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 8

Succinate-induced chemokine secretion via SUCNR1 in keratinocytes promotes CD8+ T cell migration.

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Succinate-induced chemokine secretion via SUCNR1 in keratinocytes promot...
(A) Representative immunofluorescence images and quantification of SUCNR1 (red) in keratinocytes from vitiligo patients and healthy controls (n = 5). Keratinocytes were characterized by cytokeratin 14 (green); nuclei were counterstained with DAPI (blue). Scale bars: 50 μm (left), 10 μm (middle and right). (B) The mRNA level of SUCNR1 in NHKs treated with succinate. (C) Representative images of SUCNR1 expression in succinate-treated NHKs. (D) The mRNA levels of CXCL9 and CXCL10 in NHKs treated with succinate. (E) The secretion of CXCL9 and CXCL10 in NHKs treated with succinate. (F and G) The mRNA (F) and secretion (G) levels of CXCL9 and CXCL10 in NHKs treated with succinate or pretreated with SUCNR1 siRNA prior to succinate stimulation. (H) Transwell assay showing the percentage of migrated CD8+ T cells in response to culture supernatants from succinate-treated NHKs with knockdown of SUCNR1 or with the addition of rhCXCL9 or rhCXCL10 into the Transwell system. Data are presented as mean ± SEM (A, B, and D–H) and analyzed by Student’s t test (A, B, D, and E) or 1-way ANOVA (F–H). *P < 0.05, **P < 0.01, ***P < 0.001. NHKs, normal human keratinocytes; Ctrl, control; Succ, succinate; rhCXCL9, recombinant human CXCL9; rhCXCL10, recombinant human CXCL10; rMFI, relative mean fluorescence intensity.