CB2R-cAMP-Epac1 pathway orchestrates epithelial-neural-immune interactions in atopic dermatitis

Ximin Hu¹, Yi Luo², Yiya Zhang³, Kun Liu⁴, Liyan Wu⁵, Jinjun Hou⁶, Guodun Zhao⁵, Ting Wang⁵, Yifei Liu⁵, Hongyi Cheng⁴, Xia Li⁴, Lei Zhang⁵, Libei Liu⁷, Wanying Wu⁶, Ronghua Yang⁸, Xinyan Gao⁴, Ji Li³, Heng Xu⁹, Jing Feng¹⁰

Affiliations

¹ State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Shanghai, China; Department of Burn and Plastic Surgery, Guangzhou First People's Hospital, South China University of Technology, Guangzhou, China; Department of Dermatology, Xiangya Hospital, Central South University, Changsha, China.
² State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Shanghai, China; Department of Plastic and Reconstructive Surgery, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
³ Department of Dermatology, Xiangya Hospital, Central South University, Changsha, China; Hunan Key Laboratory of Aging Biology, Xiangya Hospital, Central South University, Changsha, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China.
⁴ Institute of Acupuncture and Moxibustion, China Academy of Chinese Medical Sciences, Beijing, China.
⁵ State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Shanghai, China.
⁶ State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Shanghai, China; National Engineering Research Center of TCM Standardization Technology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
⁷ Department of Dermatology, Xiangya Hospital, Central South University, Changsha, China.
⁸ Department of Burn and Plastic Surgery, Guangzhou First People's Hospital, South China University of Technology, Guangzhou, China.
⁹ Department of Plastic and Reconstructive Surgery, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. Electronic address: xuh1990@gmail.com.
¹⁰ State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Shanghai, China; University of Chinese Academy of Sciences, Beijing, China. Electronic address: fengjing@simm.ac.cn.

PMID: 40930299
DOI: 10.1016/j.jaci.2025.08.021

CB2R-cAMP-Epac1 pathway orchestrates epithelial-neural-immune interactions in atopic dermatitis

Ximin Hu et al. J Allergy Clin Immunol. 2025.

. 2025 Sep 8:S0091-6749(25)00937-6.

doi: 10.1016/j.jaci.2025.08.021. Online ahead of print.

Authors

Affiliations

¹ State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Shanghai, China; Department of Burn and Plastic Surgery, Guangzhou First People's Hospital, South China University of Technology, Guangzhou, China; Department of Dermatology, Xiangya Hospital, Central South University, Changsha, China.
² State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Shanghai, China; Department of Plastic and Reconstructive Surgery, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
³ Department of Dermatology, Xiangya Hospital, Central South University, Changsha, China; Hunan Key Laboratory of Aging Biology, Xiangya Hospital, Central South University, Changsha, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China.
⁴ Institute of Acupuncture and Moxibustion, China Academy of Chinese Medical Sciences, Beijing, China.
⁵ State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Shanghai, China.
⁶ State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Shanghai, China; National Engineering Research Center of TCM Standardization Technology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
⁷ Department of Dermatology, Xiangya Hospital, Central South University, Changsha, China.
⁸ Department of Burn and Plastic Surgery, Guangzhou First People's Hospital, South China University of Technology, Guangzhou, China.
⁹ Department of Plastic and Reconstructive Surgery, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. Electronic address: xuh1990@gmail.com.
¹⁰ State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Shanghai, China; University of Chinese Academy of Sciences, Beijing, China. Electronic address: fengjing@simm.ac.cn.

PMID: 40930299
DOI: 10.1016/j.jaci.2025.08.021

Abstract

Background: Keratinocytes form the skin's first line of defense, not only serving as a physical barrier but also actively communicating with immune cells and sensory neurons.

Objective: This study elucidated the molecular mechanisms by which keratinocytes contribute to barrier dysfunction and neuroimmune activation in atopic dermatitis (AD).

Methods: Cannabinoid receptor 2 (CB2R) expression was assessed by RNA sequencing, quantitative reverse transcription PCR (qRT-PCR), RNAscope fluorescence, and Western blot analysis. Pharmacologic activation/inhibition or keratinocyte-specific deletion of CB2R was used to determine its role in AD-associated itch and inflammation. Behavioral assays, immunofluorescence, and qRT-PCR were used to identify downstream signaling components.

Results: CB2R expression was upregulated in the epidermis of MC903-induced AD. CB2R activation alleviated scratching and skin pathology, whereas keratinocyte-specific CB2R deletion exacerbated both. CB2R suppressed adenylate cyclase 3 activity, reducing cAMP levels and downstream Epac1 activation, thereby limiting IL-33 production. This CB2R-cAMP-Epac1-IL-33 axis regulated epidermal hyperplasia, dermal neutrophil infiltration, and chronic itch.

Conclusion: The keratinocyte CB2R-cAMP-Epac1 axis integrates epithelial, neural, and immune signaling to drive AD pathology, representing a potential therapeutic target for chronic itch and skin inflammation.

Keywords: Atopic dermatitis; CB2R; Epac1; chronic itch; keratinocyte.

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Conflict of interest statement

Disclosure statement Supported by grants from the National Natural Science Foundation of China (grants 82571383, 82171214, 82572881, 32241003, 82471233, and U24A20783) and the Shanghai Municipal Natural Science Foundation (23ZR1474500). Also supported by the National Key Research and Development Program of China (2024YFC3505305), the Strategic Priority Research Program of the Chinese Academy of Sciences (XDB1060000), the Shanghai Rising Star Program (24QB2701200), and the Shanghai “Rising Stars of Medical Talents” Youth Development Program (SHWSRS(2023)_26). Disclosure of potential conflict of interest: The authors declare that they have no relevant conflicts of interest.

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CB2R-cAMP-Epac1 pathway orchestrates epithelial-neural-immune interactions in atopic dermatitis

Affiliations

CB2R-cAMP-Epac1 pathway orchestrates epithelial-neural-immune interactions in atopic dermatitis

Authors

Affiliations

Abstract

Conflict of interest statement

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Research Materials