NCX1 represents an ionic Na+ sensing mechanism in macrophages.

Patrick Neubert,Valentin Schatz,Christian Kurts,Karl Kunzelmann,Dominik N Müller,Joachim L Schultze,Andrea Weichselbaum,Jonas Schulte-Schrepping,Waldemar Kolanus,Agnes Schröder,Thomas Quast,Maximilian Trum,Stefan Wagner,Anna-Lorena Bär,Stefan Ebner,Roland Veelken,Sabrina Geisberger,Jens Titze,Anna C Aschenbrenner,Jonathan Jantsch,Luka Krampert,Arne Homann,Peter Linz,Katrina J Binger,K Hammer ,D F Wendelborn

doi:10.1371/journal.pbio.3000722

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.

Highlights

Infection and inflammation can trigger localized accumulation of sodium (Na+) in skin [1,2,3]
We have shown that high Na+ increases nuclear factor of activated T cells 5 (NFAT5)-dependent nitric oxide synthase 2 (Nos2) expression in lipopolysaccharide (LPS)-activated MFs, resulting in increased antimicrobial nitric oxide (NO) production
In addition to organic chemical signals, the local ionic inorganic tissue microenvironment is recognized as a novel regulator of immune cell function

Summary

Introduction

Infection and inflammation can trigger localized accumulation of sodium (Na+) in skin [1,2,3]. In addition to regulating skin Na+ levels, the response of MFs to infection and/or inflammation is modulated by increased local Na+ levels. High-Na+ conditions enhanced autolysosome formation of infected MFs, which together with increased NO, facilitates increased antimicrobial responses [1,10]. These findings established that alterations in local Na+ influence MF biology, the initial molecular responses of MFs to high-Na+ environments remain unclear

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Conclusion