节 eotaxin（s）诱导的嗜酸性粒细胞增多和疾病严重程度增加。
我们提出 GSTO1-1 是 TLR4 调节的 M2 反应的新型负调节剂，作为抗炎途径。发现一种新的 HIF-1α 诱导的 eotaxin 途径，确定了缺氧与哮喘中过敏炎症严重程度调节之间未知的联系。
