Aberrant amino acid metabolism promotes neurovascular reactivity in rosacea
Tangxiele Liu, … , Zhili Deng, Ji Li
Tangxiele Liu, … , Zhili Deng, Ji Li
Published October 11, 2022
Citation Information: JCI Insight. 2022;7(22):e161870. https://doi.org/10.1172/jci.insight.161870.
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Research Article Dermatology Metabolism

Aberrant amino acid metabolism promotes neurovascular reactivity in rosacea

Abstract

Rosacea is a chronic skin disorder characterized by abnormal neurovascular and inflammatory conditions on the central face. Despite increasing evidence suggesting that rosacea is associated with metabolic disorders, the role of metabolism in rosacea pathogenesis remains unknown. Here, via a targeted metabolomics approach, we characterized significantly altered metabolic signatures in patients with rosacea, especially for amino acid-related metabolic pathways. Among these, glutamic acid and aspartic acid were highlighted and positively correlated with the disease severity in patients with rosacea. We further demonstrated that glutamic acid and aspartic acid can facilitate the development of erythema and telangiectasia, typical features of rosacea, in the skin of mice. Mechanistically, glutamic acid and aspartic acid stimulated the production of vasodilation-related neuropeptides from peripheral neurons and keratinocytes and induced the release of nitric oxide from endothelial cells and keratinocytes. Interestingly, we provided evidence showing that doxycycline can improve the symptoms of patients with rosacea possibly by targeting the amino acid metabolic pathway. These findings reveal that abnormal amino acid metabolism promotes neurovascular reactivity in rosacea and raise the possibility of targeting dysregulated metabolism as a promising strategy for clinical treatment.

Authors

Tangxiele Liu, Wenqin Xiao, Mengting Chen, Rui Mao, Xu San, Qinqin Peng, Zhixiang Zhao, Qian Wang, Hongfu Xie, Zhili Deng, Ji Li

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Figure 4

Glutamic acid and aspartic acid stimulate the production of NO from endothelial cells and keratinocytes.

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Glutamic acid and aspartic acid stimulate the production of NO from endo...
(A) Representative immunofluorescence images showing CD31 (green) and p-eNOS (red) (CD31, labeling vascular endothelial cells) expression on ear sections from amino acid gavage mice and control group. White arrows indicate the CD31+p-eNOS– endothelial cells; yellow arrows indicate the CD31+p-eNOS+ endothelial cells; white asterisks indicate the ear cartilage with the nonspecific staining or autofluorescence signals. DAPI staining (blue) indicates nuclear localization. Epi, epidermis; Der, dermis. Scale bar, 100 μm. (B) Percentage of p-eNOS+ endothelial cells (n = 5 for each group). (C) The quantification of relative fluorescence intensity in epidermis for p-eNOS (n = 5 for each group). (D) Immunoblot analysis of the p-eNOS and total eNOS in cell lysates from HDMECs after glutamic acid or aspartic acid treatment. Lamin B is the loading control. p-eNOS protein levels were analyzed relative to total eNOS. (E) DAF-FM DA staining in HDMEC after glutamic acid or aspartic acid treatment. Scale bar, 100 μm. (F) Quantification of intensity of DAF-FM DA fluorescence in HDMECs under the designated treatments (n = 30 cells). The quantification results are representative of at least 3 independent experiments. (G) Immunoblot analysis of the p-eNOS and total eNOS in cell lysates from HaCaT keratinocytes after glutamic acid or aspartic acid treatment. Lamin B is the loading control. Protein levels of p-eNOS were analyzed relative to total eNOS. (H) DAF-FM DA staining in HaCaT keratinocytes after glutamic acid or aspartic acid treatment. Scale bar, 100 μm. (I) Quantification of intensity of DAF-FM DA fluorescence in HaCaT keratinocytes under the designated treatments (n = 30 cells). The quantification results are representative of at least 3 independent experiments. All results are representative of at least 3 independent experiments. Data represent the mean ± SEM. **P < 0.01, ***P < 0.001. One-way ANOVA with Bonferroni’s post hoc test was used.