Journal Club 26.10.16

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

Qiaojuan Zhang ^{1 7}, Minji Jang ^{1 7}, Fabiana C. Dias ^{1 7}, Qian Zeng ¹, Peng Wang ¹, Heiley Tai ¹, Eman Chattha ¹, Jennifer Y. Zhang ^{2 3}, Regina S.P. Lim ⁴, Wolfgang Liedtke ^{1 5 6}, Yong Chen ^{1 3 5}

¹ Department of Neurology, Duke University School of Medicine, Durham, North Carolina, USA
² Department of Dermatology, Duke University School of Medicine, Durham, North Carolina, USA
³ Department of Pathology, Duke University School of Medicine, Durham, North Carolina, USA
⁴ Department of Dermatology, Changi General Hospital, Singapore, Singapore
⁵ Department of Anesthesiology, Duke University School of Medicine, Durham, North Carolina, USA
⁶ Department of Molecular Pathobiology, New York University, New York, New York, USA

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.

Keywords

Dorsal root ganglion sensory neurons; IL-17; Itch; Psoriasis; TRPV4