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TRPV3 facilitates metabolic alarmin-driven humoral immunity: from infection shielding to lupus flares

Cellular & Molecular Immunology (2026) Cite this article

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Barrier tissues are often viewed as local alarm systems that detect danger, recruit immune cells, and restore tissue integrity [1]. Increasing evidence indicates that the immune system may interpret barrier events as signals with systemic consequences [2]. Transient local infection at a barrier site may imprint durable antibody protection, whereas repeated barrier stress may coincide with systemic immune dysregulation [3]. As a complex autoimmune disease, systemic lupus erythematosus (SLE) exemplifies this intersection between epithelial disturbance and systemic autoimmunity. Cutaneous involvement is common, and humoral amplification marked by Tfh expansion, GC persistence, class-switched IgG, and immune-complex-driven organ damage forms a central pathological axis [4, 5]. A key unresolved question remains as to how local keratinocyte perturbation is converted into a distal lymph node program that establishes systemic antibody responses.

The first study redefined FPP, a mevalonate pathway intermediate, as an endogenous “metabolic alarmin.” Following infection or UV irradiation, keratinocyte stress programs increase mevalonate pathway activity, leading to intracellular FPP accumulation. The key mechanistic finding is that cytosolic FPP activates TRPV3, triggering Ca²⁺ influx and downstream signaling via Ca²⁺-dependent pathways that culminate in the induction of IL-6 and CCL20. Rather than producing a broad inflammatory cytokine burst, the keratinocyte module appears to be selectively tuned toward mediators that support humoral immune programming. IL-6 supports Tfh-linked programs that promote antibody production [8], while CCL20 organizes immune cell recruitment and positioning at barrier sites [9], thereby shaping downstream signals that drive lymph node priming. The results of this study follow these outputs from the epidermis to the lymph node, showing increased migratory dendritic cells, enhanced Tfh differentiation, stronger GC reactions, and higher antigen-specific IgG levels. These findings have important functional implications, demonstrating that the pathway enhances pathogen-specific antibody responses and improves protection against infection in a TRPV3-dependent manner. These observations present an evolved “infection-proofing” program that converts barrier perturbation into systemic humoral readiness, which will contribute to future vaccine design strategies.

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References

  1. Kabashima K, Honda T, Ginhoux F, Egawa G. The immunological anatomy of the skin. Nat Rev Immunol. 2019;19:19–30. https://doi.org/10.1038/s41577-018-0084-5.

    Article  CAS  PubMed  Google Scholar 

  2. Malissen B, Tamoutounour S, Henri S. The origins and functions of dendritic cells and macrophages in the skin. Nat Rev Immunol. 2014;14:417–28. https://doi.org/10.1038/nri3683.

    Article  CAS  PubMed  Google Scholar 

  3. Pasparakis M, Haase I, Nestle FO. Mechanisms regulating skin immunity and inflammation. Nat Rev Immunol. 2014;14:289–301. https://doi.org/10.1038/nri3646.

    Article  CAS  PubMed  Google Scholar 

  4. Victora GD, Nussenzweig MC. Germinal centers. Annu Rev Immunol. 2012;30:429–57. https://doi.org/10.1146/annurev-immunol-020711-075032.

    Article  CAS  PubMed  Google Scholar 

  5. Tangye SG, Ma CS, Brink R, Deenick EK. The good, the bad and the ugly — TFH cells in human health and disease. Nat Rev Immunol. 2013;13:412–26. https://doi.org/10.1038/nri3447.

    Article  CAS  PubMed  Google Scholar 

  6. Ji Z, Gao J, Zhang S, Li J, Wu H, Yao J, et al. A metabolic alarmin from keratinocytes potentiates systemic humoral immunity. Nature. 2026;652:209–19. https://doi.org/10.1038/s41586-026-10167-6.

    Article  CAS  PubMed  Google Scholar 

  7. Ji Z, Gao J, Xin Y, Li C, Lu Q, Wu H, et al. Fragrant TRPV3 agonists act as titratable organic adjuvants to amplify antigen-specific IgG response. Immun Inflamm. 2026;2:15 https://doi.org/10.1007/s44466-026-00033-5.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Dienz O, Eaton SM, Bond JP, Neveu W, Moquin D, Noubade R, et al. The induction of antibody production by IL-6 is indirectly mediated by IL-21 produced by CD4+ T cells. J Exp Med. 2009;206:69–78. https://doi.org/10.1084/jem.20081571.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Schutyser E, Struyf S, Van Damme J. The CC chemokine CCL20 and its receptor CCR6. Cytokine Growth Factor Rev. 2003;14:409–26. https://doi.org/10.1016/S1359-6101(03)00049-2.

    Article  CAS  PubMed  Google Scholar 

  10. Peier AM, Reeve AJ, Andersson DA, Moqrich A, Earley TJ, Hergarden AC, et al. A heat-sensitive TRP channel expressed in keratinocytes. Science. 2002;296:2046–9. https://doi.org/10.1126/science.1073140.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank colleagues for discussions on barrier immunology, humoral amplification, and lupus pathogenesis. Owing to space constraints, we apologize that we were unable to include citations in all the relevant studies. This work was supported by the National Natural Science Foundation of China (U25A6004, 82471821), the Hong Kong Research Grants Council (17116424, 17111222, 17103821), and the Centre for Oncology and Immunology under the Health@InnoHK Initiative funded by the Innovation and Technology Commission, Hong Kong, China.

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  1. These authors contributed equally: Yuxin Li, Yile E. Liu.

Authors and Affiliations

  1. School of Management & Engineering, Nanjing University, Nanjing, China

    Yuxin Li

  2. Jiangsu Key Laboratory of Digital Finance, Suzhou, China

    Yuxin Li

  3. The First Affiliated Hospital of Anhui Medical University and Institute of Clinical Immunology, Anhui Medical University, Hefei, China

    Yile E. Liu

  4. State Key Laboratory of Membrane Biology, School of Life Sciences, Tsinghua-Peking Center for Life Sciences, Institute for Immunology, Ministry of Education Key Laboratory of Protein Sciences, Tsinghua University, Beijing, China

    Jiachen Zhang

  5. Department of Laboratory Medicine, Institute of Medical Immunology of Jiangsu University, Affiliated Hospital of Jiangsu University, Zhenjiang, China

    Ke Rui

  6. Department of Pathology, Shenzhen Institute of Research and Innovation, University of Hong Kong, Hong Kong, China

    Liwei Lu

  7. Centre for Oncology and Immunology, Hong Kong, Science Park, Hong Kong, China

    Liwei Lu

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  1. Yuxin Li
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  2. Yile E. Liu
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Contributions

LL conceptualized the study. YL and YEL wrote the manuscript, with LL contributing to its drafting. JZ and KR revised the manuscript. All the authors have read and approved the manuscript.

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Correspondence to Liwei Lu.

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The author declares that there are no competing interests. LL is an editorial board member of Cellular & Molecular Immunology, but he has not been involved in peer review or decision-making related to the article.

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Li, Y., Liu, Y.E., Zhang, J. et al. TRPV3 facilitates metabolic alarmin-driven humoral immunity: from infection shielding to lupus flares. Cell Mol Immunol (2026). https://doi.org/10.1038/s41423-026-01433-8

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