The skin is far more than a simple physical barrier. These two researches address a fundamental question in immunology: How does a localized skin infection or injury generate a powerful, systematic antibody response to protect against pathogen spread? The teams, including collaborators from the Chinese Academy of Medical Sciences Institute of Dermatology and Tsinghua's School of Pharmaceutical Sciences, provide a compelling answer centered on the keratinocyte.
In the first study, published on March 5, 2026, Beijing time, in the journal Nature, the researchers demonstrate that upon skin infection or ultraviolet exposure, keratinocytes rapidly accumulate a metabolic intermediate called farnesyl pyrophosphate (FPP) from the mevalonate pathway. This buildup is driven by the unfolded protein response activating SREBF transcription factors. Accumulated FPP then binds directly to the intracellular domain of TRPV3 on keratinocytes, triggering calcium influx. This calcium signal activates two parallel downstream pathways—Ca2+–CaM–calcineurin–NFAT and PYK2–RAS–ERK—which in turn drive the production of key immune mediators, namely IL-6 and CCL20. IL-6 promotes the differentiation of T follicular helper cells, while CCL20 recruits migratory dendritic cells to the draining lymph nodes. Together, these factors robustly enhance germinal center reactions, leading to the potent systemic production of pathogen-specific IgG antibodies and the generation of long-lived memory B cells and plasma cells. This establishes FPP as an endogenous "alarmin" that broadcasts a local danger signal to mobilize the entire adaptive immune system.
The companion study, published on the same day in Volume 2 of the journal Immunity & Inflammation, reveals an intriguing pharmacological dimension. The team discovered that two aromatic compounds derived from medicinal plants—Carvacrol and Camphor, known for their characteristic smells—can act as titratable organic adjuvants. When co-administered locally with an antigen, these compounds significantly amplified antigen-specific IgG responses in a dose-dependent manner, with no observed toxicity at effective doses in mouse models.
Mechanistically, Carvacrol and Camphor also activate TRPV3 on keratinocytes, triggering calcium influx and the subsequent upregulation of IL-6, CCL20, and TNF. Crucially, while the endogenous activator FPP requires binding to specific intracellular sites on TRPV3 (residues R416 and K581), these exogenous fragrant agonists activate the channel through a distinct, separable mechanism. This dual mode of activation—one metabolic and one sensory—highlights the versatility of TRPV3 as a molecular nexus integrating diverse signals.
"These findings reveal an elegant system where internal metabolic alarms and external sensory cues converge on the same pathway to calibrate immune responses," explained Professor Liu. "The fact that simple, plant-derived fragrant molecules can quantitatively boost antibody production opens up exciting new avenues for vaccine adjuvant design."
The implications of this work are far-reaching. First, it identifies TRPV3, along with downstream effectors IL-6 and CCL20, as novel potential therapeutic targets for autoimmune diseases like systemic lupus erythematosus, where aberrant B cell responses drive pathology. Second, it introduces a conceptually new class of adjuvants—titratable organic compounds that act locally to amplify systemic humoral immunity. Unlike traditional adjuvants that often trigger broad inflammation, these fragrant TRPV3 agonists offer a more targeted and potentially safer approach to enhancing vaccine efficacy, with particular promise for mucosal and anti-infective vaccines. By bridging metabolism, skin biology, and humoral immunity, these studies provide a foundational framework for understanding immune crosstalk and developing next-generation immunotherapies.
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Reference
DOI: 10.1007/s44466-026-00033-5
About Immunity & Inflammation
Immunity & Inflammation is a newly launched open-access journal co-published by the Chinese Society for Immunology and Springer Nature under the leadership of Editors-in-Chief Prof. Xuetao Cao and Prof. Jules A. Hoffmann. Immunity & Inflammation aims to publish major scientific questions and cutting-edge advances that explore groundbreaking discoveries and insights across the spectrum of immunity and inflammation, from basic science to translational and clinical research.
Website: https://link.springer.com/journal/44466
About the Authors
About Prof. Wanli Liu from Tsinghua University
Prof. Wan is a Tenured Professor in the School of Life Sciences at Tsinghua University and an investigator at the Tsinghua-Peking Joint Center for Life Sciences. He is a recipient of the National Science Fund for Distinguished Young Scholars and has been honored with the China Youth Science and Technology Award, the Tan Jiazhen Life Science Award, and the Shulan Medical Award. His research focuses on the molecular mechanisms of B-cell receptor-mediated immune activation and antibody responses.
About Prof. Qianjin Lu from Chinese Academy of Medical Sciences
Prof. Lu is a Tenured Professor at Peking Union Medical College, Executive Director of the Institute of Dermatology at the Chinese Academy of Medical Sciences. As the primary investigator, he has received numerous awards including the National Science and Technology Progress Award (Second Class), the ILDS Distinguished Service Award, the NACDA Distinguished Research Achievement Award in Dermatology, the Ho Leung Ho Lee Foundation Award for Outstanding Chinese Physicians, the Wu Jieping-Paul Janssen Medical Award, the Tan Jiazhen Clinical Medicine Award, and the National Award for Innovation and Excellence. His research focuses on the pathogenesis and clinical diagnosis, and treatment of immune-related skin diseases.
About Prof. Haijing Wu from Central South University
Prof. Wu is a Professor at the Second Xiangya Hospital of Central South University and a distinguished professor at the Furong Laboratory. Her research focuses on neuro-immune crosstalk, metabolic immunology, and the pathogenesis of autoimmune diseases.
Funding information
Wanli Liu is supported by grants from National Natural Science Foundation of China (32141004, 32430035, and 32441097), Shenzhen Medical Research Fund (C2404002 and B2402012), Ministry of Science and Technology of China Grants (2021YFC2302403) and Beijing Natural Science Foundation (Z230014). Qianjin Lu is supported by grants from National Key R&D Program of China (2022YFC3601800), the Major Program of the National Natural Science Foundation of China (82595960), the Key Program of National Natural Science Foundation of China (82430102), the Special Program of National Natural Science Foundation of China (NO. 32141004), the CAMS Innovation Fund for Medical Sciences (No.2021-I2M-1-059), and the Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences (2020-RC320-003). Haijing Wu is supported by grants from National Key R&D Program of China (2021YFC2702004), National Natural Science Foundation of China (82373448 and 82173425), the Major Scientific Research Program for High-Level Health Personnel in Hunan Province Health and Family Planning Commission (No.2023041), and the Hunan Provincial Natural Science Foundation Key Project (2025JJ30036). This study is also supported by research funds from Center for Life Sciences, Institute for Immunology at Tsinghua University.
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