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Salt transiently inhibits mitochondrial energetics in mononuclear phagocytes

Authors

  • S. Geisberger
  • H. Bartolomaeus
  • P. Neubert
  • R. Willebrand
  • C. Zasada
  • T. Bartolomaeus
  • V. McParland
  • D. Swinnen
  • A. Geuzens
  • A. Maifeld
  • L. Krampert
  • M. Vogl
  • A. Mähler
  • N. Wilck
  • L. Marko
  • E. Tilic
  • S.K. Forslund
  • K.J. Binger
  • J. Stegbauer
  • R. Dechend
  • M. Kleinewietfeld
  • J. Jantsch
  • S. Kempa
  • D.N. Müller

Journal

  • Circulation

Citation

  • Circulation

Abstract

  • BACKGROUND: Dietary high salt (HS) is a leading risk factor for mortality and morbidity. Serum sodium transiently increases postprandially, but can also accumulate at sites of inflammation affecting differentiation and function of innate and adaptive immune cells. Here, we focus on how changes in extracellular sodium, mimicking alterations in the circulation and tissues, affect the early metabolic, transcriptional and functional adaption of human and murine mononuclear phagocytes (MNP). METHODS: Using Seahorse technology, pulsed stable isotope-resolved metabolomics and enzyme activity assays we characterize the central carbon metabolism and mitochondrial function of human and murine MNP under HS in vitro. HS as well as pharmacologic uncoupling of the electron transport chain (ETC) under normal salt (NS) is used to analyze mitochondrial function on immune cell activation and function (as determined by E.coli killing and CD4(+) T cell migration capacity). In two independent clinical studies we analyze the impact of a HS diet over two weeks (NCT02509962) and short-term salt challenge by a single meal (NCT04175249) on mitochondrial function of human monocytes in vivo. RESULTS: Extracellular sodium was taken up into the intracellular compartment followed by the inhibition of mitochondrial respiration in murine and human macrophages (MΦ). Mechanistically, HS reduces mitochondrial membrane potential, ETC complex II activity, oxygen consumption, and ATP production independently of the polarization status of MΦ. Subsequently, cell activation is altered with improved bactericidal function in HS-treated M1-like MΦ and diminished CD4(+) T cell migration in HS-treated M2-like MΦ. Pharmacologic uncoupling of the ETC under NS phenocopies HS-induced transcriptional changes and bactericidal function of human and murine MNP. Clinically, also in vivo rise in plasma sodium concentration within the physiological range reversibly reduces mitochondrial function in human monocytes. In both, a 14-day and single meal HS challenge, healthy volunteers displayed a plasma sodium increase of ̃x = 2mM and ̃x = 2.3mM, respectively, that correlated with decreased monocytic mitochondrial oxygen consumption. CONCLUSIONS: Our data identify the disturbance of mitochondrial respiration as the initial step by which HS mechanistically influences immune cell function. While these functional changes might help to resolve bacterial infections, a shift towards pro-inflammation could accelerate inflammatory CVD.


DOI

doi:10.1161/CIRCULATIONAHA.120.052788