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NCX1 represents an ionic Na(+) sensing mechanism in macrophages

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Item Type:Article
Title:NCX1 represents an ionic Na(+) sensing mechanism in macrophages
Creators Name:Neubert, P. and Homann, A. and Wendelborn, D. and Bär, A.L. and Krampert, L. and Trum, M. and Schröder, A. and Ebner, S. and Weichselbaum, A. and Schatz, V. and Linz, P. and Veelken, R. and Schulte-Schrepping, J. and Aschenbrenner, A.C. and Quast, T. and Kurts, C. and Geisberger, S. and Kunzelmann, K. and Hammer, K. and Binger, K.J. and Titze, J. and Müller, D.N. and Kolanus, W. and Schultze, J.L. and Wagner, S. and Jantsch, J.
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 Ca(2+) loss. Here, we show that the Na(+)/Ca(2+) exchanger 1 (NCX1, also known as solute carrier family 8 member A1 [SLC8A1]) plays a critical role in HS-triggered Na(+) influx, concomitant Ca(2+) 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.
Keywords:Alternative Splicing, Calcium, Extracellular Space, Gene Silencing, Ion Channel Gating, Ions, Lipopolysaccharides, Macrophages, Nitric Oxide, RAW 264.7 Cells, Sodium, Sodium Chloride, Sodium-Calcium Exchanger, Animals, Mice
Source:PLoS Biology
Publisher:Public Library of Science
Page Range:e3000722
Date:22 June 2020
Official Publication:https://doi.org/10.1371/journal.pbio.3000722
PubMed:View item in PubMed

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