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The role of sodium in modulating immune cell function

Abstract

Sodium intake is undoubtedly indispensable for normal body functions but can be detrimental when taken in excess of dietary requirements. The consequences of excessive salt intake are becoming increasingly clear as high salt consumption persists across the globe. Salt has long been suspected to promote the development of hypertension and cardiovascular diseases and is now also recognized as a potential modulator of inflammatory and autoimmune diseases through its direct and indirect effects on immune cells. The finding that, in addition to the kidneys, other organs such as the skin regulate sodium levels in the body prompted new hypotheses, including the concept that skin-resident macrophages might participate in tissue sodium regulation through their interactions with lymphatic vessels. Moreover, immune cells such as macrophages and different T cell subsets are found in sodium-rich interstitial microenvironments, where sodium levels modulate their function. Alterations to the intestinal bacterial community induced by excess dietary salt represent another relevant axis whereby salt indirectly modulates immune cell function. Depending on the inflammatory context, sodium might either contribute to protective immunity (for example, by enhancing host responses against cutaneous pathogens) or it might contribute to immune dysregulation and promote the development of cardiovascular and autoimmune diseases.

Key points

  • Salt (sodium chloride) is an important environmental factor that influences various immune cells at biological barriers, including the skin, intestine and kidney.

  • Innate and adaptive immune cells can sense hypertonic sodium in the interstitium, which subsequently affects their differentiation and/or function.

  • Salt-enhanced pro-inflammatory responses may be beneficial for the clearance of invasive pathogens but they might also promote hypertension and chronic immune-mediated diseases.

  • Salt also affects immune cells through its effects on the composition of the gut microbiome.

  • Clinical studies on the role of salt in immune-mediated diseases partly confirm experimental findings, but further investigation is needed.

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Fig. 1: Salt promotes activation of pro-inflammatory macrophages.
Fig. 2: High salt promotes pathogenic TH17 cells and inhibits the suppressive function of Treg cells.
Fig. 3: High salt affects immune cells in different organs.

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Acknowledgements

The authors thank E. G. Avery (Max Delbruck Center for Molecular Medicine, Berlin, Germany) for critically reviewing the manuscript before submission. N.W. is funded by the Berlin Institute of Health (Clinician Scientist Program), Berlin, Germany.

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Nature Reviews Nephrology thanks A. Kirabo, P. Mehrotra and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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N.W. and D.N.M. researched the data and wrote the article with major input from H.B., L.M. and A.B. All authors discussed the content, reviewed and edited the manuscript before submission.

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Correspondence to Dominik N. Müller.

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Glossary

Western diet

Diet characterized, for example, by the consumption of high amounts of red meat, dairy products, sugars, unsaturated fats and salt (typically consumed in pre-processed foods).

Glycosaminoglycans

(GAGs). Linear, negatively charged carbohydrates, often bound to glycoproteins in the extracellular matrix, where they determine the biomechanical properties of the interstitial space.

Intestinal microbiome

Collective genomes of the community of intestinal microorganisms, which include bacteria, viruses and fungi.

Acute cellulitis

Acute bacterial infection of the skin affecting the dermis and adjacent subcutaneous fat.

Osmolytes

Osmotically active particles (for example, ions or proteins) that are dissolved in the cytosol and the extracellular fluid and affect cell volume and other cellular processes.

Hypertonicity

A state in which the extracellular space contains more solutes than the cytosol.

Naive T cells

Mature T cells (helper T cells or cytotoxic T cells) that have not encountered their cognate antigens in peripheral tissues.

16S ribosomal RNA (rRNA) sequencing

Sequencing of the 16S rRNA amplicon, a common, culture-independent method used to identify and compare bacterial phylogeny and taxonomy in a microbial sample.

Essential hypertension

Chronic elevation of blood pressure in the systemic circulation that cannot be assigned to an identifiable cause; also known as primary or idiopathic hypertension, it affects approximately 90% of all patients with high blood pressure.

Isoketal-modified proteins

Proteins oxidatively modified by highly reactive γ-ketoaldehydes (also referred to as isoketals, formed by peroxidation of arachidonic acid induced by free radicals). Isoketals adduct to lysine residues on proteins and extensively crosslink proteins.

Subpressor dose

Low dose of a given substance that leads to an increase in blood pressure.

Clinically isolated syndrome

A single episode of neurological symptoms and inflammatory demyelination in humans that is isolated in time and compatible with a possible future development of multiple sclerosis.

23Na MRI

Non-invasive method for imaging of tissue sodium using the nuclear magnetic resonance signal of sodium nuclei; quantification is performed by placing phantoms of known sodium concentration within the field of view.

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Wilck, N., Balogh, A., Markó, L. et al. The role of sodium in modulating immune cell function. Nat Rev Nephrol 15, 546–558 (2019). https://doi.org/10.1038/s41581-019-0167-y

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