Sodium and its manifold impact on our immune system
Authors: Katarzyna Jobin, Dominik N. Müller, Jonathan Jantsch, Christian Kurts
Journal: Trends in Immunology (2021)

A HSD can stimulate local tissue-specific accumulation of sodium in mice and humans.Increases in sodium concentration can amplify inflammatory macrophage and T cell responses in mice and humans.A HSD can affect systemic immune responses by altering the intestinal microbiome and its immunomodulatory metabolites in mice and humans.A HSD can systemically suppress neutrophil-mediated immune responses by causing hyperglucorticoidism without diurnal rhythm in mice and humans.The effect of a HSD on immunity is dependent on the tissue/organ affected, the type of immune cells implicated, and the presence and type of disease. The Western diet is rich in salt, and a high salt diet (HSD) is suspected to be a risk factor for cardiovascular diseases. It is now widely accepted that an experimental HSD can stimulate components of the immune system, potentially exacerbating certain autoimmune diseases, or alternatively, improving defenses against certain infections, such as cutaneous leishmaniasis. However, recent findings show that an experimental HSD may also aggravate other infections (e.g., pyelonephritis or systemic listeriosis). Here, we discuss the modulatory effects of a HSD on the microbiota, metabolic signaling, hormonal responses, local sodium concentrations, and their effects on various immune cell types in different tissues. We describe how these factors are integrated, resulting either in immune stimulation or suppression in various tissues and disease settings. The Western diet is rich in salt, and a high salt diet (HSD) is suspected to be a risk factor for cardiovascular diseases. It is now widely accepted that an experimental HSD can stimulate components of the immune system, potentially exacerbating certain autoimmune diseases, or alternatively, improving defenses against certain infections, such as cutaneous leishmaniasis. However, recent findings show that an experimental HSD may also aggravate other infections (e.g., pyelonephritis or systemic listeriosis). Here, we discuss the modulatory effects of a HSD on the microbiota, metabolic signaling, hormonal responses, local sodium concentrations, and their effects on various immune cell types in different tissues. We describe how these factors are integrated, resulting either in immune stimulation or suppression in various tissues and disease settings. Salt (NaCl) used to be so rare and valuable that in the 17th century for instance, the Duchy of Bavaria and the city of Salzburg entered into war over it. Even the word ‘salary' reflects the preciousness that salt once had [1.Kurlansky M. Salt. Walker Books, 2010Google Scholar]. Due to geotechnological advances, salt nowadays is neither rare nor expensive. We love it and, thus, we eat a lot of it. Typical diets in Western countries and China contain more than 10 g per day [2.Tan Monique et al.Twenty-four-hour urinary sodium and potassium excretion in China: a systematic review and meta-analysis.J. Am. Heart Assoc. 2019; 8e012923Crossref PubMed Scopus (31) Google Scholar]. The high salt content of diets in industrialized countries is suspected to be a risk factor that drives mortality and disease burden [3.Cook N.R. et al.Sodium intake and all-cause mortality over 20 years in the trials of hypertension prevention.J. Am. Coll. Cardiol. 2016; 68: 1609-1617Crossref PubMed Scopus (104) Google Scholar]. The connection between elevated salt consumption and hypertension was first proposed more than 50 years ago [4.Titze J. Luft F.C. Speculations on salt and the genesis of arterial hypertension.Kidney Int. 2017; 91: 1324-1335Abstract Full Text Full Text PDF PubMed Scopus (32) Google Scholar], and remains intensively discussed, especially since recent work questioned this connection [5.Messerli F.H. et al.Sodium intake, life expectancy, and all-cause mortality.Eur. Heart J. 2020; ehaa947Crossref PubMed Scopus (6) Google Scholar]. Furthermore, recent studies have uncovered new links of salt to our health, especially through the proinflammatory effects of sodium [6.Hucke S. et al.Sodium chloride promotes pro-inflammatory macrophage polarization thereby aggravating CNS autoimmunity.J. Autoimmun. 