Background & Aims
Itch represents one of the cardinal symptoms of psoriasis. Despite recent clinical studies have demonstrated the effectiveness of blocking antibodies targeting IL17 and its receptor IL17R in alleviating psoriatic itch [1-4], significant questions remain unanswered. In particular, the crucial cellular site of action and the signaling pathway of IL17/IL17R in psoriatic itch remain largely elusive. Itch sensation relies on dorsal root ganglion (DRG)/trigeminal ganglion (TG) sensory neurons that transmit pruriceptive signals from the periphery to the central nervous system [5]. We aim to elucidate whether and how IL17/IL17R in sensory neurons contributes to psoriatic itch.
Methods
Employing an animal model of psoriatic itch-induced by imiquimod (IMQ) [6], we first examined whether systemic inhibition of IL17 or IL17R attenuates IMQ-induced scratching behaviors. We then utilized IL17R conditional knockout (cKO) to determine whether sensory neurons serve as the key cellular site for IL17/IL17R signaling in promoting psoriatic itch. Using in vitro assay with cultured neurons and in vivo assay with the IMQ model, we next examined whether IL17/IL17R regulates the expression of TRPV4, a pruritic ion channel [7], in sensory neurons.
Results
Using the IMQ model, we observed that IL17RA and IL17RC are upregulated in DRG neurons. Notably, cKO of il17ra or il17rc in sensory neurons almost abolished psoriatic itch. Furthermore, our in vitro assay with cultured neurons and in vivo assay demonstrated that IL17R upregulates TRPV4 in DRG neurons via ERK signaling pathway. Specific deletion of Trpv4 or suppression of phosphorylation of ERK in sensory neurons mitigated psoriatic itch.
Conclusions
These findings suggest that sensory neurons serve as the key cellular site for IL17/IL17R signaling in promoting psoriatic itch. In addition, sensory neuron IL17/IL17R signaling drives psoriatic itch via the pruritic ion channel TRPV4.
References
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6. Sakai K, Sanders KM, Youssef MR, Yanushefski KM, Jensen L, Yosipovitch G, Akiyama T. Mouse model of imiquimod-induced psoriatic itch. Pain. 2016;157(11):2536-2543.
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Presenting Author
Yong Chen
Poster Authors
Topics
- Specific Pain Conditions/Pain in Specific Populations: Itch