Hypertonic sodium-induced alterations in electrolyte balance and their impact on macrophage immunometabolism and function

• Applicant: Professor Dr. Jonathan Jantsch
• Subject Area: Immunology ; Cell Biology
• Term: from 2019 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 412370980

• Final Report Year: 2025

Final Report Abstract

The increase in local sodium availability that occurs during inflammatory and infectious processes enhances the proinflammatory activation of macrophages and their antimicrobial activity. This project investigated the mechanisms by which macrophages detect increased sodium availability and the role of immune metabolism in this context. We provided evidence that the sodium-calcium exchanger (NCX) 1 in macrophages plays an important role in mediating increased proinflammatory and antimicrobial activity. It contributed to sodium influx into macrophages and activated osmoregulatory signaling pathways, leading to increased proinflammatory activation and improved antimicrobial defense. However, high-salt conditions did not only activate osmoprotective signaling cascades: increases in sodium availability also led to a disruption of mitochondrial electron transport, thereby influencing the metabolism of macrophages and their function. However, increasing intracellular sodium availability by inhibiting Na⁺/K⁺-ATPase only mimicked the change in macrophage function induced by high-salt conditions if extracellular tonicity was also increased at the same time. This work demonstrates how local sodium availability controls macrophage function in complex ways.

Publications

• NCX1 represents an ionic Na+ sensing mechanism in macrophages. PLOS Biology, 18(6), e3000722.
  Neubert, Patrick; Homann, Arne; Wendelborn, David; Bär, Anna-Lorena; Krampert, Luka; Trum, Maximilian; Schröder, Agnes; Ebner, Stefan; Weichselbaum, Andrea; Schatz, Valentin; Linz, Peter; Veelken, Roland; Schulte-Schrepping, Jonas; Aschenbrenner, Anna C.; Quast, Thomas; Kurts, Christian; Geisberger, Sabrina; Kunzelmann, Karl; Hammer, Karin ... & Jantsch, Jonathan
  
• Salt Transiently Inhibits Mitochondrial Energetics in Mononuclear Phagocytes. Circulation, 144(2), 144-158.
  Geisberger, Sabrina; Bartolomaeus, Hendrik; Neubert, Patrick; Willebrand, Ralf; Zasada, Christin; Bartolomaeus, Thomas; McParland, Victoria; Swinnen, Dries; Geuzens, Anneleen; Maifeld, András; Krampert, Luka; Vogl, Marion; Mähler, Anja; Wilck, Nicola; Markó, Lajos; Tilic, Ekin; Forslund, Sofia K.; Binger, Katrina J.; Stegbauer, Johannes ... & Müller, Dominik N.
  
• Sodium and its manifold impact on our immune system. Trends in Immunology, 42(6), 469-479.
  Jobin, Katarzyna; Müller, Dominik N.; Jantsch, Jonathan & Kurts, Christian
  
• Salt sensitivity includes effects on immune cell signalling and metabolism. Nature Reviews Immunology, 23(6), 341-342.
  Müller, Dominik N.; Geisberger, Sabrina; Kleinewietfeld, Markus & Jantsch, Jonathan
  
• Simultaneous Increases in Intracellular Sodium and Tonicity Boost Antimicrobial Activity of Macrophages. Cells, 12(24), 2816.
  Krampert, Luka; Ossner, Thomas; Schröder, Agnes; Schatz, Valentin & Jantsch, Jonathan
  
• Sodium as an Important Regulator of Immunometabolism. Hypertension, 81(3), 426-435.
  Miyauchi, Hidetaka; Geisberger, Sabrina; Luft, Friedrich C.; Wilck, Nicola; Stegbauer, Johannes; Wiig, Helge; Dechend, Ralf; Jantsch, Jonathan; Kleinewietfeld, Markus; Kempa, Stefan & Müller, Dominik N.