pH and Proton Sensor GPR65 Determine Susceptibility to Atopic Dermatitis.
pH and Proton Sensor GPR65 Determine Susceptibility to Atopic Dermatitis.
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DOI：
10.4049/jimmunol.2001363
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发表时间：
2021-07-01
期刊：
影响因子：
--
通讯作者：
Mackay CR
中科院分区：
文献类型：
--
作者：
Xie L;McKenzie CI;Qu X;Mu Y;Wang Q;Bing N;Naidoo K;Alam MJ;Yu D;Gong F;Ang C;Robert R;Marques FZ;Furlotte N;Hinds D;Gasser O;23andMe Research Team;Xavier RJ;Mackay CR
GPR 65的pH传感调节各种炎症条件，但其在皮肤中的作用仍然未知。在这里，我们进行了一项全表型关联研究（PheWAS），并报告说，GPR 65内含子SNP rs 8005161的T等位基因，它减少了GPR 65信号传导，显示出与特应性皮炎，除了炎症性肠病和哮喘，如前所述的显着关联。与人类中的这种遗传关联一致，我们表明，小鼠中GPR 65的缺乏导致特应性皮炎的MC 903实验模型中的疾病明显加重。GPR 65的缺乏也增加了体外中性粒细胞迁移。此外，小鼠中GPR 65缺陷导致T细胞表达更高的炎性细胞因子肿瘤坏死因子α（TNFα）。在人类中，来自rs 8005161杂合子个体的CD 4 + T细胞在PMA/离子霉素刺激后表达更高水平的TNFα，特别是在pH 6.0条件下。GPR 65的pH传感似乎对调节特应性皮炎的发病机制很重要。
pH-sensing by GPR65 regulates various inflammatory conditions but its role in skin remains unknown. Here we performed a phenome-wide association study (PheWAS) and report that the T allele of GPR65 intronic SNP rs8005161, which reduces GPR65 signaling, showed a significant association with atopic dermatitis, in addition to inflammatory bowel diseases and asthma, as previously reported. Consistent with this genetic association in humans, we show that deficiency of GPR65 in mice resulted in markedly exacerbated disease in the MC903 experimental model of atopic dermatitis. Deficiency of GPR65 also increased neutrophil migration in vitro. Moreover, GPR65 deficiency in mice resulted in higher expression of the inflammatory cytokine tumor necrosis factor α (TNFα) by T cells. In humans, CD4+ T cells from rs8005161 heterozygous individuals expressed higher levels of TNFα after PMA/ionomycin stimulation, particularly under pH 6.0 conditions. pH sensing by GPR65 appears to be important for regulating the pathogenesis of atopic dermatitis.
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影响因子：
5.3
作者：
Alam MJ;Xie L;Ang C;Fahimi F;Willingham SB;Kueh AJ;Herold MJ;Mackay CR;Robert R
通讯作者：
Robert R
影响因子：
30.8
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影响因子：
6.5
作者：
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通讯作者：
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影响因子：
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作者：
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通讯作者：
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影响因子：
3.6
作者：
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通讯作者：
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