342 Single-cell RNA-seq reveals keratinocytes and fibroblasts are potential key cellular targets of IL-31 in prurigo nodularis

Prurigo nodularis (PN) is a chronic skin condition characterized by the presence of multiple nodules. It causes severe pruritus, which leads to serious impairment in quality of life. The upregulation of interleukin (IL)-31 in PN lesions has been known for years, and recently, an anti-human IL-31 receptor A monoclonal antibody, nemolizumab, demonstrated efficacy in PN in phase III clinical study (OLYMPIA 2). This result confirmed that IL-31 plays a pivotal role in the pathogenesis of PN. It has also been reported that IL-31 receptors are expressed not only in some leukocyte subsets and dorsal root ganglia (DRG) neurons but also in keratinocytes and fibroblasts in a steady state or under inflamed conditions, which is considered to be related to barrier dysfunction and tissue remodeling. However, it remains to be elucidated how IL-31 is involved in the pathogenesis and unique clinical features of PN. To investigate the cellular targets of IL-31 in PN, we performed single-cell RNA sequence (scRNA-seq) using skin biopsy samples from PN patients (n = 3) and normal subjects (n = 3). Among 11 cell types identified in the dataset, IL-31 receptor A was expressed most highly in keratinocytes, and its expression levels were increased in PN compared to normal skin. Fibroblasts expressed IL-31 receptor A at the second highest level, and the percentage of activated fibroblasts with the upregulation of transforming growth factor-β signaling was increased in PN. We validated these results with immunohistochemical staining and in situ hybridization. Our data suggests that not only immune cells and DRG neurons, but also keratinocytes and fibroblasts are potential key cellular targets of IL-31 in PN.