IL-13-Amphiregulin pathway exacerbates itch in allergic contact dermatitis

Xiaolong Dai ¹, Xinrong Yan ¹, Michael Kitching ², Rengang Luo ², Renkai Zhu ², Owen Wang ³, Szymon Kupiec ⁴, Weiwei Chen ⁵, Jiafu Wang ², Jianghui Meng ⁶

J Invest Dermatol 2026 Oct 5:S0022-202X(26)03764-4.  doi: 10.1016/j.jid.2026.09.852.Online ahead of print.

Itch is an instinctive sensory response that provokes scratching and serves as a protective mechanism against potential threats. It is a pervasive and distressing symptom across many dermatological and systemic disorders, particularly atopic dermatitis (AD) and allergic contact dermatitis (ACD), each of which affects nearly 20% of the population. Persistent itch disrupts the skin barrier, fuelling disease chronicity through a self-perpetuating itch–scratch cycle that worsens lesions and diminishes quality of life. The underlying mechanisms remain largely unknown.
Amphiregulin (AREG), recently implicated in chronic pain is a member of the epidermal growth factor (EGF) family and a type 2 cytokine–associated protein that binds to the epidermal growth factor receptor (EGFR) to regulate cell proliferation, differentiation, and migration (Zaiss et al., 2015). Beyond epithelial cells, AREG is also produced by mast cells, basophils, type 2 innate lymphoid cells (ILC2s), and regulatory CD4⁺ T cells (Zaiss et al., 2015). Initially expressed as a membrane-anchored precursor protein, AREG is cleaved by ADAM17 (a disintegrin and metalloprotease 17), facilitating EGFR signalling that contributes to inflammation and tissue repair. AREG has been implicated in multiple inflammatory disorders, including psoriasis, arthritis, and AD, by promoting inflammatory cytokine expression, keratinocyte proliferation, and epidermal remodelling. However, the role of AREG dysregulation in itch pathogenesis remains undefined. This study aims to elucidate the role of AREG signalling in skin upon T 2 cytokine stimulation and the resulting alterations in
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neurocutaneous communication in both acute and chronic itch models. We will also evaluate the effect of an anti-AREG neutralising antibody on itch generation.