NCX1 represents an ionic Na<sup>+</sup> sensing mechanism in macrophages

by 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.

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