From skin to spinal Cord: How IL-17a Drives psoriatic chronic itch.

Abstract

Interleukin-17a (IL-17a) has been established as a master regulator of inflammatory cascades in psoriasis pathogenesis. Monoclonal antibodies targeting IL-17a have demonstrated significant efficacy in relieving psoriasis-related symptoms, including the rapid alleviation of chronic itching. However, whether IL-17a is involved in chronic psoriatic pruritus and the specific mechanisms of its action remain poorly understood. In this study, we demonstrate that IL-17a significantly exacerbates chronic itch in a murine model of psoriasis. Mechanistically, IL-17a upregulation in psoriatic skin tissues activated the IL-17a receptor (IL-17Ra) in sensory neurons, subsequently promoting the expression of IL-6 in dorsal root ganglion (DRG) neurons. This neuron-derived IL-6 is transported via sensory nerve fibers to the spinal dorsal horn (SDH), where it triggers astrocyte activation and subsequent IL-1β secretion to potentiates chronic itch signaling in psoriasis. Our findings uncover a neuroimmune circuit in which IL-17a-IL-17Ra signaling on sensory neurons mediates the propagation of pruritic signals from peripheral skin to the central nervous system, with spinal IL-6-astrocyte-IL-1β axis serving as an amplifier of psoriatic pruritus.