Hypoxia-inducible factor prolyl hydroxylase inhibitors suppressed thymic stromal lymphopoietin production and allergic responses in a mouse air-pouch-type ovalbumin sensitization model
Hypoxia-inducible factor prolyl hydroxylase inhibitors suppressed thymic stromal lymphopoietin production and allergic responses in a mouse air-pouch-type ovalbumin sensitization model
复制标题
缺氧诱导因子脯氨酰羟化酶抑制剂抑制小鼠气囊型卵清蛋白致敏模型中胸腺基质淋巴细胞生成素的产生和过敏反应
DOI：
10.1016/j.intimp.2023.110127
复制
发表时间：
2023
影响因子：
5.6
通讯作者：
Hirasawa N.
中科院分区：
文献类型：
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作者：
Segawa R;Kyoda T;Yagisawa M;Muramatsu T;Hiratsuka M;Hirasawa N.
特应性皮炎（AD）是一种过敏性皮肤病，由过度的2型免疫反应引发。胸腺基质淋巴细胞生成素（TSLP）是一种上皮源性细胞因子，通过树突状细胞活化诱导2型免疫应答。因此，TSLP抑制剂可能成为一种新型的抗过敏药物。缺氧诱导因子（HIF）在上皮细胞中的激活有助于几种稳态现象，如再上皮化。然而，HIF激活对皮肤中TSLP产生和免疫激活的影响仍不清楚。在这项研究中，我们发现，选择性HIF脯氨酰羟化酶抑制剂（PHD抑制剂），诱导HIF激活，抑制TSLP的生产在小鼠卵清蛋白（OVA）致敏模型。PHD抑制剂还抑制肿瘤坏死因子-α（TNF-α）的产生，这是该小鼠模型和巨噬细胞系中TSLP产生的主要诱导剂。与这些发现一致，PHD抑制剂抑制血清中OVA特异性IgE水平和OVA诱导的过敏反应。此外，我们发现了一个直接抑制TSLP表达的人角质形成细胞系介导的HIF激活。总之，我们的研究结果表明，PHD抑制剂通过抑制TSLP的产生发挥抗过敏作用。控制HIF激活系统在AD中具有治疗潜力。
Atopic dermatitis (AD) is an allergic skin disease, triggered by excessive type 2 immune reactions. Thymic stromal lymphopoietin (TSLP) is an epithelial-derived cytokine that induces type 2 immune response through dendritic cell activation. Therefore, TSLP inhibitors may serve as novel antiallergic drugs. Hypoxia-inducible factor (HIF) activation in the epithelia contributes to several homeostatic phenomena, such as re-epithelialization. However, the effects of HIF activation on TSLP production and immune activation in the skin remain unclear. In this study, we found that selective HIF prolyl hydroxylase inhibitors (PHD inhibitors), which induce HIF activation, suppressed TSLP production in a mouse ovalbumin (OVA) sensitization model. PHD inhibitors also suppressed the production of tumor necrosis factor-alpha (TNF-α), which is a major inducer of TSLP production, in this mouse model and in a macrophage cell line. Consistent with these findings, PHD inhibitors suppressed OVA-specific IgE levels in the serum and OVA-induced allergic responses. Furthermore, we found a direct suppressive effect on TSLP expression in a human keratinocyte cell line mediated by HIF activation. Taken together, our findings suggest that PHD inhibitors exert antiallergic effects by suppressing TSLP production. Controlling the HIF activation system has therapeutic potential in AD.