Selective Agonist of TRPML2 Reveals Direct Role in Chemokine Release From Innate Immune Cells

Elife. 2018 Nov 27;7:e39720. doi: 10.7554/eLife.39720.

Abstract

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.

Keywords: CCL2; Mcoln2; TRPML; TRPML2; biochemistry; chemical biology; lysosome; macrophage; mouse.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Movement / drug effects
  • Chemokine CCL2 / metabolism*
  • Immunologic Factors / metabolism
  • Macrophages / drug effects
  • Macrophages / metabolism*
  • Mice, Inbred C57BL
  • Transient Receptor Potential Channels / agonists*

Substances

  • Ccl2 protein, mouse
  • Chemokine CCL2
  • Immunologic Factors
  • Mcoln2 protein, mouse
  • Transient Receptor Potential Channels

Grant support

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.