Selective agonist of TRPML2 reveals direct role in chemokine release from innate immune cells.
Selective agonist of TRPML2 reveals direct role in chemokine release from innate immune cells.
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DOI：
10.7554/elife.39720
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发表时间：
2018-11-27
期刊：
影响因子：
7.7
通讯作者：
Grimm C
中科院分区：
文献类型：
--
作者：
Plesch E;Chen CC;Butz E;Scotto Rosato A;Krogsaeter EK;Yinan H;Bartel K;Keller M;Robaa D;Teupser D;Holdt LM;Vollmar AM;Sippl W;Puertollano R;Medina D;Biel M;Wahl-Schott C;Bracher F;Grimm C
细胞因子和趋化因子由包括巨噬细胞在内的多种免疫细胞产生和分泌。值得注意的是，人们对这些炎症介质是如何从各种免疫细胞中释放出来的知之甚少。本研究显示，内溶酶体阳离子通道TRPML2在小鼠巨噬细胞的趋化因子运输和分泌中起直接作用。为了证明TRPML2在这些过程中的急性和直接参与，产生了第一个同种型选择性TRPML2通道激动剂ML2-SA1。ML2-SA1不仅可以直接刺激巨噬细胞释放趋化因子CCL2，还可以刺激巨噬细胞迁移，从而模拟CCL2的功能。内溶酶体膜片钳实验表明，内源性TRPML2在早期/循环核内体中表达，ML2-SA1促进早期/循环核内体的运输，表明CCL2是通过这一途径运输和分泌的。这些数据提供了先天免疫应答中TRPML2激活、CCL2释放和巨噬细胞迁移刺激之间的直接联系。
Cytokines and chemokines are produced and secreted by a broad range of immune cells including macrophages. Remarkably, little is known about how these inflammatory mediators are released from the various immune cells. Here, the endolysosomal cation channel TRPML2 is shown to play a direct role in chemokine trafficking and secretion from murine macrophages. To demonstrate acute and direct involvement of TRPML2 in these processes, the first isoform-selective TRPML2 channel agonist was generated, ML2-SA1. ML2-SA1 was not only found to directly stimulate release of the chemokine CCL2 from macrophages but also to stimulate macrophage migration, thus mimicking CCL2 function. Endogenous TRPML2 is expressed in early/recycling endosomes as demonstrated by endolysosomal patch-clamp experimentation and ML2-SA1 promotes trafficking through early/recycling endosomes, suggesting CCL2 being transported and secreted via this pathway. These data provide a direct link between TRPML2 activation, CCL2 release and stimulation of macrophage migration in the innate immune response.