2016; 67: 90-101Crossref PubMed Scopus (83) Google Scholar, 7.Ip W.K.E. Medzhitov R. Macrophages monitor tissue osmolarity and induce inflammatory response through NLRP3 and NLRC4 inflammasome activation.Nat. 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Immunol. 2019; 10: 1141Crossref PubMed Scopus (10) Google Scholar, 13.He W. et al.High-salt diet inhibits tumour growth in mice via regulating myeloid-derived suppressor cell differentiation.Nat. Commun. 2020; 11: 1732Crossref PubMed Scopus (10) Google Scholar, 14.Binger K.J. et al.High salt reduces the activation of IL-4– and IL-13–stimulated macrophages.J. Clin. Invest. 2015; 125: 4223Crossref PubMed Scopus (149) Google Scholar]. On the one hand, HSD can stimulate certain components of the immune system, namely, to combat pathogens more efficiently [10.Jantsch J. et al.Cutaneous Na+ storage strengthens the antimicrobial barrier function of the skin and boosts macrophage-driven host defense.Cell Metab. 2015; 21: 493-501Abstract Full Text Full Text PDF PubMed Scopus (168) Google Scholar,11.Zhang W.-C. et al.Elevated sodium chloride drives type I interferon signaling in macrophages and increases antiviral resistance.J. Biol. 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Autoimmun. 2016; 67: 90-101Crossref PubMed Scopus (83) Google Scholar,16.Kleinewietfeld M. et al.Sodium chloride drives autoimmune disease by the induction of pathogenic TH17 cells.Nature. 2013; 496: 518-522Crossref PubMed Scopus (784) Google Scholar,17.Wu C. et al.Induction of pathogenic TH17 cells by inducible salt-sensing kinase SGK1.Nature. 2013; 496: 513-517Crossref PubMed Scopus (602) Google Scholar]. Moreover, HSD can boost osteoclast activity and thereby facilitate orthodontic tooth movement [18.Schröder A. et al.Dietary salt accelerates orthodontic tooth movement by increased osteoclast activity.Int. J. Mol. Sci. 2021; 22: 596Crossref Scopus (1) Google Scholar] and augment proinflammatory activation of microglia, which can aggravate stroke injury [19.Zhang T. et al.Excess salt intake promotes M1 microglia polarization via a p38/MAPK/AR-dependent pathway after cerebral ischemia in mice.Int. Immunopharmacol. 2020; 81: 106176Crossref PubMed Scopus (4) Google Scholar]. Of note, salt-losing tubulopathies (see Glossary) that result in sodium loss, have enhanced susceptibility to mucosal infections in humans [20.Evans R.D.R. et al.Inherited salt-losing tubulopathies are associated with immunodeficiency due to impaired IL-17 responses.Nat. Commun. 2020; 11: 4368Crossref PubMed Scopus (4) Google Scholar]. Likewise, treating renal transplant patients with loop diuretics, which causes the excretion of sodium, can increase the incidence of urinary tract infections in these patients [21.Casper J. et al.Renal transplant recipients receiving loop diuretic therapy have increased urinary tract infection rate and altered medullary macrophage polarization marker expression.Kidney Int. 2018; 94: 993-1001Abstract Full Text Full Text PDF PubMed Scopus (6) Google Scholar]. This has led to the current view that sodium is generally immunostimulatory depending on the local microenvironment [22.Schatz V. et al.Elementary immunology: Na+ as a regulator of immunity.Pediatr. Nephrol. 2017; 32: 201-210Crossref PubMed Scopus (37) Google Scholar,23.Wilck N. et al.The role of sodium in modulating immune cell function.Nat. Rev. Nephrol. 