pH 和质子传感器 GPR65 决定特应性皮炎的易感性。
pH and Proton Sensor GPR65 Determine Susceptibility to Atopic Dermatitis.
机构信息
Department of Microbiology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia.
Hypertension Research Laboratory, School of Biological Sciences, Monash University, Clayton, Victoria, Australia.
出版信息
J Immunol. 2021 Jul 1;207(1):101-109. doi: 10.4049/jimmunol.2001363. Epub 2021 Jun 16.
pH sensing by GPR65 regulates various inflammatory conditions, but its role in skin remains unknown. In this study, we performed a phenome-wide association study and report that the T allele of -intronic single-nucleotide polymorphism 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 TNF-α by T cells. In humans, CD4 T cells from rs8005161 heterozygous individuals expressed higher levels of TNF-α after PMA/ionomycin stimulation, particularly under pH 6 conditions. pH sensing by GPR65 appears to be important for regulating the pathogenesis of atopic dermatitis.
GPR65 通过感知 pH 值来调节各种炎症状态，但它在皮肤中的作用尚不清楚。在这项研究中，我们进行了一项表型全基因组关联研究，报告称-内含子单核苷酸多态性 rs8005161 的 T 等位基因（该等位基因可降低 GPR65 信号）与特应性皮炎显著相关，除了先前报道的炎症性肠病和哮喘。与人类的这种遗传关联一致，我们发现小鼠中 GPR65 的缺失导致 MC903 特应性皮炎实验模型中的疾病明显加重。GPR65 的缺失也增加了体外中性粒细胞的迁移。此外，小鼠中 GPR65 的缺失导致 T 细胞中促炎细胞因子 TNF-α的表达增加。在人类中，PMA/离子霉素刺激后，rs8005161 杂合子个体的 CD4 T 细胞表达更高水平的 TNF-α，尤其是在 pH 值为 6 的条件下。GPR65 通过感知 pH 值来调节特应性皮炎发病机制似乎很重要。
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