Pain Research Center, Department of Anesthesiology, University of Cincinnati Medical Center, Cincinnati, Ohio, USA.
Department of Physiology, Medical School, Hanyang University, Seoul, Korea.
J Invest Dermatol. 2020 Nov;140(11):2221-2229.e6. doi: 10.1016/j.jid.2020.03.959. Epub 2020 Apr 11.
Psoriasis is an inflammatory skin disease associated with itch, which is a troublesome symptom with a few therapeutic options. TRPC4 is highly expressed in dorsal root ganglia (DRGs). Recently, we have revealed itch signaling in DRG neurons by which TRPC4 mediates itch to serotonergic antidepressants and demonstrated the antipruritic effect of the TRPC4 inhibitor ML204. However, the role of TRPC4 in acute and chronic itch is still largely unknown. Here, we have characterized the expression of TRPC4 in peptidergic DRG neurons and showed that acute itch induced by serotonin and histamine was attenuated in Trpc4-knockout mice and ML204-treated mice. We have also shown that silencing TRPC4 in DRG and its inhibition by intradermal injections were also effective in decreasing psoriatic itch after the repeated application of imiquimod, which is a preclinical model of psoriasis. Of clinical relevance, intradermal injections of ML204 in psoriasiform skin significantly reversed imiquimod-established chronic itch and cutaneous inflammation. Given that TRPC4 is expressed in human DRGs and a specific inhibitor is in clinical trials, our data not only expand our understanding of itch and psoriasis, but also reveal TRPC4 as a potential therapeutic target with considerable translational benefits.
银屑病是一种炎症性皮肤病，伴有瘙痒，这是一种棘手的症状，治疗选择有限。TRPC4 在背根神经节（DRG）中高度表达。最近，我们揭示了 DRG 神经元中的瘙痒信号，其中 TRPC4 介导瘙痒对 5-羟色胺能抗抑郁药，并证明了 TRPC4 抑制剂 ML204 的止痒作用。然而，TRPC4 在急性和慢性瘙痒中的作用在很大程度上仍不清楚。在这里，我们描述了 TRPC4 在肽能 DRG 神经元中的表达，并表明 5-羟色胺和组胺诱导的急性瘙痒在 Trpc4 敲除小鼠和 ML204 处理的小鼠中减弱。我们还表明，在 DRG 中沉默 TRPC4 及其通过皮内注射抑制也可有效减少咪喹莫特（一种银屑病的临床前模型）重复应用后的银屑病瘙痒。具有临床相关性的是，皮内注射 ML204 可显著逆转咪喹莫特诱导的慢性瘙痒和皮肤炎症。鉴于 TRPC4 表达在人类 DRG 中，并且一种特异性抑制剂正在临床试验中，我们的数据不仅扩展了我们对瘙痒和银屑病的认识，而且还揭示了 TRPC4 作为具有相当转化效益的潜在治疗靶点。
