ImmunoSensation - the immune sensory system

PLoS Biol . 2020 Jun 22

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

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.

PMID: 32569301