Neuronal Mechanisms of Psoriatic Itch: Role of IL-17R\/ERK\/TRPV4 Signaling Pathway<\/p>\n\n\n\n
Qiaojuan Zhang 1 7<\/sup>, Minji Jang 1 7<\/sup>, Fabiana C. Dias 1 7<\/sup>, Qian Zeng 1<\/sup>, Peng Wang 1<\/sup>, Heiley Tai 1<\/sup>, Eman Chattha 1<\/sup>, Jennifer Y. Zhang 2 3<\/sup>, Regina S.P. Lim 4<\/sup>, Wolfgang Liedtke 1<\/sup> 5<\/sup> 6<\/sup>, Yong Chen 1<\/sup> 3<\/sup> 5<\/sup><\/p>\n\n\n\n 1<\/sup> Department of Neurology, Duke University School of Medicine, Durham, North Carolina, USA Itch represents a major disease burden of psoriasis. Despite recent clinical studies showing the effectiveness of IL-17\u2013 and IL-17R\u2013blocking 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<\/em> or Il17rc<\/em> 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\u2013regulated kinase (ERK) signaling pathway. Specific deletion of Trpv4<\/em> 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.<\/p>\n\n\n\n Dorsal root ganglion sensory neurons; IL-17; Itch; Psoriasis; TRPV4<\/p>\n\n\n\n
2<\/sup> Department of Dermatology, Duke University School of Medicine, Durham, North Carolina, USA
3<\/sup> Department of Pathology, Duke University School of Medicine, Durham, North Carolina, USA
4<\/sup> Department of Dermatology, Changi General Hospital, Singapore, Singapore
5<\/sup> Department of Anesthesiology, Duke University School of Medicine, Durham, North Carolina, USA
6<\/sup> Department of Molecular Pathobiology, New York University, New York, New York, USA<\/p>\n\n\n\nKeywords<\/strong><\/h2>\n\n\n\n