Open AccessNCX1 represents an ionic Na+ sensing mechanism in macrophages
Author(s) -
Patrick Neubert,
Arne Homann,
D F 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,
K Hammer,
Katrina J. Binger,
Jens Titze,
Dominik N. Müller,
Waldemar Kolanus,
Joachim L. Schultze,
Stefan Wagner,
Jonathan Jantsch
Publication year - 2020
Publication title -
plos biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.127
H-Index - 271
eISSN - 1545-7885
pISSN - 1544-9173
DOI - 10.1371/journal.pbio.3000722
Subject(s) - proinflammatory cytokine , microbiology and biotechnology , inflammation , biology , extracellular , nitric oxide , downregulation and upregulation , transcription factor , intracellular , macrophage , biophysics , biochemistry , immunology , in vitro , endocrinology , gene
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.