From neuroimmune circuits to targeted therapy of chronic pruritus.

Chronic pruritus (CP) is a debilitating symptom of various human diseases and significantly reduces quality of life, underscoring its clinical relevance. CP can accompany non-skin-borne diseases such as chronic kidney disease, but it is also a hallmark of many dermatological diseases. Most pruritic skin diseases are characterized by dysregulated immune responses, indicating a close relationship between CP and skin inflammation. Major breakthroughs over the last 2 decades have transformed our understanding of how immune cells and the nervous system interact to promote itch and scratching behavior in pruritic inflammatory skin diseases such as atopic dermatitis. This bidirectional neuroimmune crosstalk is fundamental for understanding the mechanistic basis of CP and opens new avenues for targeted treatment strategies. This translational review provides an up-to-date overview of the biological basis of itch, its clinical implications, and modern therapeutic options for CP; pruritic inflammatory skin diseases constitute a central focus. The first part summarizes the anatomical structures and physiological processes underlying itch transmission, with emphasis on neuroimmune communication. Endogenous itch-inducing molecules, or pruritogens, are a central element of this crosstalk and drive CP at the neurocutaneous interface. The second part of the review discusses these pruritogens in detail, with particular attention to their clinical relevance for the treatment of CP across dermatological and selected nondermatological conditions. SIGNIFICANCE STATEMENT: Chronic pruritus is a debilitating symptom of many human diseases, including pruritic inflammatory skin diseases such as atopic dermatitis. This review provides an up-to-date overview of the biological basis of itch, highlights neuroimmune crosstalk in particular, and discusses the clinical and therapeutic relevance of pruritogens acting at the neurocutaneous interface.