Neuronal Mechanisms of Psoriatic Itch: Role of IL-17R/ERK/TRPV4 Signaling Pathway

Abstract

Itch represents a major disease burden of psoriasis. Despite recent clinical studies showing the effectiveness of IL-17- and IL-17R-blocking antibodies in alleviating psoriatic itch, significant questions remain unanswered. Specifically, the crucial cellular site of action and the impacted signaling pathway of IL-17/IL-17R in psoriatic itch are elusive. Itch sensation relies on dorsal root ganglion (DRG) sensory neurons that transmit pruriceptive signals from the periphery to the CNS. IL-17RA and IL-17RC, 2 cognate receptors for IL-17, are expressed in DRG neurons. In this study, we demonstrated that IL-17RA and IL-17RC are upregulated in DRG neurons in a mouse model of psoriasis induced by imiquimod. Notably, conditional knockout of Il17ra or Il17rc in sensory neurons potently attenuated psoriasis-like itch. Furthermore, our in vitro assay with cultured neurons and in vivo experiment with animal model of psoriasis demonstrated that IL-17RA and IL-17RC upregulate the pruritic ion channel TRPV4 in DRG neurons through the extracellular signal-regulated kinase (ERK) signaling pathway. Specific deletion of Trpv4 or suppression of phosphorylation of ERK in DRG neurons mitigated psoriasis-like itch. These findings suggest that the IL-17R/ERK/TRPV4 signaling pathway in sensory neurons plays a significant role in psoriatic itch.