2019; 15: 546-558Crossref PubMed Scopus (21) Google Scholar]. On the other hand, recent findings have uncovered the immunosuppressive effects of sodium [24.Jobin K. et al.A high-salt diet compromises antibacterial neutrophil responses through hormonal perturbation.Sci. Transl. Med. 2020; 12eaay3850Crossref PubMed Scopus (12) Google Scholar,25.Matthias J. et al.Salt generates anti-inflammatory Th17 cells but amplifies pathogenicity in proinflammatory cytokine microenvironments.J. Clin. Invest. 2020; 130: 4587-4600Crossref PubMed Scopus (8) Google Scholar]. Thus, a comprehensive theory about when and where sodium is immunostimulatory or suppressive is wholly lacking at present. Here, we wish to draw a broader picture of the complex systemic immune regulatory circuits induced by dietary sodium and its local effects. We discuss sodium uptake and tissue storage, local effects on immune cells, systemic effects through the microbiota and endocrine alterations, as well as specific effects in immune-mediated diseases and infections, with a focus on pyelonephritis. We hypothesize that a bird’s-eye view of immunology that encompasses anatomical, physiological, and microbiological factors, may allow to predict the effects of a HSD on certain diseases, and may also reconcile reports in the literature that are seemingly contradictory. Theoretically, a HSD may affect our organism via direct or indirect, local or systemic effects (Figure 1A,B ). Specifically, preclinical studies with rodents using experimental sodium-rich diets revealed that sodium can accumulate in skin, thymus, liver, and spleen [13.He W. et al.High-salt diet inhibits tumour growth in mice via regulating myeloid-derived suppressor cell differentiation.Nat. Commun. 2020; 11: 1732Crossref PubMed Scopus (10) Google Scholar,26.Machnik A. et al.Macrophages regulate salt-dependent volume and blood pressure by a vascular endothelial growth factor-C-dependent buffering mechanism.Nat. Med. 2009; 15: 545-552Crossref PubMed Scopus (603) Google Scholar, 27.Wiig H. et al.Immune cells control skin lymphatic electrolyte homeostasis and blood pressure.J. Clin. Invest. 2013; 123: 2803-2815Crossref PubMed Scopus (236) Google Scholar, 28.Titze J. et al.Osmotically inactive skin Na+ storage in rats.Am. J. Physiol. Renal Physiol. 2003; 285: F1108-F1117Crossref PubMed Scopus (157) Google Scholar] and, in addition, sodium may be potentially stored in endothelial surface layers [29.Olde Engberink R.H.G. et al.Clinical impact of tissue sodium storage.Pediatr. Nephrol. 2020; 35: 1373-1380Crossref PubMed Scopus (5) Google Scholar], and thus act locally on surrounding cells. Moreover, there is evidence in mice that the kidney and bone marrow can lose salt upon dietary experimental HSD [24.Jobin K. et al.A high-salt diet compromises antibacterial neutrophil responses through hormonal perturbation.Sci. Transl. Med. 2020; 12eaay3850Crossref PubMed Scopus (12) Google Scholar,30.Schröder A. et al.Osteoprotective action of low-salt diet requires myeloid cell-derived NFAT5.JCI Insight. 2019; 4e127868Crossref PubMed Scopus (7) Google Scholar], and consequently, these tissues display a lower sodium content upon HSD than low salt diet (LSD). In general, HSD does not uniformly result in sodium accumulation in all tissues. In addition, these responses may depend on the genetic background of animals and organisms studied [15.de Oliveira C.B.S. et al.The influence of salt intake on the course of experimental toxoplasmosis in outbred or inbred mouse strains.Rev. Patol. Trop. J. Trop. Pathol. 2018; 47: 87-99Crossref Google Scholar]. These findings highlight the importance of quantifying tissue sodium concentrations, and ideally chloride, in further studies addressing the local effects of these electrolytes under high salt diet or LSDs. It is not completely clear why, when, or how sodium accumulates in tissues. Correlative analysis of glycosaminoglycan content, and its charge capacity in rodents [26.Machnik A. et al.Macrophages regulate salt-dependent volume and blood pressure by a vascular endothelial growth factor-C-dependent buffering mechanism.Nat. Med. 2009; 15: 545-552Crossref PubMed Scopus (603) Google Scholar,31.Titze J. et al.Glycosaminoglycan polymerization may enable osmotically inactive Na+ storage in the skin.Am. J. Physiol. Heart Circ. Physiol. 