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.

Abstract

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