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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.

The underlying mechanisms of pruritus and chronic pruritus (CP) in particular, remain poorly understood; however, current research has revealed promising new concepts in which the importance of the interaction of neuronal cells of different classes, immune cells and keratinocytes is becoming increasingly clearer.In this review article the current concepts in pruritus research are presented and summarized.This is a review article based on the current literature.Different classes of sensory afferents, such as mechano-insensitive C‑fibers (histaminergic pruritus) and non-histaminergic pruriceptive C‑fibers and Aδ-fibers are involved in CP. The central sensitization in CP manifests as hyperknesis and alloknesis, the latter triggered by Aβ-fibers and Merkel cells. In recent years, the importance of inflammatory cells, such as Th1 and Th2 cells but also basophilic, eosinophilic granulocytes and mast cells has become clear. In CP there appears to be close communication between neuronal cells, immune cells and keratinocytes. Recent studies have focused on proinflammatory interleukins, such as IL-31, IL‑4 and IL-13 and their receptors. The Janus kinase/signal transducers and activators of transcription (JAK/STAT) signaling pathway also plays an important role in the triggered signaling cascades that ultimately lead to pruritus perception. Therefore, in current treatment studies not only the interleukins and their receptors but also the JAK/STAT signaling pathway are directly targeted.The discovery of new mechanisms and interactions in CP highlights the complexity of this disease. Even if this and the treatment options derived from this are already very promising, a much better understanding of the mechanisms of CP is urgently needed in order to enable further options for an optimized treatment.HINTERGRUND: Die dem Pruritus, insbesondere dem chronischen Pruritus (CP), zugrundeliegenden Mechanismen sind nach wie vor nicht hinreichend verstanden. Aktuelle Forschungen zeigen jedoch vielversprechende neue Konzepte auf, bei denen die Bedeutung der Interaktion von neuronalen Zellen verschiedener Klassen, Immunzellen und Keratinozyten immer klarer wird.In diesem Übersichtsartikel sollen aktuelle Konzepte in Pruritusforschung dargestellt und zusammengeführt werden.Es handelt sich um eine Übersichtsarbeit, für die aktuelle Literatur zugrunde gelegt wurde.Verschiedene Klassen von sensorischen Afferenzen wie mechanoinsensitive C‑Fasern (histaminerger Pruritus) und nichthistaminerge prurizeptive C‑ und Aδ-Fasern sind an CP beteiligt. Die zentrale Sensibilisierung bei CP äußert sich als Hyperknesis und Alloknesis, wobei letztere durch Aβ-Fasern und Merkel-Zellen ausgelöst wird. In den vergangenen Jahren ist die Bedeutung von Entzündungszellen wie Th1- und Th2-Zellen, aber auch basophilen-, eosinophilen Granulozyten und Mastzellen deutlich geworden. Bei CP scheint eine enge Kommunikation zwischen neuronalen Zellen, Immunzellen und Keratinozyten zu bestehen. Neuere Studien konzentrierten sich auf proinflammatorische Interleukine (IL), wie IL-31, IL‑4 und IL-13, und deren Rezeptoren. In den ausgelösten Signalkaskaden, die letztlich zur Prurituswahrnehmung führen, spielt auch der JAK/STAT(Januskinase/„signal transducers and activators of transcription“)-Signalweg eine wichtige Rolle. In aktuellen Therapiestudien werden daher nicht nur die Interleukine und ihre Rezeptoren, sondern auch der JAK/STAT-Signalweg direkt angegangen.Die Entdeckung neuer Mechanismen und Interaktionen bei CP machen die Komplexität dieser Erkrankung deutlich. Auch wenn diese und die hieraus abgeleiteten Therapieoptionen bereits sehr vielversprechend sind, ist ein noch besseres Verständnis der Mechanismen bei CP dringend notwendig, um weitere Optionen für eine optimierte Therapie zu ermöglichen.

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.