PLoS Biology (Jun 2020)

NCX1 represents an ionic Na+ sensing mechanism in macrophages.

  • Patrick Neubert,
  • Arne Homann,
  • David Wendelborn,
  • Anna-Lorena Bär,
  • Luka Krampert,
  • Maximilian Trum,
  • Agnes Schröder,
  • Stefan Ebner,
  • Andrea Weichselbaum,
  • Valentin Schatz,
  • Peter Linz,
  • Roland Veelken,
  • Jonas Schulte-Schrepping,
  • Anna C Aschenbrenner,
  • Thomas Quast,
  • Christian Kurts,
  • Sabrina Geisberger,
  • Karl Kunzelmann,
  • Karin Hammer,
  • Katrina J Binger,
  • Jens Titze,
  • Dominik N Müller,
  • Waldemar Kolanus,
  • Joachim L Schultze,
  • Stefan Wagner,
  • Jonathan Jantsch

DOI
https://doi.org/10.1371/journal.pbio.3000722
Journal volume & issue
Vol. 18, no. 6
p. e3000722

Abstract

Read online

Inflammation and infection can trigger local tissue Na+ accumulation. This Na+-rich environment boosts proinflammatory activation of monocyte/macrophage-like cells (MΦs) and their antimicrobial activity. Enhanced Na+-driven MΦ function requires the osmoprotective transcription factor nuclear factor of activated T cells 5 (NFAT5), which augments nitric oxide (NO) production and contributes to increased autophagy. However, the mechanism of Na+ sensing in MΦs remained unclear. High extracellular Na+ levels (high salt [HS]) trigger a substantial Na+ influx and Ca2+ loss. Here, we show that the Na+/Ca2+ exchanger 1 (NCX1, also known as solute carrier family 8 member A1 [SLC8A1]) plays a critical role in HS-triggered Na+ influx, concomitant Ca2+ efflux, and subsequent augmented NFAT5 accumulation. Moreover, interfering with NCX1 activity impairs HS-boosted inflammatory signaling, infection-triggered autolysosome formation, and subsequent antibacterial activity. Taken together, this demonstrates that NCX1 is able to sense Na+ and is required for amplifying inflammatory and antimicrobial MΦ responses upon HS exposure. Manipulating NCX1 offers a new strategy to regulate MΦ function.