2004; 287: H203-H208Crossref PubMed Scopus (194) Google Scholar,32.Schafflhuber M. et al.Mobilization of osmotically inactive Na+ by growth and by dietary salt restriction in rats.Am. J. Physiol. Renal Physiol. 2007; 292: F1490-F1500Crossref PubMed Scopus (80) Google Scholar] and humans [33.Fischereder M. et al.Sodium storage in human tissues is mediated by glycosaminoglycan expression.Am. J. Physiol. Renal Physiol. 2017; 313: F319-F325Crossref PubMed Scopus (27) Google Scholar], suggested that negatively charged glycosaminoglycans may at least partially contribute to tissue sodium accumulation by binding positively charged ions [26.Machnik A. et al.Macrophages regulate salt-dependent volume and blood pressure by a vascular endothelial growth factor-C-dependent buffering mechanism.Nat. Med. 2009; 15: 545-552Crossref PubMed Scopus (603) Google Scholar,31.Titze J. et al.Glycosaminoglycan polymerization may enable osmotically inactive Na+ storage in the skin.Am. J. Physiol. Heart Circ. Physiol. 2004; 287: H203-H208Crossref PubMed Scopus (194) Google Scholar, 32.Schafflhuber M. et al.Mobilization of osmotically inactive Na+ by growth and by dietary salt restriction in rats.Am. J. Physiol. Renal Physiol. 2007; 292: F1490-F1500Crossref PubMed Scopus (80) Google Scholar, 33.Fischereder M. et al.Sodium storage in human tissues is mediated by glycosaminoglycan expression.Am. J. Physiol. Renal Physiol. 2017; 313: F319-F325Crossref PubMed Scopus (27) Google Scholar]. In addition, there is evidence from studies with rodents that this sodium storage in the skin generates a hypertonic environment [27.Wiig H. et al.Immune cells control skin lymphatic electrolyte homeostasis and blood pressure.J. Clin. Invest. 2013; 123: 2803-2815Crossref PubMed Scopus (236) Google Scholar]. How hypertonic fluid microdomains can be generated is unclear. One study modeled existing data and concluded that there might be a cutaneous countercurrent system similar to the kidney [34.Hofmeister L.H. et al.Tissue sodium storage: evidence for kidney-like extrarenal countercurrent systems?.Pflugers Arch. 2015; 467: 551-558Crossref PubMed Scopus (45) Google Scholar], allowing the generation of a hypertonic cutaneous fluid compartment rich in sodium. In this model, the lymphatics would represent a tubular/collecting duct-like system that drains sodium from the skin [34.Hofmeister L.H. et al.Tissue sodium storage: evidence for kidney-like extrarenal countercurrent systems?.Pflugers Arch. 2015; 467: 551-558Crossref PubMed Scopus (45) Google Scholar]. This model matches the findings that sodium content is substantially higher in cutaneous lymphatics of rodents compared to surrounding tissue [27.Wiig H. et al.Immune cells control skin lymphatic electrolyte homeostasis and blood pressure.J. Clin. Invest. 2013; 123: 2803-2815Crossref PubMed Scopus (236) Google Scholar]. In preclinical mouse and rat models, a HSD increased the compartment of circulating classical monocytes compared to a normal salt diet [35.Fan A. et al.High-salt diet decreases mechanical thresholds in mice that is mediated by a CCR2-dependent mechanism.J. Neuroinflammation. 2020; 17: 179Crossref PubMed Scopus (3) Google Scholar], and dermal macrophage numbers relative to LSD [26.Machnik A. et al.Macrophages regulate salt-dependent volume and blood pressure by a vascular endothelial growth factor-C-dependent buffering mechanism.Nat. Med. 2009; 15: 545-552Crossref PubMed Scopus (603) Google Scholar,27.Wiig H. et al.Immune cells control skin lymphatic electrolyte homeostasis and blood pressure.J. Clin. Invest. 