Rethinking interleukin-31: A neuroimmune orchestrator of itch beyond Th2 immunity

Interleukin (IL)-31 has emerged as a pivotal mediator of pruritus. Since its initial identification, substantial progress has been made in elucidating the role of IL-31 in itch pathophysiology, particularly its direct effects on peripheral sensory neurons. Elevated IL-31 expression has been documented in a wide range of pruritic skin diseases, including atopic dermatitis, prurigo nodularis, and systemic disorders. Beyond its pruritogenic activity, IL-31 is increasingly recognized as a neuroimmune cytokine that links immune-cell activation to sensory-neuronal circuits and, in some contexts, may also exert immunomodulatory effects. IL-31 signals through a heterodimeric receptor complex composed of IL-31 receptor α and oncostatin M receptor β, activating downstream pathways. In sensory neurons, IL-31 receptor signaling defines a distinct pruritic pathway, but emerging human transcriptomic data indicate that IL-31-responsive neurons are more heterogeneous than the canonical murine NP3 subset, highlighting an important translational consideration. In this review, we summarize current knowledge regarding IL-31 biology, including its cellular sources, receptor expression, and signaling mechanisms, and discuss its role in both pruritic and non-pruritic diseases. We further evaluate therapeutic strategies targeting the IL-31/IL-31 receptor axis and consider the emerging concept that IL-31 blockade may relieve itch while simultaneously disinhibiting dendritic cell-driven type 2 inflammatory programs in selected contexts.