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The underlying mechanisms of chronic pruritus (CP), which is often very debilitating for patients, are still not well understood. Over the past few years, peripheral and central mechanisms involving different classes of pruriceptive and nociceptive neuron (e.g., C- and Aδ-fibers), immune cells (e.g., eosinophils, basophils, Th1, Th2, and mast cells) and epithelial cells (e.g., keratinocytes) have been investigated. Based on these, numerous promising target-specific therapies are under development. In this review, we highlight the cells, key mediators, and receptors involved in itch perception and CP, and conclude by summarizing the therapies developed for these conditions.

Background Prurigo nodularis (PN) is a debilitating, difficult-to-treat, intensely pruritic, chronic inflammatory skin disease characterized by hyperkeratotic skin nodules. The pathogenesis of PN is not well understood but is believed to involve cross talk between sensory nerve fibers, immune cells, and the epidermis. It is centered around the neuroimmune cytokine IL-31, driving an intractable itch–scratch cycle. Objective We sought to provide a comprehensive view of the transcriptomic changes in PN skin and characterize the mechanism of action of the anti–IL-31 receptor inhibitor nemolizumab. Method RNA sequencing of biopsy samples obtained from a cohort of patients treated with the anti–IL-31 receptor inhibitor nemolizumab and taken at baseline and week 12. Generation and integration of patient data with RNA-Seq data generated from reconstructed human epidermis stimulated with IL-31 and other proinflammatory cytokines. Results Our results demonstrate that nemolizumab effectively decreases IL-31 responses in PN skin, leading to effective suppression of downstream inflammatory responses including TH2/IL-13 and TH17/IL-17 responses. This is accompanied by decreased keratinocyte proliferation and normalization of epidermal differentiation and function. Furthermore, our results demonstrate how transcriptomic changes associated with nemolizumab treatment correlate with improvement in lesions, pruritus, stabilization of extracellular matrix remodeling, and processes associated with cutaneous nerve function. Conclusion These data demonstrate a broad response to IL-31 receptor inhibition with nemolizumab and confirm the critical upstream role of IL-31 in PN pathogenesis.

Scratching and scratch-induced injuries, including neuroanatomical alterations, are key characteristics of chronic pruritus entities of different origins. The aim of this study was to link gene expression (array hybridization, qPCR) with DNA methylation (array hybridization) and neuroanatomy (PGP9.5 staining) in chronic nodular prurigo (CNPG), atopic dermatitis (AD), brachioradial pruritus (BRP), and matched healthy controls. Specific signatures of gene expression and DNA methylation clearly discriminated pruritic lesional skin from nonpruritic skin in CNPG and from healthy skin of volunteers, respectively. Although intraepidermal nerve fiber density was indiscriminately reduced, the level of epidermal branching, assessed by a semiquantitative pattern analysis, differentiated the entities (CNPGBRPAD). Correspondingly, repellent SEMA3A showed the highest expression in AD, whereas axonal growth-promoting nerve GF was most prominent in CNPG and BRP. Overexpression of genes for nerve fiber regeneration (NELL2/NFKB/ARTN) was found in AD and CNPG but not in BRP. Our findings suggest that differential branching patterns rather than mere innervation density separate chronic itch conditions and reflect disease-specific local expression profiles. In pruritic dermatoses (AD and CNPG), nerve injury and subsequent sprouting may primarily result from chronic scratching, whereas genuine neuropathy is expected to underlie BRP.