2013; 123: 2803-2815Crossref PubMed Scopus (236) Google Scholar,36.Machnik A. et al.Mononuclear phagocyte system depletion blocks interstitial tonicity-responsive enhancer binding protein/vascular endothelial growth factor C expression and induces salt-sensitive hypertension in rats.Hypertension. 2010; 55: 755-761Crossref PubMed Scopus (136) Google Scholar]. A mechanism was proposed in which cutaneous macrophages regulated the abundance of skin lymph capillaries [26.Machnik A. et al.Macrophages regulate salt-dependent volume and blood pressure by a vascular endothelial growth factor-C-dependent buffering mechanism.Nat. Med. 2009; 15: 545-552Crossref PubMed Scopus (603) Google Scholar,27.Wiig H. et al.Immune cells control skin lymphatic electrolyte homeostasis and blood pressure.J. Clin. Invest. 2013; 123: 2803-2815Crossref PubMed Scopus (236) Google Scholar]. Accordingly, osmoprotective signaling through the transcription factor nuclear factor of activated T cells 5 (NFAT5), also known as tonicity-responsive enhancer binding protein 5 (TonEBP) [37.Choi S.Y. et al.The evolving role of TonEBP as an immunometabolic stress protein.Nat. Rev. Nephrol. 2020; 16: 352-364Crossref PubMed Scopus (18) Google Scholar] in macrophages, removed excess sodium and prevented HSD-induced hypertension in these rodent models [26.Machnik A. et al.Macrophages regulate salt-dependent volume and blood pressure by a vascular endothelial growth factor-C-dependent buffering mechanism.Nat. Med. 2009; 15: 545-552Crossref PubMed Scopus (603) Google Scholar,27.Wiig H. et al.Immune cells control skin lymphatic electrolyte homeostasis and blood pressure.J. Clin. Invest. 2013; 123: 2803-2815Crossref PubMed Scopus (236) Google Scholar]. Of note, the exact role of NFAT5 and macrophages in local ionic balance has been reviewed elsewhere [22.Schatz V. et al.Elementary immunology: Na+ as a regulator of immunity.Pediatr. Nephrol. 2017; 32: 201-210Crossref PubMed Scopus (37) Google Scholar,26.Machnik A. et al.Macrophages regulate salt-dependent volume and blood pressure by a vascular endothelial growth factor-C-dependent buffering mechanism.Nat. Med. 2009; 15: 545-552Crossref PubMed Scopus (603) Google Scholar,38.Müller D.N. et al.Sodium in the microenvironment regulates immune responses and tissue homeostasis.Nat. Rev. Immunol. 2019; 19: 243-254Crossref PubMed Scopus (31) Google Scholar]. In humans, an experimental HSD (≥ approximately 12 g NaCl/day for 7–14 days) also resulted in the accumulation of Na+ [39.Selvarajah V. et al.Novel mechanism for buffering dietary salt in humans: effects of salt loading on skin sodium, vascular endothelial growth factor C, and blood pressure.Hypertension. 2017; 70: 930-937Crossref PubMed Scopus (32) Google Scholar] and macrophages [40.Wenstedt E.F.E. et al.Salt increases monocyte CCR2 expression and inflammatory responses in humans.JCI Insight. 2019; 4e130508Crossref PubMed Scopus (7) Google Scholar] in the skin, strongly suggesting that this system might be operative in humans as well. It is unclear why sodium concentrations can be decreased in the bone marrow upon HSD exposure in mice [30.Schröder A. et al.Osteoprotective action of low-salt diet requires myeloid cell-derived NFAT5.JCI Insight. 2019; 4e127868Crossref PubMed Scopus (7) Google Scholar]. Perhaps processes of proper hematopoiesis and cell proliferation might require lower sodium concentrations than immune cell activation, given that higher tissue osmolality may be encountered by infiltrating immune cells such as dendritic cells (DC) and T cells in secondary lymphatics [13.He W. et al.High-salt diet inhibits tumour growth in mice via regulating myeloid-derived suppressor cell differentiation.Nat. Commun. 2020; 11: 1732Crossref PubMed Scopus (10) Google Scholar,41.Go W.Y. et al.NFAT5/TonEBP mutant mice define osmotic stress as a critical feature of the lymphoid microenvironment.Proc. Natl. Acad. Sci. U. S. A. 2004; 101: 10673-10678Crossref PubMed Scopus (203) Google Scholar]. In line with this, relative to controls, increased tonicity in cancer cell lines has augmented the effectiveness of cytotoxic activity of death receptors [42.Sirtl S. et al.Hypertonicity-enforced BCL-2 addiction unleashes the cytotoxic potential of death receptors.Oncogene. 