角质形成细胞释放的代谢性警报素增强系统性体液免疫，这一成果由清华大学刘万里课题组经过不懈努力而取得。相关论文于2026年3月4日发表于国际顶尖学术期刊《自然》杂志上。

本研究发现，甲羟戊酸途径代谢中间体法尼酯焦磷酸（FPP）作为内源性警报蛋白，可通过角化细胞衍生的IL-6和CCL20增强IgG抗体反应。这个信号轴增强了T滤泡辅助细胞和迁移树突状细胞的分化。感染或紫外线照射后，FPP通过未折叠蛋白反应-SREBF途径介导的甲羟戊酸途径的激活在角化细胞内积累，放大引流淋巴结的生发中心（GC）反应。

在机制上，胞质中积累的FPP通过与其胞内结构域结合，诱导Ca²⁺内流，随后激活钙调素-钙调磷酸酶-NFAT和PYK2-RAS-ERK途径，从而增强IL-6和CCL20的产生。这条FPP-TRPV3-IL-6 / CCL20-GC轴增强了病原体特异性抗体的产生，在野生型而非trpv3缺陷小鼠中具有保护作用。系统性红斑狼疮（SLE）皮肤病变和病原体感染的同主题皮肤的单细胞RNA测序分析表明，该信号轴过度激活，特别是在TRPV3高角化细胞亚群中。在无主题的SLE模型中，该轴的激活与疾病病理加剧相关。因此，FPP通过TRPV3-IL-6 / CCL20-GC信号轴增强全身体液免疫，为SLE疫苗佐剂和潜在治疗方法的开发提供了见解。

据介绍，局部感染如何引发全身体液免疫尚不清楚。

附：英文原文

Title: A metabolic alarmin from keratinocytes potentiates systemic humoral immunity

Author: Ji, Zhenglin, Gao, Ji, Zhang, Shaocun, Li, Jiajie, Wu, Haijing, Yao, Jing, Ma, Xianqiang, Xin, Yue, Zhu, Yongjie, Zhao, Meng, Zhao, Zhidan, Shen, Kai, Wu, Tao, Qian, Xinmin, Wang, Juanjuan, An, Haoran, Li, Yuxin, Sun, Wenbo, Zhao, Qiancheng, Zhou, Xiaoying, Gao, Ruiyu, Duan, Qinghui, Li, Cuifeng, Geng, Xiaoke, Yang, Ming, Xiao, Rong, Liu, Juan, Wang, Wang, Wang, Ji, Fu, Yesheng, Zhang, Jing-Ren, Chen, Xiangjun, Tong, Pei, Cheng, Gong, Qi, Hai, Wu, Li, Zeng, Wenwen, Xi, Qiaoran, Zhang, Lingqiang, Lai, Yuping, Yang, Wei, Zhang, Yonghui, Lu, Qianjin, Liu, Wanli

Issue&Volume: 2026-03-04

Abstract: How a local infection triggers systemic humoral immunity remains unclear. Here we identify farnesyl pyrophosphate (FPP), a mevalonate pathway metabolic intermediate1, as an endogenous alarmin that enhances IgG antibody responses through keratinocyte-derived IL-6 and CCL20. This signalling axis potentiates the differentiation of T follicular helper cells and migratory dendritic cells2,3. FPP accumulates within keratinocytes after infection or ultraviolet irradiation through the activation of the mevalonate pathway mediated by the unfolded protein response–SREBF pathway, amplifying germinal centre (GC) responses in draining lymph nodes. Mechanistically, accumulated FPP in the cytosol engages transient receptor potential vanilloid 3 (TRPV3) by binding to its intracellular domains, inducing Ca2+ influx that subsequently activates the calmodulin–calcineurin–NFAT and PYK2–RAS–ERK pathways to enhance IL-6 and CCL20 production. This FPP–TRPV3–IL-6/CCL20–GC axis potentiates pathogen-specific antibody production, conferring protection in wild-type but not TRPV3-deficient mice. Single-cell RNA-sequencing analyses of systemic lupus erythematosus (SLE) skin lesions and pathogen-infected mouse skin demonstrate hyperactivation of this signalling axis, particularly in the TRPV3high keratinocyte subset. In mouse models of SLE, the activation of this axis correlates with exacerbated disease pathology. Thus, FPP potentiates systemic humoral immunity through the TRPV3–IL-6/CCL20–GC signalling axis, providing insights for the development of vaccine adjuvants and potential therapeutics for SLE.

DOI: 10.1038/s41586-026-10167-6

Source: https://www.nature.com/articles/s41586-026-10167-6