Gain-of-function of TRPM4 predisposes mice to psoriasiform dermatitis.
Gain-of-function of TRPM4 predisposes mice to psoriasiform dermatitis.
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DOI：
10.3389/fimmu.2022.1025499
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发表时间：
2022
影响因子：
7.3
通讯作者：
中科院分区：
文献类型：
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瞬时受体电位melastatin 4（TRPM 4）是一种钙激活的单价阳离子通道，在广泛的细胞中表达。我们先前报道了TRPM 4的两个功能获得性（GoF）突变是进行性对称性红斑角化病（PSEK）的原因，PSEK与银屑病具有相似的临床和组织病理学特征。使用CRISPR/Cas9技术，我们产生了TRPM 4 I1029 M小鼠，其具有与在人PSEK中发现的两种基因突变之一（相当于人TRPM 4 I1033 M）等同的突变。使用这种突变小鼠，我们在细胞和表型水平上检查了TRPM 4 GoF的作用，以阐明PSEK的病理机制。在不存在实验刺激的情况下，TRPM 4 I1029 M小鼠未显示表型。然而，当用咪喹莫特（IMQ）治疗时，TRPM 4 I1029 M小鼠比野生型（WT）更容易患上更严重的银屑病样皮炎（PsD），其特征在于表达CCR 6的γδ T细胞的积累更大，Il 17 a的mRNA水平更高。在TRPM 4 I1029 M小鼠中，树突状细胞表现出增强的迁移，角质形成细胞表现出增加的增殖。此外，TRPM 4抑制剂格列本脲改善了WT和TRPM 4 I1029 M小鼠的PsD。我们的研究结果表明，TRPM 4活性的升高可能通过膜电位的升高和下游细胞信号的改变而增强对皮肤刺激的易感性，从而导致炎症的增强。我们的研究结果进一步表明TRPM 4抑制剂在银屑病中可能的治疗应用。
Transient receptor potential melastatin 4 (TRPM4) is a Ca2+-activated, monovalent cation channel that is expressed in a wide range of cells. We previously reported two gain-of-function (GoF) mutations of TRPM4 as the cause of progressive symmetric erythrokeratodermia (PSEK), which shares similar clinical and histopathological features with psoriasis. Using CRISPR/Cas9 technology, we generated TRPM4I1029M mice that have the equivalent mutation to one of the two genetic mutations found in human PSEK (equivalent to human TRPM4I1033M). Using this mutant mice, we examined the effects of TRPM4 GoF at the cellular and phenotypic levels to elucidate the pathological mechanisms underlying PSEK. In the absence of experimental stimulation, TRPM4I1029M mice did not show a phenotype. When treated with imiquimod (IMQ), however, TRPM4I1029M mice were predisposed to more severe psoriasiform dermatitis (PsD) than wild-type (WT), which was characterized by greater accumulation of CCR6-expressing γδ T cells and higher mRNA levels of Il17a. In TRPM4I1029M mice, dendritic cells showed enhanced migration and keratinocytes exhibited increased proliferation. Moreover, a TRPM4 inhibitor, glibenclamide, ameliorated PsD in WT and TRPM4I1029M mice. Our results indicate elevated TRPM4 activities boosted susceptibility to cutaneous stimuli, likely through elevation of membrane potential and alteration of downstream cellular signaling, resulting in enhanced inflammation. Our results further suggest a possible therapeutic application of TRPM4 inhibitors in psoriasis.
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影响因子：
30.5
作者：
通讯作者：
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影响因子：
56.9
作者：
Launay, P;Cheng, H;Kinet, JP
通讯作者：
Kinet, JP
影响因子：
82.9
作者：
Schattling, Benjamin;Steinbach, Karin;Friese, Manuel A.
通讯作者：
Friese, Manuel A.
DOI：
10.3791/56027
发表时间：
2017-07-14
期刊：
Journal of visualized experiments : JoVE
影响因子：
--
作者：
Li F;Adase CA;Zhang LJ
通讯作者：
Zhang LJ
全长人类 TRPM4 的结构
DOI：
10.1073/pnas.1722038115
发表时间：
2018-03-06
影响因子：
11.1
作者：
Duan J;Li Z;Li J;Santa-Cruz A;Sanchez-Martinez S;Zhang J;Clapham DE
通讯作者：
Clapham DE