2018; 37: 4122-4136Crossref PubMed Scopus (8) Google Scholar] which are involved in hematopoiesis as well [43.Zauli G. Secchiero P. The role of the TRAIL/TRAIL receptors system in hematopoiesis and endothelial cell biology.Cytokine Growth Factor Rev. 2006; 17: 245-257Crossref PubMed Scopus (119) Google Scholar]. Of note, mice consuming a LSD did not show higher sodium in the bone marrow if myeloid cells did not express NFAT5 [30.Schröder A. et al.Osteoprotective action of low-salt diet requires myeloid cell-derived NFAT5.JCI Insight. 2019; 4e127868Crossref PubMed Scopus (7) Google Scholar], suggesting that this transcription factor might contribute to mediating sodium accumulation in this organ. However, as these possibilities remain speculative, further studies are needed to understand regulatory circuits involving sodium in the bone marrow. By contrast, a sodium loss in the kidneys of mice fed a HSD might be explained by available knowledge; under normal conditions, the kidney uses sodium and urea to create an osmotic gradient between the kidney cortex and the medulla, to reabsorb water from the glomerular ultrafiltrate [44.Dantzler W.H. et al.Urine-concentrating mechanism in the inner medulla: function of the thin limbs of the loops of Henle.Clin. J. Am. Soc. Nephrol. 2014; 9: 1781-1789Crossref PubMed Scopus (45) Google Scholar]. Under a HSD, the kidneys excrete excess sodium by switching off sodium reabsorption [45.Kitada K. et al.High salt intake reprioritizes osmolyte and energy metabolism for body fluid conservation.J. Clin. 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However, mechanistic insight for sodium storage in other tissues remains poorly understood. Sodium tissue accumulation can also occur in a diet-independent manner. Human long-lasting sodium balance studies demonstrate that under resting conditions, total body sodium concentrations follow an infradian rhythmicity that is under hormonal control [47.Rakova N. et al.Long-term space flight simulation reveals infradian rhythmicity in human Na(+) balance.Cell Metab. 2013; 17: 125-131Abstract Full Text Full Text PDF PubMed Scopus (216) Google Scholar]. Infection and inflammation can cause sodium build-up in afflicted human and mouse skin tissues in a diet-independent manner [10.Jantsch J. et al.Cutaneous Na+ storage strengthens the antimicrobial barrier function of the skin and boosts macrophage-driven host defense.Cell Metab. 2015; 21: 493-501Abstract Full Text Full Text PDF PubMed Scopus (168) Google Scholar,48.Schwartz L. et al.Is inflammation a consequence of extracellular hyperosmolarity?.J. Inflamm. (Lond.). 2009; 6: 21Crossref Scopus (72) Google Scholar,49.Matthias J. et al.Sodium chloride is an ionic checkpoint for human TH2 cells and shapes the atopic skin microenvironment.Sci. Transl. Med. 2019; 11eaau0683Crossref PubMed Scopus (16) Google Scholar]. Increased sodium concentrations have been found in brain lesions of multiple sclerosis patients [50.Inglese M. et al.Brain tissue sodium concentration in multiple sclerosis: a sodium imaging study at 3 tesla.Brain. 2010; 133: 847-857Crossref PubMed Scopus (149) Google Scholar], fibrotic skin in patients with diffuse cutaneous systemic sclerosis [51.Kopp C. et al.Na+ deposition in the fibrotic skin of systemic sclerosis patients detected by 23Na-magnetic resonance imaging.Rheumatology (Oxford). 2017; 56: 556-560Crossref PubMed Scopus (20) Google Scholar], and in the skin of patients with lipedema [52.Crescenzi R. et al.Tissue sodium content is elevated in the skin and subcutaneous adipose tissue in women with lipedema.Obesity (Silver Spring). 