Selective agonist of TRPML2 reveals direct role in chemokine release from innate immune cells
Eva Plesch,
Cheng-Chang Chen,
Elisabeth Butz,
Anna Scotto Rosato,
Einar K Krogsaeter,
Hua Yinan,
Karin Bartel,
Marco Keller,
Dina Robaa,
Daniel Teupser,
Lesca M Holdt,
Angelika M Vollmar,
Wolfgang Sippl,
Rosa Puertollano,
Diego Medina,
Martin Biel,
Christian Wahl-Schott,
Franz Bracher,
Christian Grimm
Affiliations
Eva Plesch
Department of Pharmacy, Center for Drug Research and Center for Integrated Protein Science Munich, Ludwig Maximilian University of Munich, Munich, Germany
Cheng-Chang Chen
Department of Pharmacy, Center for Drug Research and Center for Integrated Protein Science Munich, Ludwig Maximilian University of Munich, Munich, Germany
Department of Pharmacy, Center for Drug Research and Center for Integrated Protein Science Munich, Ludwig Maximilian University of Munich, Munich, Germany
Anna Scotto Rosato
Telethon Institute of Genetics and Medicine, Naples, Italy
Department of Pharmacology and Toxicology, Medical Faculty, Ludwig Maximilian University of Munich, Munich, Germany
Hua Yinan
Cell Biology and Physiology Center, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, United States
Karin Bartel
Department of Pharmacy, Center for Drug Research and Center for Integrated Protein Science Munich, Ludwig Maximilian University of Munich, Munich, Germany
Marco Keller
Department of Pharmacy, Center for Drug Research and Center for Integrated Protein Science Munich, Ludwig Maximilian University of Munich, Munich, Germany
Dina Robaa
Department of Pharmaceutical Chemistry, Institute of Pharmacy, Martin Luther University of Halle-Wittenberg, Halle, Germany
Daniel Teupser
Institute of Laboratory Medicine, University Hospital Munich, Munich, Germany
Lesca M Holdt
Institute of Laboratory Medicine, University Hospital Munich, Munich, Germany
Angelika M Vollmar
Department of Pharmacy, Center for Drug Research and Center for Integrated Protein Science Munich, Ludwig Maximilian University of Munich, Munich, Germany
Wolfgang Sippl
Department of Pharmaceutical Chemistry, Institute of Pharmacy, Martin Luther University of Halle-Wittenberg, Halle, Germany
Cell Biology and Physiology Center, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, United States
Diego Medina
Telethon Institute of Genetics and Medicine, Naples, Italy
Martin Biel
Department of Pharmacy, Center for Drug Research and Center for Integrated Protein Science Munich, Ludwig Maximilian University of Munich, Munich, Germany
Christian Wahl-Schott
Institute for Neurophysiology, Hannover Medical School, Hannover, Germany
Franz Bracher
Department of Pharmacy, Center for Drug Research and Center for Integrated Protein Science Munich, Ludwig Maximilian University of Munich, Munich, Germany
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.
