Sensory Neuron-Expressed TRPC4 Is a Target for the Relief of Psoriasiform Itch and Skin Inflammation in Mice
Sensory Neuron-Expressed TRPC4 Is a Target for the Relief of Psoriasiform Itch and Skin Inflammation in Mice
复制标题
DOI：
10.1016/j.jid.2020.03.959
复制
发表时间：
2020-11-01
影响因子：
6.5
通讯作者：
Berta, Temugin
中科院分区：
文献类型：
--
作者：
Lee, Sang Hoon;Tonello, Raquel;Berta, Temugin
牛皮癣是一种炎症性皮肤病与瘙痒，这是一个麻烦的症状与一些治疗方案。TRPC 4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传导，TRPC 4通过该信号传导介导瘙痒对多巴胺能抗抑郁药的反应，并证明了TRPC 4抑制剂ML 204的抗瘙痒作用。然而，TRPC 4在急性和慢性瘙痒中的作用在很大程度上仍然未知。在这里，我们的特点是TRPC 4肽能DRG神经元的表达，并表明，急性瘙痒引起的5-羟色胺和组胺在Trpc 4基因敲除小鼠和ML 204治疗的小鼠减弱。我们还表明，在重复应用咪喹莫特（其是银肩病的临床前模型）后，DRG中的TRPC 4沉默及其通过皮内注射的抑制也有效地减少银肩病瘙痒。具有临床意义的是，在银屑病样皮肤中皮内注射ML 204显著逆转了咪喹莫特建立的慢性瘙痒和皮肤炎症。鉴于TRPC 4在人类DRG中表达，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理解，而且还揭示了TRPC 4作为具有相当大的翻译益处的潜在治疗靶点。
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.