角质形成细胞的代谢警告蛋白增强全身体液免疫
A metabolic alarmin from keratinocytes potentiates systemic humoral immunity.
摘要(中文译文)
局部感染如何引发全身体液免疫尚不清楚。在这里，我们鉴定出焦磷酸法尼酯（FPP），一种甲羟戊酸途径代谢中间体，是一种内源性报警蛋白，通过角质形成细胞衍生的IL-6和CCL20增强IgG抗体反应。该信号轴增强T滤泡辅助细胞和迁移性树突状细胞的分化。感染或紫外线照射后，FPP通过激活由未折叠蛋白反应SREBF途径介导的甲羟戊酸途径在角质形成细胞内积聚，放大引流淋巴结中的生发中心（GC）反应。从机制上讲，细胞质中积累的FPP通过与其细胞内结构域结合，诱导钙内流，从而激活钙调素-钙调神经磷酸酶NFAT和PYK2-RAS-ERK通路，增强IL-6和CCL20的产生，从而与瞬时受体电位香草酸3（TRPV3）结合。这种FPP-TRPV3-IL-6/CCL20-GC轴增强了病原体特异性抗体的产生，在野生型小鼠中提供了保护，但在TRPV3缺陷小鼠中没有。系统性红斑狼疮（SLE）皮肤病变和病原体感染的小鼠皮肤的单细胞RNA测序分析表明，该信号轴过度激活，特别是在TRPV3角质形成细胞亚群中。在SLE的小鼠模型中，该轴的激活与疾病病理的加重有关。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。
Abstract
How a local infection triggers systemic humoral immunity remains unclear. Here we identify farnesyl pyrophosphate (FPP), a mevalonate pathway metabolic intermediate, 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 cells. 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 Ca 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 TRPV3 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.
如何引用
AMA
Zhenglin Ji, Ji Gao, Shaocun Zhang, Jiajie Li, Haijing Wu, Jing Yao, et al. A metabolic alarmin from keratinocytes potentiates systemic humoral immunity.. Nature. 2026; doi:10.1038/s41586-026-10167-6.
APA
Zhenglin Ji, Ji Gao, Shaocun Zhang, Jiajie Li, Haijing Wu, Jing Yao, et al (2026). A metabolic alarmin from keratinocytes potentiates systemic humoral immunity.. Nature. https://doi.org/10.1038/s41586-026-10167-6
GB/T 7714
Zhenglin Ji, Ji Gao, Shaocun Zhang, Jiajie Li, Haijing Wu, Jing Yao, et al. A metabolic alarmin from keratinocytes potentiates systemic humoral immunity.[J]. Nature, 2026 doi:10.1038/s41586-026-10167-6.
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