IL-31 blockade elevates thymus and activation-regulated chemokine by lifting LAMP3⁺CD1c⁺ mature dendritic cells from calcitonin gene–related peptide–calcitonin receptor–like neuroimmune suppression in atopic dermatitis - 04/04/26

Doi : 10.1016/j.jaci.2026.02.044

Akira Honryo, MS ^a,^b, Toshihiro Masuda, PhD ^a,^c,^d, Satoshi Nakamizo, MD, PhD ^a,^e, Takuya Takafuji, PhD ^c, Fuuka Minami, DVM ^a, Satoru Yonekura, MD, PhD ^a, Midori Uchibayashi ^a,^c,^d, Kenichi Inoue ^f, Hiroshi Kiyonari, PhD ^f, Masafumi Yamanaka ^a, Hiroyuki Irie, MD ^a, Chisa Nakashima, MD, PhD ^g, Saeko Nakajima, MD, PhD ^a,^d, Atsushi Otsuka, MD, PhD ^g,^⁎ , Ryota Asahina, DVM, PhD ^a,^h,^⁎ , Kenji Kabashima, MD, PhD ^a,^i,^⁎

^a Department of Dermatology, Kyoto University Graduate School of Medicine, Kyoto, Japan

^b Research and Development Department, Ikeda Mohando, Toyama, Japan

^c Drug Development Research Laboratories, Maruho, Kyoto, Japan

^d Department of Drug Discovery for Inflammatory Skin Diseases, Kyoto University Graduate School of Medicine, Kyoto, Japan

^e Alliance Laboratory for Advanced Medical Research, Kyoto University Graduate School of Medicine, Kyoto, Japan

^f Laboratory for Animal Resources and Genetic Engineering, RIKEN Center for Biosystems Dynamics Research, Hyogo, Japan

^g Department of Dermatology, Faculty of Medicine, Kindai University, Osaka, Japan

^h Center for One Medicine Innovative Translational Research (COMIT), Institute for Advanced Study, Gifu University, Gifu, Japan

ⁱ A∗STAR Skin Research Labs (A∗SRL), Singapore Immunology Network (SIgN), and Skin Research Institute of Singapore (SRIS), Agency for Science, Technology, and Research (A∗STAR), Singapore

^∗ Corresponding authors: Kenji Kabashima, MD, PhD, Department of Dermatology, Kyoto University Graduate School of Medicine, 54 Shogoin-Kawara, Sakyo-ku, Kyoto, 606-8507, Japan. Department of Dermatology Kyoto University Graduate School of Medicine 54 Shogoin-Kawara Sakyo-ku Kyoto 606-8507 Japan ^∗∗ Ryota Asahina, DVM, PhD, Center for One Medicine Innovative Translational Research (COMIT), Institute for Advanced Study, Gifu University, 1-1 Yanagido, Gifu, 501-1193, Japan. Center for One Medicine Innovative Translational Research (COMIT) Institute for Advanced Study Gifu University 1-1 Yanagido Gifu 501-1193 Japan ^∗∗∗ Atsushi Otsuka, MD, PhD, Department of Dermatology, Faculty of Medicine, Kindai University, 377-2 Ohno-higashi, Osaka-Sayama, Osaka, 589-8511, Japan. Department of Dermatology Faculty of Medicine Kindai University 377-2 Ohno-higashi Osaka-Sayama Osaka 589-8511 Japan

Sous presse. Épreuves corrigées par l'auteur. Disponible en ligne depuis le Saturday 04 April 2026

Graphical abstract

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Abstract

Background

Nemolizumab reduces pruritus and skin lesions in patients with atopic dermatitis (AD), yet some patients develop cutaneous adverse events (CAEs) with increased serum thymus- and activation-regulated chemokine (TARC); mechanisms are unclear.

Objective

We sought to define systemic changes and the mechanism underlying TARC elevation after IL-31 receptor A (IL-31RA) blockade.

Methods

Serum proteomics (Olink), MC903 models with or without anti–IL-31RA, single-cell RNA sequencing of AD skin with in situ validation, functional assays using human dendritic cells (DCs), and human dorsal root ganglion analyses with ligand–receptor inference were integrated.

Results

In patients with CAEs, TARC levels increased and correlated with type 2 markers. In mice, IL-31RA blockade increased serum and dermal TARC without broad transcriptomic shifts. A Ccl17 -T2A-GFP reporter localized TARC to dermal DCs, enriched in type 2 conventional DCs. In patients, CCL17 localized to LAMP3 ⁺ CD1c ⁺ mature DCs in situ. Analyses supported calcitonin gene–related peptide (CGRP) signaling via the calcitonin receptor–like (CALCRL) signaling from IL-31RA/oncostatin M receptor–positive nociceptors to mature DCs; CGRP reduced DC maturation and TARC in vitro .

Conclusion

Findings support an IL-31–dependent CGRP-CALCRL neuroimmune brake that restrains DC maturation and TARC. IL-31RA blockade disinhibits this circuit, linking antipruritic therapy to DC-driven chemokine programs and offering a rationale for stronger TARC responses in patients than in the MC903 model. Monitoring TARC and neuroimmune context may aid management of nemolizumab-treated patients with AD.

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Key words : Interleukin-31, calcitonin gene–related peptide, thymus- and activation-regulated chemokine, dendritic cell, neuroimmune interactions, atopic dermatitis

Abbreviations used : AD, APC, CAE, CALCA/B, CALCR, CCL, CCR7, cDC1/2, CGRP, DC, dLN, DRG, EtOH, GFP, IL-31RA, LAMP3, MoDC, OSMR, scRNA-Seq, T2A, TARC