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

doi:10.1371/journal.pbio.3000722

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.

Authors

Patrick Neubert¹, Arne Homann¹, David Wendelborn¹, Anna-Lorena Bär¹, Luka Krampert¹, Maximilian Trum², Agnes Schröder³, Stefan Ebner^{1

4}, Andrea Weichselbaum¹, Valentin Schatz¹, Peter Linz⁵, Roland Veelken⁶, Jonas Schulte-Schrepping⁷, Anna C Aschenbrenner^{7

8}, Thomas Quast⁹, Christian Kurts¹⁰, Sabrina Geisberger^{11

12}, Karl Kunzelmann¹³, Karin Hammer², Katrina J Binger¹⁴, Jens Titze¹⁵, Dominik N Müller^{11

12}, Waldemar Kolanus⁹, Joachim L Schultze^{7

16}, Stefan Wagner², Jonathan Jantsch¹

Affiliations

¹ Institute of Clinical Microbiology and Hygiene, University Hospital of Regensburg and University of Regensburg, Regensburg, Germany.
² Department of Internal Medicine II, University Hospital of Regensburg and University of Regensburg, Regensburg, Germany.
³ Institute of Orthodontics, University Hospital of Regensburg, Regensburg, Germany.
⁴ Max Planck Institute of Biochemistry, Martinsried, Germany.
⁵ Institute of Radiology, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany.
⁶ Department of Internal Medicine 4, University Hospital Erlangen, Erlangen, Germany.
⁷ Department for Genomics and Immunoregulation, Life and Medical Sciences (LIMES) Institute, University of Bonn, Bonn, Germany.
⁸ Department of Internal Medicine and Radboud Center for Infectious Diseases (RCI), Radboud University Medical Center, Nijmegen, the Netherlands.
⁹ Molecular Immunology and Cell Biology LIMES Institute, University of Bonn, Bonn, Germany.
¹⁰ Institute of Experimental Immunology, University of Bonn, Bonn, Germany.
¹¹ Experimental and Clinical Research Center (ECRC), a cooperation of Charité-Universitätsmedizin Berlin and Max Delbruck Center for Molecular Medicine, Berlin, Germany.
¹² Max Delbruck Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany.
¹³ Institute of Physiology, University of Regensburg, Regensburg, Germany.
¹⁴ Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Bundoora, Australia.
¹⁵ Cardiovascular and Metabolic Disorders, Duke-NUS Medical School, Singapore.
¹⁶ Platform for Single Cell Genomics & Epigenomics at the German Center for Neurodegenerative Diseases (DZNE) and the University of Bonn, Bonn, Germany.

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.

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*

Substances

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

Grants and funding

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.