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Sodium in the microenvironment regulates immune responses and tissue homeostasis

Abstract

During tissue inflammation, immune cells infiltrate the interstitial space of target organs, where they sense and adapt to local environmental stimuli. Such stimuli include not only pathogens but also local factors such as the levels of oxygenation, nutrients and electrolytes. An important electrolyte in this regard is sodium (Na+). Recent in vivo findings have shown a role of Na+ storage in the skin for electrolyte homeostasis. Thereby, Na+ intake may influence the activation status of the immune system through direct effects on T helper cell subsets and innate immune cells in tissues such as the skin and other target organs. Furthermore, high Na+ intake has been shown to alter the composition of the intestinal microbiota, with indirect effects on immune cells. The results suggest regulatory roles for Na+ in cardiovascular disease, inflammation, infection and autoimmunity.

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Fig. 1: Water conservation under different salt conditions.
Fig. 2: Effects of high salt conditions on CD4+ T cells and macrophages.
Fig. 3: High salt concentrations affect immune cell and target organ function.
Fig. 4: Western-pattern diets induce dysbiosis and affect intestinal barrier function.

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Acknowledgements

The authors acknowledge F. C. Luft, H. Wiig and J. Jantsch for their critical and helpful input. M.K. was supported by the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation program (640116), by a SALK-grant from the government of Flanders, Belgium, and by an Odysseus-grant of the Research Foundation Flanders (FWO), Belgium. N.W. and D.N.M. are members of and were supported by the DZHK (German Centre for Cardiovascular Research), Germany. N.W. is a participant in the Clinician Scientist Program funded by the Berlin Institute of Health (BIH), Germany.

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Nature Reviews Immunology thanks S. Z. Duan, D. Hafler and other anonymous reviewer(s) for their contribution to the peer review of this work.

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Glossary

Isotonic

Two solutions are isotonic when they have the same effective osmole concentration and thus the same osmotic pressure.

Nonosmotic

Not following the rules of osmosis, which is the spontaneous net movement of solvent molecules through a selectively permeable membrane into a region of higher solute concentration.

MARS500 project

A psychosocial isolation experiment conducted between 2007 and 2011 by Russia, the European Space Agency and China in preparation for an unspecified future manned spaceflight to the planet Mars.

Circaseptan

Relating to a 7-day cycle for biological processes of life.

Infradian

A rhythm with a period longer than the period of a circadian rhythm.

Pressure natriuresis

A mechanism for the long-term control of arterial pressure, whereby an increase in renal perfusion pressure leads to increased Na+ excretion.

Sodium magnetic resonance imaging

(Na-MRI). A technique using a magnetic field with a special coil to allow for visualization of 23Na in living tissue.

Primary aldosteronism

A disease that involves the excess production of aldosterone by the adrenal glands, resulting in high blood pressure.

M1 and M2 macrophages

M1 and M2 are classifications historically used to define macrophages activated in vitro as pro-inflammatory (when classically activated with IFNγ and lipopolysaccharide) or anti-inflammatory (when alternatively activated with IL-4 or IL-10), respectively. However, in vivo, macrophages are highly specialized, transcriptomically dynamic and extremely heterogeneous with regard to their phenotypes and functions, which are continuously shaped by their tissue microenvironment. Therefore, the M1 or M2 classification is too simplistic to explain the true nature of in vivo macrophages, although these terms are still often used to indicate whether the macrophages in question are more pro-inflammatory or anti-inflammatory.

Central osmoreceptors

Sensory receptors found primarily in the hypothalamus of most homeothermic organisms that detect changes in osmotic pressure.

Vasopressin

A peptide hormone released from the posterior pituitary in response to extracellular fluid hypertonicity, which leads to re-absorption of solute-free water in the kidney tubules as well as vasoconstriction.

Atrial natriuretic peptide

A peptide hormone secreted by the atria in the heart, which reduces an expanded extracellular fluid volume by increasing renal Na+ excretion.

Renin–angiotensin–aldosterone system

A hormone system regulating blood pressure and fluid balance.

Albuminuria

A pathological condition in which the plasma protein albumin is abnormally present in the urine.

Diabetes insipidus

A pathological condition characterized by the production of large amounts of dilute urine and increased thirst.

Segmented filamentous bacteria

(SFB). Members of the gut microbiota of rodents, fish and chickens, with morphological resemblance to bacterial filaments that were previously observed in the guts of insects.

Operational taxonomic units

Clusters of (microbial) organisms grouped by DNA sequence similarity of a specific taxonomic marker gene.

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Müller, D.N., Wilck, N., Haase, S. et al. Sodium in the microenvironment regulates immune responses and tissue homeostasis. Nat Rev Immunol 19, 243–254 (2019). https://doi.org/10.1038/s41577-018-0113-4

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