2018; 26: 310-317Crossref PubMed Scopus (28) Google Scholar] relative to healthy controls. Furthermore, there is evidence from noninvasive 23Na-MRI imaging that sodium concentrations in cancerous human brain and breast tissue are increased as well, relative to controls [53.Ouwerkerk R. et al.Elevated tissue sodium concentration in malignant breast lesions detected with noninvasive 23Na MRI.Breast Cancer Res. Treat. 2007; 106: 151-160Crossref PubMed Scopus (127) Google Scholar,54.Leslie T.K. et al.Sodium homeostasis in the tumour microenvironment.Biochim. Biophys. Acta (BBA) Rev. Cancer. 2019; 1872: 188304Crossref PubMed Scopus (15) Google Scholar]. Overall, the mechanisms contributing to diet-independent local sodium accumulation are ill-defined. It is reasonable to speculate that sodium changes reflect an inflammation-triggered reprogramming of the extracellular tissue matrix [34.Hofmeister L.H. et al.Tissue sodium storage: evidence for kidney-like extrarenal countercurrent systems?.Pflugers Arch. 2015; 467: 551-558Crossref PubMed Scopus (45) Google Scholar,38.Müller D.N. et al.Sodium in the microenvironment regulates immune responses and tissue homeostasis.Nat. Rev. Immunol. 2019; 19: 243-254Crossref PubMed Scopus (31) Google Scholar,55.Bonnans C. et al.Remodelling the extracellular matrix in development and disease.Nat. Rev. Mol. Cell Biol. 2014; 15: 786-801Crossref PubMed Scopus (1636) Google Scholar]. In addition to local tissue sodium accumulation, there is evidence in a model of isolated guinea pig trachea that hypertonic conditions exist in the airways on mucosal surface liquids due to water evaporation under steady state conditions [56.Shephard K.L. Rahmoune H. Evaporation-induced changes in airway surface liquid on an isolated guinea pig trachea.J. Appl. Physiol. (1985). 1994; 76: 1156-1165Crossref PubMed Scopus (17) Google Scholar]. Therefore, alveolar macrophages might be especially well adapted to operate in sodium-rich environments. Overall, these findings demonstrate that in addition to dietary factors, inflammatory conditions and local anatomical peculiarities might also affect the local sodium balance. For several years, interest has been growing to understand the impact of these ionic tissue signals on immune cell responses. Indeed, immune cells are not only equipped to adjust to these sodium-rich microdomains, but salt conditions can also profoundly influence the functions of immune cells [22.Schatz V. et al.Elementary immunology: Na+ as a regulator of immunity.Pediatr. Nephrol. 2017; 32: 201-210Crossref PubMed Scopus (37) Google Scholar,23.Wilck N. et al.The role of sodium in modulating immune cell function.Nat. Rev. Nephrol. 2019; 15: 546-558Crossref PubMed Scopus (21) Google Scholar,38.Müller D.N. et al.Sodium in the microenvironment regulates immune responses and tissue homeostasis.Nat. Rev. Immunol. 2019; 19: 243-254Crossref PubMed Scopus (31) Google Scholar]. For instance, high salt conditions enhance the proinflammatory activation of mouse macrophages, while limiting their anti-inflammatory potential [6.Hucke S. et al.Sodium chloride promotes pro-inflammatory macrophage polarization thereby aggravating CNS autoimmunity.J. Autoimmun. 2016; 67: 90-101Crossref PubMed Scopus (83) Google Scholar, 7.Ip W.K.E. Medzhitov R. Macrophages monitor tissue osmolarity and induce inflammatory response through NLRP3 and NLRC4 inflammasome activation.Nat. Commun. 2015; 6: 6931Crossref PubMed Scopus (105) Google Scholar, 8.Zhang W.-C. et al.High salt primes a specific activation state of macrophages, M(Na).Cell Res. 2015; 25: 893-910Crossref PubMed Scopus (119) Google Scholar, 9.Berry M.R. et al.Renal sodium gradient orchestrates a dynamic antibacterial defense zone.Cell. 2017; 170: 860-874.e19Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar,12.Willebrand R. et al.High salt inhibits tumor growth by enhancing antitumor immunity.Front. Immunol. 2019; 10: 1141Crossref PubMed Scopus (10) G