NCX1 represents an ionic Na+ sensing mechanism in macrophages Academic Article uri icon

abstract

  • 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.

authors

  • Neubert, P
  • Homann, A
  • Wendelborn, D
  • Bär, AL
  • Krampert, L
  • Trum, M
  • Schröder, A
  • Ebner, S
  • Weichselbaum, A
  • Schatz, V
  • Linz, P
  • Veelken, R
  • Schulte-Schrepping, J
  • Aschenbrenner, AC
  • Quast, T
  • Kurts, C
  • Geisberger, S
  • Kunzelmann, K
  • Hammer, K
  • Binger, Katrina J
  • Titze, J
  • Müller, DN
  • Kolanus, W
  • Schultze, JL
  • Wagner, S
  • Jantsch, J

publication date

  • 2020