NCX1 represents an ionic Na+ sensing mechanism in macrophages

PLoS Biol. 2020 Jun 22;18(6):e3000722. doi: 10.1371/journal.pbio.3000722. eCollection 2020 Jun.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alternative Splicing / genetics
  • Animals
  • Calcium / metabolism
  • Extracellular Space / metabolism
  • Gene Silencing / drug effects
  • Ion Channel Gating / drug effects
  • Ions
  • Lipopolysaccharides / pharmacology
  • Macrophages / drug effects
  • Macrophages / metabolism*
  • Mice
  • Nitric Oxide / biosynthesis
  • RAW 264.7 Cells
  • Sodium / metabolism*
  • Sodium Chloride / pharmacology
  • Sodium-Calcium Exchanger / metabolism*


  • Ions
  • Lipopolysaccharides
  • Sodium-Calcium Exchanger
  • sodium-calcium exchanger 1
  • Nitric Oxide
  • Sodium Chloride
  • Sodium
  • Calcium

Grant support

JJ received funding from the DFG (JA1993/6-1) and DFG SFB 1350 grant (project nr. 387509280, TPB5). SW is funded by DFG grants WA 2539/4-1, 5-1, and 7-1, by a DFG SFB 1350 grant (project nr. 387509280, TPA6), and by the Deutsches Zentrum für Herz-Kreislauf-Forschung ([DZHK]; German Center for Cardiovascular Research). JJ, SW, and KH are supported by the ReForM C program of the Medical Faculty University of Regensburg. JLS received funding from the DFG under Germany’s Excellence Strategy – EXC2151 – 390873048 and the EU under project SYSCID (grant nr. 733100). DNM is supported by the DZHK and the DFG (SFB 1365). The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.