TRPV4 Plays a Role in Matrix Stiffness-Induced Macrophage Polarization.
TRPV4 Plays a Role in Matrix Stiffness-Induced Macrophage Polarization.
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DOI：
10.3389/fimmu.2020.570195
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发表时间：
2020
影响因子：
7.3
通讯作者：
Rahaman SO
中科院分区：
文献类型：
--
作者：
Dutta B;Goswami R;Rahaman SO
巨噬细胞的表型极化被认为是先天免疫和各种病理生理条件下必不可少的。我们现在已经确定了机械线索调节巨噬细胞极化的分子机制的关键方面。我们发现，瞬时受体电位香草酸4（TRPV 4），机械敏感离子通道，介导基板刚度诱导的巨噬细胞极化。使用原子力显微镜，我们发现TRPV 4功能的基因消融消除了皮肤组织中纤维化诱导的基质硬度产生。我们已经确定，较硬的皮肤组织以TRPV 4依赖的方式促进M1巨噬细胞亚型;软组织则不然。我们的体外结果进一步验证了这些发现，该结果表明，单独的硬基质（50 kPa）以TRPV 4依赖性方式增加巨噬细胞M1标志物的表达，并且通过添加可溶性因子进一步增强了这种反应;软基质（1 kPa）均未发生这种反应。从功能获得性测定的结果可以看出，在M1巨噬细胞极化谱中对TRPV 4的直接需求是对刚度增加的响应，其中TRPV 4的重新引入显著上调了TRPV 4 KO巨噬细胞中M1标志物的表达。总之，这些数据提供了关于TRPV 4在基质硬度诱导的巨噬细胞极化谱中的作用的新见解，这些见解可以在组织工程和再生医学以及靶向治疗中进行探索。
Phenotypic polarization of macrophages is deemed essential in innate immunity and various pathophysiological conditions. We have now determined key aspects of the molecular mechanism by which mechanical cues regulate macrophage polarization. We show that Transient Receptor Potential Vanilloid 4 (TRPV4), a mechanosensitive ion channel, mediates substrate stiffness-induced macrophage polarization. Using atomic force microscopy, we showed that genetic ablation of TRPV4 function abrogated fibrosis-induced matrix stiffness generation in skin tissues. We have determined that stiffer skin tissue promotes the M1 macrophage subtype in a TRPV4-dependent manner; soft tissue does not. These findings were further validated by our in vitro results which showed that stiff matrix (50 kPa) alone increased expression of macrophage M1 markers in a TRPV4-dependent manner, and this response was further augmented by the addition of soluble factors; neither of which occurred with soft matrix (1 kPa). A direct requirement for TRPV4 in M1 macrophage polarization spectrum in response to increased stiffness was evident from results of gain-of-function assays, where reintroduction of TRPV4 significantly upregulated the expression of M1 markers in TRPV4 KO macrophages. Together, these data provide new insights regarding the role of TRPV4 in matrix stiffness-induced macrophage polarization spectrum that may be explored in tissue engineering and regenerative medicine and targeted therapeutics.
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影响因子：
5.8
作者：
Chauhan A;Sun Y;Sukumaran P;Quenum Zangbede FO;Jondle CN;Sharma A;Evans DL;Chauhan P;Szlabick RE;Aaland MO;Birnbaumer L;Sharma J;Singh BB;Mishra BB
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作者：
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通讯作者：
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作者：
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Planus, Emmanuelle
影响因子：
64.5
作者：
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通讯作者：
Discher DE
DOI：
10.1073/pnas.1005333107
发表时间：
2010-11-02
影响因子：
11.1
作者：
Everaerts, Wouter;Zhen, Xiaoguang;Voets, Thomas
通讯作者：
Voets, Thomas