Selective agonist of TRPML2 reveals direct role in chemokine release from innate immune cells

eLife - Tập 7
Eva Plesch1, Cheng‐Chang Chen1, Elisabeth Butz1, Anna Scotto Rosato2, Einar Krogsaeter3, Huajie Yue4,5, Karin Bartel1, Marco Keller1, Dina Robaa6, Daniel Teupser7, Lesca M. Holdt7, Angelika M. Vollmar1, Wolfgang Sippl6, Rosa Puertollano4,5, Diego L. Medina2, Martin Biel1, Christian Wahl‐Schott8, Franz Bracher1, Christian Grimm3
1Department of Pharmacy, Center for Drug Research and Center for Integrated Protein Science Munich, Ludwig Maximilian University of Munich, Munich, Germany;
2Telethon Institute of Genetics and Medicine, Naples, Italy
3Department of Pharmacology and Toxicology, Medical Faculty, Ludwig Maximilian University of Munich, Munich, Germany;
4Cell Biology and Physiology Center, National Heart,
5Cell Biology and Physiology Center, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, United States
6Department of Pharmaceutical Chemistry, Institute of Pharmacy, Martin Luther University of Halle-Wittenberg, Halle, Germany;
7Institute of Laboratory Medicine, University Hospital Munich, Munich, Germany;
8Institute for Neurophysiology, Hannover Medical School, Hannover, Germany

Tóm tắt

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.

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