2. Academic Validation
  3. A metabolic alarmin from keratinocytes potentiates systemic humoral immunity

A metabolic alarmin from keratinocytes potentiates systemic humoral immunity

  • Nature. 2026 Apr;652(8108):209-219. doi: 10.1038/s41586-026-10167-6.
Zhenglin Ji # 1 2,  Ji Gao # 1,  Shaocun Zhang # 3,  Jiajie Li # 1,  Haijing Wu # 4 5,  Jing Yao # 6,  Xianqiang Ma # 7,  Yue Xin # 4,  Yongjie Zhu # 1,  Meng Zhao # 1,  Zhidan Zhao 4,  Kai Shen 4,  Tao Wu 8,  Xinmin Qian 8,  Juanjuan Wang 9,  Haoran An 9,  Yuxin Li 1,  Wenbo Sun 1,  Qiancheng Zhao 7,  Xiaoying Zhou 7,  Ruiyu Gao 1,  Qinghui Duan 1,  Cuifeng Li 1 2,  Xiaoke Geng 1,  Ming Yang 4,  Rong Xiao 4,  Juan Liu 10,  Wang Wang 11,  Ji Wang 12,  Yesheng Fu 13,  Jing-Ren Zhang 9,  Xiangjun Chen 14,  Pei Tong 15,  Gong Cheng 9,  Hai Qi 8,  Li Wu 8,  Wenwen Zeng 8,  Qiaoran Xi 1,  Lingqiang Zhang 13,  Yuping Lai 11,  Wei Yang 6,  Yonghui Zhang 16,  Qianjin Lu 17 18,  Wanli Liu 19
Affiliations

Affiliations

  • 1 State Key Laboratory of Membrane Biology, School of Life Sciences, Tsinghua-Peking Center for Life Sciences, Institute for Immunology, China Ministry of Education Key Laboratory of Protein Sciences, Tsinghua University, Beijing, China.
  • 2 The First Affiliated Hospital of Anhui Medical University, Institute of Clinical Immunology, Hefei, China.
  • 3 Department of Rheumatology and Immunology, Peking University Third Hospital, Beijing, China.
  • 4 Department of Dermatology, the Second Xiangya Hospital of Central South University, Hunan Key Laboratory of Medical Epigenomics, Changsha, China.
  • 5 The Furong Laboratory, Changsha, China.
  • 6 Department of Biophysics, Department of Neurobiology of the Fourth Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
  • 7 School of Pharmaceutical Sciences, Tsinghua-Peking Center for Life Sciences, Beijing Frontier Research Center for Biological Structure, Tsinghua University, Beijing, China.
  • 8 Institute for Immunology, School of Medicine, Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing, China.
  • 9 Center for Infectious Disease Research, School of Medicine, Tsinghua University, Beijing, China.
  • 10 National Key Laboratory of Immunity and Inflammation, Naval Medical University, Shanghai, China.
  • 11 Shanghai Key Laboratory of Regulatory Biology, School of Life Sciences, East China Normal University, Shanghai, China.
  • 12 Institute of Precision Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
  • 13 State Key Laboratory of Medical Proteomics, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, China.
  • 14 Zhejiang Key Laboratory of Multi-Omics in Infection and Immunity, Center for Infectious Disease Research, School of Medicine, Westlake University, Hangzhou, China.
  • 15 Key Laboratory of Immune Response and Immunotherapy, Institute of Health and Medicine, Hefei Comprehensive National Science Center, Hefei, China.
  • 16 School of Pharmaceutical Sciences, Tsinghua-Peking Center for Life Sciences, Beijing Frontier Research Center for Biological Structure, Tsinghua University, Beijing, China. [email protected].
  • 17 Department of Dermatology, the Second Xiangya Hospital of Central South University, Hunan Key Laboratory of Medical Epigenomics, Changsha, China. [email protected].
  • 18 Hospital for Skin Diseases, Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing, China. [email protected].
  • 19 State Key Laboratory of Membrane Biology, School of Life Sciences, Tsinghua-Peking Center for Life Sciences, Institute for Immunology, China Ministry of Education Key Laboratory of Protein Sciences, Tsinghua University, Beijing, China. [email protected].
  • # Contributed equally.
PMID: 41781621 DOI: 10.1038/s41586-026-10167-6
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.

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