Cao Xuechen, Yu Yongkai, Yao Hang, Zheng Yujie, Lu Jiawei, Feng Yifei, Pei Tongxin, Li Ziyu, Lu Ming, Lu Yan
Department of Dermatology, Jiangsu Province Hospital and Nanjing Medical University First Affiliated Hospital, Nanjing, Jiangsu, 210029, China.
Department of Pharmacology, Jiangsu Key Laboratory of Neurodegeneration, Nanjing Medical University, Nanjing, Jiangsu, 211166, China.
Mol Med. 2025 May 14;31(1):186. doi: 10.1186/s10020-025-01236-z.
Vitiligo is an acquired skin depigmentation disorder often accompanied by leukoderma and leukotrichia. Half of vitiligo patients experience episodes of stress.
We established a chronic unpredictable mild stimulation (CUMS) model in C57BL/6 J mice to simulate chronic mental stress-induced leukoderma and leukotrichia. Single-cell RNA sequencing was performed to determine the immune landscape and to characterize the relationship between immune-stromal cells. Immunohistochemistry was employed for validation.
We discovered a similar pro-inflammatory micro-environment composed of keratinocytes and fibroblasts similar to that in human vitiligo. Macrophages in CUMS mice expressed high levels of inflammatory factors and were inclined to an M1 pro-inflammatory phenotype. Two distinct clusters of melanocytes were also identified: Mel2, defined as melanocyte stem cells, and Mel3, defined as mature melanocytes. Mel2 cells were prone to pyroptosis and necroptosis, while Mel3 cells were susceptible to oxidative stress, mitochondrial dysfunction, and ferroptosis. Compared with control mice, higher expression of CXCL16 on dendritic cells and of the CXCL16 ligand, CXCR6, on γδT cells were observed in leukoderma. Dendritic cells and natural killer T cells in the CUMS mouse spleen exhibited elevated levels of CXCL16 and CXCR6, respectively. Activation of the CXCL16-CXCR6 axis and a non-specific immune response in our CUMS model might imitate chronic mental stress-induced vitiligo in humans better than CD8 + cytotoxic T lymphocyte-mediated models.
We discovered two melanocyte clusters with distinct fates and a pro-inflammatory micro-environment with CXCL16-CXCR6 axis activation of antigen-presenting cells and other innate immunocytes that might provide new insights into the pathogenesis of stress-induced vitiligo.
白癜风是一种获得性皮肤色素脱失性疾病，常伴有白斑和白发。一半的白癜风患者会经历应激发作。
我们在C57BL/6 J小鼠中建立了慢性不可预测轻度刺激（CUMS）模型，以模拟慢性精神应激诱导的白斑和白发。进行单细胞RNA测序以确定免疫格局并表征免疫基质细胞之间的关系。采用免疫组织化学进行验证。
我们发现了一种由角质形成细胞和成纤维细胞组成的类似人类白癜风的促炎微环境。CUMS小鼠中的巨噬细胞表达高水平的炎症因子，并倾向于M1促炎表型。还鉴定出了两个不同的黑素细胞簇：Mel2，定义为黑素细胞干细胞；Mel3，定义为成熟黑素细胞。Mel2细胞易发生焦亡和坏死性凋亡，而Mel3细胞易受氧化应激、线粒体功能障碍和铁死亡的影响。与对照小鼠相比，在白斑中观察到树突状细胞上CXCL16以及γδT细胞上CXCL16配体CXCR6的表达更高。CUMS小鼠脾脏中的树突状细胞和自然杀伤T细胞分别表现出CXCL16和CXCR6水平升高。与CD8 + 细胞毒性T淋巴细胞介导的模型相比，我们的CUMS模型中CXCL16 - CXCR6轴的激活和非特异性免疫反应可能更能模拟人类慢性精神应激诱导的白癜风。
我们发现了两个命运不同的黑素细胞簇以及一个抗原呈递细胞和其他先天免疫细胞激活CXCL16 - CXCR6轴的促炎微环境，这可能为应激诱导型白癜风的发病机制提供新的见解。
