Journal club 2024.06.21

Neuronal BST2: A Pruritic Mediator alongside Protease-Activated Receptor 2 in the IL-27eDriven Itch Pathway

Yanqing Li1, Weiwei Chen1, Xingyun Zhu1, Huiyuan Mei1, Martin Steinhoff2,3,4,5,6,7,
Joerg Buddenkotte2,3,4, Jinhai Wang1, Wenhao Zhang1, Zhenghui Li8, Xiaolong Dai1, Chunxu Shan9, Jiafu Wang9,10 and Jianghui Meng9,10

1School of Life Sciences, Henan University, Henan, China; 2Department of Dermatology and Venereology, Hamad Medical Corporation, Doha, Qatar; 3Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar; 4Dermatology Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar; 5Department of Dermatology, Weill Cornell Medicine-Qatar, Doha, Qatar; 6College of Medicine, Qatar University, Doha, Qatar; 7Israel Englander Department of Dermatology, Weill Cornell Medicine, New York, New York, USA; 8Department of Neurosurgery, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, China; and 9School of Biotechnology, Faculty of Science and Health, Dublin City University, Dublin, Ireland 10These authors contributed equally as senior authors.\

Correspondence: Jianghui Meng, School of Biotechnology, Faculty of Science and Health, Dublin City University, Glasnevin Avenue, Dublin 9, Ireland. E-mail: Jianghui.meng@dcu.ie

Abbreviations: AD, atopic dermatitis; HC, healthy control; LAD, lesional atopic dermatitis; mTGN, murine trigeminal ganglionic neuron; PAR2, pro- tease-activated receptor 2; phKC, primary human keratinocyte; STAT, signal transducer and activator of transcription; Th, T helper

Received 29 October 2023; revised 11 January 2024; accepted 27 January 2024; accepted manuscript published online XXX; corrected proof published online XXX

Chronic itch is a common and complex symptom often associated with skin diseases such as atopic dermatitis (AD). Although IL-27 is linked to AD, its role and clinical significance in itch remain undefined. We sought to investigate IL-27 function in itch using tissue-specific transgenic mice, various itch models, behavior scoring, RNA sequencing, and cytokine/kinase array. Our findings show that IL-27 receptors were overexpressed in human AD skin. Intradermal IL-27 injection failed to directly induce itch in mice but upregulated skin protease- activated receptor 2 (PAR2) transcripts, a key factor in itch and AD. IL-27 activated human keratinocytes, increasing PAR2 transcription and activity. Coinjection of SLIGRL (PAR2 agonist) and IL-27 in mice heightened PAR2-mediated itch. In addition, IL-27 boosted BST2 transcription in sensory neurons and keratinocytes. BST2 was upregulated in AD skin, and its injection in mice induced itch-like response. BST2 colocalized with sensory nerve branches in AD skin from both human and murine models. Sensory neurons released BST2, and mice with sensory neuronespecific BST2 knockout displayed reduced itch responses. Overall, this study provides evidence that skin IL-27/PAR2 and neuronal IL-27/BST2 axes are implicated in cutaneous inflammation and pruritus. The discovery of neuronal BST2 in pruritus shed light on BST2 in the itch cascade.

Keywords: Atopic dermatitis, BST2, IL-27, itch, PAR2
Journal of Investigative Dermatology (2024) -, -e-; doi:10.1016/j.jid.2024.01.025