Transient receptor potential vanilloid 4-expressing macrophages and keratinocytes contribute differentially to allergic and nonallergic chronic itch.
Transient receptor potential vanilloid 4-expressing macrophages and keratinocytes contribute differentially to allergic and nonallergic chronic itch.
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DOI：
10.1016/j.jaci.2017.05.051
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发表时间：
2018-03
期刊：
影响因子：
--
通讯作者：
Hu H
中科院分区：
文献类型：
--
作者：
Luo J;Feng J;Yu G;Yang P;Mack MR;Du J;Yu W;Qian A;Zhang Y;Liu S;Yin S;Xu A;Cheng J;Liu Q;O'Neil RG;Xia Y;Ma L;Carlton SM;Kim BS;Renner K;Liu Q;Hu H
慢性瘙痒是一种非常虚弱的症状，是许多医学疾病的基础，没有普遍有效的治疗方法。尽管感觉神经节和脊髓中独特的神经元信号级联信号已被证明在慢性瘙痒的发病机制中起关键作用，但皮肤相关细胞的作用仍不清楚。我们试图研究瞬时受体电位香草素4(TRPV4)介导的过敏性和非过敏性慢性瘙痒的皮肤机制。采用实时荧光定量RT-PCR方法检测TRPV4在慢性瘙痒皮肤标本和健康对照皮肤标本中的表达。以Trpv4eGFF小鼠为研究对象，通过免疫荧光染色、钙离子成像和膜片钳记录等方法研究TRPV4在皮肤中的表达和功能。采用遗传学和药理学方法研究了TRPV4在SADBE诱导的变态反应性接触性皮炎引起的小鼠皮肤干燥、慢性瘙痒和自发性抓挠模型中的作用和潜在机制。TRPV4在小鼠真皮巨噬细胞和表皮角质形成细胞中选择性表达。巨噬细胞和角质形成细胞中TRPV4的谱系特异性缺失分别减少了小鼠过敏性和非过敏性慢性瘙痒。重要的是，与健康对照组相比，慢性特发性瘙痒(CIP)患者的皮肤活检组织中TRPV4的表达显著增加。此外，在过敏性和非过敏性慢性瘙痒中，依赖TRPV4的慢性瘙痒需要5-羟色胺信号，而不同的5-羟色胺受体的激活是次要的。我们的研究揭示了先前未知的机制，即在皮肤中表达TRPV4的上皮细胞和免疫细胞关键地和动态地介导慢性瘙痒，并揭示了治疗慢性瘙痒的新靶点。
Chronic itch is a highly debilitating symptom that underlies many medical disorders with no universally effective treatments. Although unique neuronal signaling cascades in the sensory ganglia and spinal cord have been shown to critically promote the pathogenesis of chronic itch, the role of skin-associated cells remains poorly understood. We sought to examine the cutaneous mechanisms underlying transient receptor potential vanilloid 4 (TRPV4) -mediated allergic and non-allergic chronic itch. The expression of TRPV4 in chronic itch and healthy control skin preparations was examined by real-time RT-PCR. Trpv4eGFF mice were used to study the expression and function of TRPV4 in the skin by immunofluorescence staining, calcium imaging, and patch-clamp recordings. Genetic and pharmacological approaches were employed to examine the role and underlying mechanisms of TRPV4 in mouse models of dry skin associated chronic itch and spontaneous scratching associated with SADBE-induced allergic contact dermatitis. TRPV4 is selectively expressed by dermal macrophages and epidermal keratinocytes in mice. Lineage-specific deletion of TRPV4 in macrophages and keratinocytes reduces allergic and non-allergic chronic itch in mice, respectively. Importantly, TRPV4 expression is significantly elevated in skin biopsies from patients with chronic idiopathic pruritus (CIP) in comparison to skin from healthy control subjects. Moreover, TRPV4-dependent chronic itch requires 5-HT signaling secondary to activation of distinct 5-HT receptors in both allergic and non-allergic chronic itch conditions. Our study reveals previously unrecognized mechanisms by which TRPV4-expressing epithelial and immune cells in the skin critically and dynamically mediate chronic itch, and unravels novel targets for therapeutics in the setting of chronic itch.
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影响因子：
16.2
作者：
Lechner, Stefan G.;Markworth, Soeren;Lewin, Gary R.
通讯作者：
Lewin, Gary R.
DOI：
10.1073/pnas.1735416100
发表时间：
2003-11-11
影响因子：
11.1
作者：
Liedtke, W;Friedman, JM
通讯作者：
Friedman, JM
影响因子：
3.3
作者：
Akiyama T;Carstens E
通讯作者：
Carstens E
影响因子：
4.8
作者：
Chung, MK;Lee, H;Caterina, MJ
通讯作者：
Caterina, MJ
DOI：
10.1007/978-3-642-54215-2_12
发表时间：
2014-01-01
期刊：
MAMMALIAN TRANSIENT RECEPTOR POTENTIAL (TRP) CATION CHANNELS, VOL I
影响因子：
--
作者：
Garcia-Elias, Anna;Mrkonjic, Sanela;Valverde, Miguel A.
通讯作者：
Valverde, Miguel A.