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. 2025 Oct;156(4):1066-1081.e12.
doi: 10.1016/j.jaci.2025.05.011. Epub 2025 May 26.

Type 2 cytokines pleiotropically modulate sensory nerve architecture and neuroimmune interactions to mediate itch

Mithilesh Kumar Jha  1 , Yingnan Han  2 , Zhipeng Liu  2 , Yannis Hara  1 , Ingeborg M Langohr  3 , Caroline Morel  3 , Colleen L Maloney  3 , Peter Piepenhagen  3 , Heming Xing  2 , Corneliu A Bodea  2 , Dinesh S Bangari  3 , Hamid Mattoo  2 , Alexandra Hicks  4
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Free article

Type 2 cytokines pleiotropically modulate sensory nerve architecture and neuroimmune interactions to mediate itch

Mithilesh Kumar Jha et al. J Allergy Clin Immunol. 2025 Oct.
Free article

Abstract

Background: Anti-type 2 cytokine therapies represent promising interventions for chronic itch; however, their precise mechanisms in restoring nerve architecture and mitigating inflammation and pruritus remain incompletely understood.

Objectives: This study aimed to elucidate the mechanistic roles of IL-4, IL-13, and IL-31 in the pathophysiology of itch associated with type 2 inflammatory skin diseases.

Methods: The effect of IL-4, IL-13, and/or IL-31 on neurite outgrowth and/or transcriptomic changes was analyzed in human and mouse dorsal root ganglion (DRG) neuronal cultures. Mouse ear pinnae were processed for histologic, transcriptomic, and proteomic analyses 4 days after intradermal injection of IL-4, IL-13, and/or IL-31. To evaluate functional correlations with neuronal responses, mice were subcutaneously challenged with IL-4, IL-13, and/or IL-31, and scratching behavior was monitored. Association between IL-4/IL-13-IL-4Rα axis and severity of atopic dermatitis was evaluated through correlative analyses of human DRG transcriptomic changes and atopic dermatitis transcriptomic datasets (GSE130588 and BioMaP-Consortium).

Results: IL-4 and IL-13 promote mouse and human DRG sensory neuron growth, with effects similar to or greater than IL-31. In mice, intradermal IL-4, IL-13, and IL-31 increased epidermal nerve growth; however, only IL-4 and IL-13 induced hyperplasia and immune cell recruitment. Multiomic analyses revealed that IL-4 and IL-13 have a broader impact on neuroimmune interactions than IL-31. In a murine DRG neuron-eosinophil coculture, IL-4Rα blockade reduced neurite growth. IL-13 and IL-31 elicited acute scratching, demonstrating their roles as direct pruritogens; IL-4 synergistically enhanced IL-13-induced itch, resulting in greater pruritic responses than IL-31. Additionally, a set of itch-associated genes upregulated by IL-4 and IL-13 and downregulated by dupilumab-mediated IL-4Rα blockade in human DRG neuronal cultures showed positive correlation with atopic dermatitis severity.

Conclusions: These findings establish the IL-4/IL-13-IL-4Rα axis as a key regulator of inflammatory skin nerve innervation, neuroimmune interactions, barrier integrity, and itch response, highlighting its mechanistic role in modulating sensory neuronal function and shaping the inflammatory microenvironment that drives itch pathophysiology.

Keywords: IL-13; IL-31; IL-4; itch; neuroarchitecture; neuroimmune interactions; sensory neurons; type 2 inflammation.

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Conflict of interest statement

Disclosure statement Sponsored by Sanofi and Regeneron Pharmaceuticals. The BIOMAP project has received funding from the Innovative Medicines Initiative 2 Joint Undertaking (JU) under grant agreement 821511. The JU receives support from the European Union’s Horizon 2020 research and innovation program and the European Federation of Pharmaceutical Industries and Associations. This article reflects only the authors’ views, and the JU is not responsible for any use that may be made of the information it contains. Disclosure of potential conflict of interest: All authors were employees of Sanofi at the time of conduct of the study, and they may hold stock and/or stock options in the company.