Hyperglycemia aggravates vitiligo through succinate/SUCNR1-mediated T cell activation
Pan Kang, Yuqian Chang, Tingting Wang, Xiuli Yi, Yinghan Wang, Pengran Du, Jiaxi Chen, Baizhang Li, Shuli Li, Zhongjun Shao, Jianru Chen, Chunying Li
Pan Kang, Yuqian Chang, Tingting Wang, Xiuli Yi, Yinghan Wang, Pengran Du, Jiaxi Chen, Baizhang Li, Shuli Li, Zhongjun Shao, Jianru Chen, Chunying Li
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Research Article Autoimmunity Dermatology Immunology

Hyperglycemia aggravates vitiligo through succinate/SUCNR1-mediated T cell activation

Abstract

Vitiligo is an autoimmune skin disease characterized by depigmentation, mainly due to CD8+ T cell–mediated destruction of melanocytes. Hyperglycemia exacerbates autoimmune responses and is associated with vitiligo; however, the underlying immunometabolic mechanisms are poorly understood. Here, we demonstrated the correlation between hyperglycemia and vitiligo in a case-control study and demonstrated that hyperglycemia aggravated vitiligo based on a mouse model. Targeted metabolomics identified succinate as the potential metabolite mediating hyperglycemia-aggravated vitiligo. Mechanistically, succinate promotes the activation of CD8+ T cells through succinate receptor 1 (SUCNR1) and promotes keratinocytes to secrete CXCL9 and CXCL10 by enhancing the stability and nuclear translocation of hypoxia-inducible factor-1α, facilitating the skin-homing of CD8+ T cells. Thus, hyperglycemia aggravates vitiligo through succinate/SUCNR1 axis–regulated CD8+ T cell hyperactivation. Our study provides insights into the long-observed yet previously unclear mechanism by which hyperglycemia accelerates vitiligo progression and highlights SUCNR1 as a potential therapeutic target.

Authors

Pan Kang, Yuqian Chang, Tingting Wang, Xiuli Yi, Yinghan Wang, Pengran Du, Jiaxi Chen, Baizhang Li, Shuli Li, Zhongjun Shao, Jianru Chen, Chunying Li

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Figure 6

Succinate aggravates vitiligo through SUCNR1.

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Succinate aggravates vitiligo through SUCNR1. (A) Schematic presentation...
(A) Schematic presentation of vitiligo, hyperglycemia, and succinate-treated mouse model establishment. Thus, 3 groups of mice (Vitiligo, Vitiligo + Hyperglycemia, Vitiligo + Succinate) were studied here. (B) Representative tail skin images of mice in each group at week 10 and the tail pigmentation percentages of mice in each group (n = 4) in 10 consecutive weeks. (C) Representative whole-mount immunofluorescence staining images (upper) and corresponding heatmaps (low) of melanocytes (red) and CD8+ T cells (green) in the tail skin epidermis of mice in each group. Numbers of melanocytes and CD8+ T cells in each group (n = 4) are shown. (D) Quantification of CD45–CD117+ melanocytes and CD3+CD8+ T cells in tail epidermis of mice in each group (n = 4). Data are presented as mean ± SEM and analyzed by 1-way ANOVA (B–D). **P < 0.01; ***P < 0.001. Vit, vitiligo; Hg, hyperglycemia; Succ, succinate.