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pH and Proton Sensor GPR65 Determine Susceptibility to Atopic Dermatitis
Liang Xie1,2, Craig I McKenzie3,4, Xinyan Qu5
1Department of Microbiology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia.
Journal of Immunology (Baltimore, Md. : 1950)
|June 17, 2021
Summary
GPR65 pH sensing is crucial for skin inflammation. Genetic variants linked to reduced GPR65 signaling correlate with atopic dermatitis, and GPR65 deficiency exacerbates this condition in mice.
Area of Science:
- Immunology
- Dermatology
- Genetics
Background:
- G protein-coupled receptor 65 (GPR65) is known to regulate inflammatory conditions.
- Its specific role in skin inflammation, particularly atopic dermatitis, has not been elucidated.
- GPR65 functions as a pH sensor, influencing cellular responses in acidic environments.
Purpose of the Study:
- To investigate the role of GPR65 in the pathogenesis of atopic dermatitis.
- To determine the association between GPR65 genetic variations and atopic dermatitis.
- To explore the functional impact of GPR65 deficiency on skin inflammation.
Main Methods:
- Phenome-wide association study (PWAS) to identify genetic associations with atopic dermatitis.
- Utilized a mouse model (MC903) to study atopic dermatitis development in GPR65-deficient mice.
- In vitro assays to assess neutrophil migration and T cell cytokine production (TNF-α) under varying pH conditions.
Main Results:
- A single-nucleotide polymorphism (rs8005161) in GPR65 was significantly associated with atopic dermatitis.
- GPR65-deficient mice exhibited exacerbated atopic dermatitis.
- GPR65 deficiency led to increased neutrophil migration and elevated TNF-α expression in T cells, especially at pH 6.
Conclusions:
- GPR65 plays a significant role in regulating the pathogenesis of atopic dermatitis.
- Genetic variations affecting GPR65 signaling are linked to increased susceptibility to atopic dermatitis.
- GPR65-mediated pH sensing is a key factor in controlling skin inflammation.
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