Roles of TRPM4 in immune responses in keratinocytes and identification of a novel TRPM4-activating agent
Roles of TRPM4 in immune responses in keratinocytes and identification of a novel TRPM4-activating agent
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DOI：
10.1016/j.bbrc.2023.02.062
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发表时间：
2023-03-03
影响因子：
3.1
通讯作者：
Ishii, Ken J.
中科院分区：
文献类型：
--
作者：
Saito, Kaori (Otsuka);Fujita, Fumitaka;Ishii, Ken J.
皮肤是内部器官和环境之间的保护界面，不仅作为物理屏障，而且作为免疫器官。然而，皮肤中的免疫系统尚未完全了解。作为热敏瞬时受体电位（TRP）通道家族的成员，TRPM 4在免疫细胞中充当调节受体，最近报道在人皮肤和角质形成细胞中表达。然而，TRPM 4在角质形成细胞中的免疫应答中的功能尚未研究。在这项研究中，我们发现用已知的TRPM 4激动剂BTP 2治疗减少了正常人表皮角质形成细胞和永生化人表皮角质形成细胞（HaCaT细胞）中肿瘤坏死因子（TNF）α诱导的细胞因子产生。在TRPM 4缺陷型HaCaT细胞中没有观察到这种降低精氨酸的作用，表明TRPM 4有助于控制角质形成细胞中细胞因子的产生。此外，我们确定了一种新的TRPM 4活化剂--硫酸钾铝。硫酸铝钾通过储存操纵的Ca 2刺进入表达人TRPM 4的HEK 293 T细胞中减少Ca 2刺内流。我们进一步证实，铝钾硫酸诱发TRPM 4介导的电流，显示TRPM 4激活的直接证据。此外，用硫酸铝钾处理减少了HaCaT细胞中由TNF α诱导的细胞因子表达。总之，我们的数据表明，TRPM 4可能通过抑制角质形成细胞中细胞因子的产生而作为治疗皮肤炎症反应的新靶点，并且硫酸铝钾是通过TRPM 4活化来预防不良皮肤炎症的有用成分。(c)2023爱思唯尔公司All rights reserved.
The skin is a protective interface between the internal organs and environment and functions not only as a physical barrier but also as an immune organ. However, the immune system in the skin is not fully understood. A member of the thermo-sensitive transient receptor potential (TRP) channel family, TRPM4, which acts as a regulatory receptor in immune cells, was recently reported to be expressed in human skin and keratinocytes. However, the function of TRPM4 in immune responses in keratinocytes has not been investigated. In this study, we found that treatment with BTP2, a known TRPM4 agonist, reduced cytokine production induced by tumor necrosis factor (TNF) a in normal human epidermal keratinocytes and in immortalized human epidermal keratinocytes (HaCaT cells). This cytokine-reducing effect was not observed in TRPM4-deficient HaCaT cells, indicating that TRPM4 contributed to the control of cytokine production in keratinocytes. Furthermore, we identified aluminum potassium sulfate, as a new TRPM4 activating agent. Aluminum potassium sulfate reduced Ca2 thorn influx by store-operated Ca2 thorn entry in hu-man TRPM4-expressing HEK293T cells. We further confirmed that aluminum potassium sulfate evoked TRPM4-mediated currents, showing direct evidence for TRPM4 activation. Moreover, treatment with aluminum potassium sulfate reduced cytokine expression induced by TNFa in HaCaT cells. Taken together, our data suggested that TRPM4 may serve as a new target for the treatment of skin inflam-matory reactions by suppressing the cytokine production in keratinocytes, and aluminum potassium sulfate is a useful ingredient to prevent undesirable skin inflammation through TRPM4 activation. (c) 2023 Elsevier Inc. All rights reserved.