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Increased salt intake has been associated with cardiovascular disease,1 and it has been suggested that reductions in dietary salt could substantially reduce cardiovascular events and medical costs and, therefore, should be a public health target.2 The relationship between salt intake and cardiovascular diseases involves the complex interplay of several factors that include age, sex, the renin–angiotensin–aldosterone and kallikrein–kinin systems, sympathetic nervous system activity, endothelial function, and redox balance.3 In addition, it is now recognized that the immune system plays an active role in the development and progression of hypertension, and salt intake not only drives hemodynamic changes but is also associated with changes in the immune responses. Here we review the evidence that indicates that salt intake modulates immune function and salt-driven proinflammatory reactivity induces vascular endothelial dysfunction, immune cell activation, and cytokine secretion, all of which are central characteristics of hypertensive cardiovascular disease.

Salt, Leukocyte Adhesion, and Endothelial Dysfunction

Endothelial dysfunction is one of the central characteristics of hypertension and is associated with overexpression of leukocyte adhesion molecules and local inflammation. In spontaneously hypertensive rats, overexpression of ICAM-1 (intercellular adhesion molecule-1), MCP-1 (monocyte chemotactic protein-1), and macrophage adhesion ligand-1 (a cell-surface protein expressed in most leukocytes) has been demonstrated in association with increased monocyte endothelial adhesiveness. These findings play a role in end-organ damage.47 Takahashi et al4 studied changes in leukocyte adhesiveness induced by sodium intake in Dahl salt–sensitive rats. They examined adhesion of leukocytes to retinal vessels using acridine orange fluoroscopy and scanning laser ophthalmoscope and followed the expression of adhesion molecules in the kidney. After only 3 days of a diet with 8% NaCl, before hypertension developed, leukocyte adhesion was increased in association with increments in mRNA synthesis of MCP-1 and ICAM-1 in the kidney. Anti-CD18 antibodies inhibited these early effects of high salt intake and attenuated subsequent functional (proteinuria, glomerular filtration rate) and histological (glomerular sclerosis) kidney damage. In contrast, the beneficial effects of Losartan were only observed at later stages, when hypertension had already developed. To be sure, high perfusion pressure, by itself, is a factor that drives T cell infiltration in the kidney as shown best by the experiments of Evans et al.8 These investigators8 placed an occluding aortic balloon between the renal arteries to dissociate the perfusion pressure between the 2 kidneys: the left kidney blood pressure remained normal, whereas the right kidney was hypertensive after 7 days of high salt intake. Renal infiltration by T cells (CD4+ and CD8+ T cells), CD45R+ B cells, and CD11b/c+ monocytes and macrophages, as well as kidney injury, was significantly blunted in the left normotensive kidney. This study8 confirmed that high blood pressure damaged the kidneys and suggested that the combination of high blood pressure and high salt intake is more deleterious than high salt intake alone. Nevertheless, the observation that a high-salt diet could induce inflammatory changes before hypertension developed4 uncovered the existence of salt-independent and hypertension-dependent phases in the pathogenesis of salt-sensitive hypertension.4 Furthermore, early development of endothelial–leukocyte interactions suggest the potential dangers of even short periods of high salt intake (eg, episodes of binge eating) if other genetic and environmental risk factors are present.
Wild et al9 reported that sodium-induced increase in leukocyte adhesion was mediated by reactive oxygen species and endothelial nitric oxide synthase. They further showed that the augmented responses induced by high sodium were present in conditions of nonuniform shear stress: endothelial cells grown in a model of arterial bifurcation show an exaggerated proatherogenic secretion of TNF-α (tumor necrosis factor-α) in response to high sodium concentrations.9
Dmitrieva and Burg10 further investigated the effect of high sodium concentration on human umbilical vein endothelial cell cultures using polymerase chain reaction arrays. They found that the expressions of many genes are stimulated by high sodium concentrations, including VCAM-1 (vascular adhesion molecule 1), E-selectin, and MCP-1. ET1 (endothelial-derived endothelin 1) is also stimulated by a high salt intake in the spontaneously hypertensive rat, and its overexpression seems to play a regulatory role in the skin buffering of a sodium load.6
An increase in extracellular sodium within the physiological range is also associated with the stimulation of the coagulation system with increased risk of thrombosis. Studies by Dmitrieva and Burg10 have shown that hypernatremia induced by mild dehydration (mean serum sodium ≈150 mmol/L) upregulates tonicity-regulated transcription factor NFAT5 (nuclear factor of activated T cells 5) and its binding to the promoter of vWF (von Willebrandt factor) gene. vWF protein increases in liver, lung, and blood, and the increment in vWF in blood was associated with increase in the D-dimer fibrin degradation product, indicating ongoing activation of coagulation and thrombolysis by hypernatremia.

Salt and Proinflammatory Cytokines

Hypertension is recognized to be a state of chronic inflammation, with elevated levels of inflammatory cytokines and with activation of the immune system,1113 and recent studies suggest that salt may directly influence the release of these inflammatory cytokines. IL (interleukin)-6 is one of the most consistently elevated cytokines in human hypertension.14 In Dahl salt–sensitive rats, a high-salt diet induces an increase in IL-6 in the kidney that is relevant to the development of high blood pressure and organ damage because hypertension, albuminuria, and renal injury are all attenuated by the administration of anti-IL-6 antibody.15
High sodium and hyperosmolarity also induce the production of MIP-2 (macrophage inflammatory protein-2) and TNF-α and synergistically increase MIP-2 production induced by lipopolysaccharide or TNF-α.16 In subtotal nephrectomized rats, an increase in salt intake increases macrophage inflammation in the heart and peritoneal wall in association with increased mRNA for IL-6, MCP-1, Sgk1 (serum and glucocorticoid-inducible kinase 1), and TonEBP (tonicity-responsive enhancer binding protein). The macrophage infiltration was dependent on the TonEBP-MCP1 axis because it was abrogated by TonEBP siRNA, as well as in the mice deficient in CCR2 (chemokine receptor 2, receptor of MCP-1).17
Taken together, these studies consistently indicate that high salt stimulates the production of several cytokines that promote inflammation and organ damage.

Salt and Immune Cells

High salt concentrations or high-salt diet can also directly affect immune cells, resulting in a proinflammatory immune response (Table). The best recognized of these are the salt-induced IL-23-dependent polarization of the CD4+ T cells to the T helper 17 cells (TH17) phenotype. The TH17 cells generation is the result of activation of the p38/MAPK (mitogen activated protein kinases) pathway involving NFAT5 (also called TonEBP) and SGK1.18,19 The clinical relevance of salt-induced Th17 generation has been shown by the increased severity of experimental autoimmune encephalomyelitis that is induced by a high-salt diet.18 In experimental models of angiotensin II–induced hypertension and in deoxyccorticosterone acetate–salt hypertension, high sodium intake has also been found to enhance IL-17A production via an SGK1-dependent pathway.20 Increments in IL17 are associated with increased renal sodium reabsorption that are relevant in hypertensive models associated with increased activity of renal sodium transporters21 and in the inflammation that characterizes the peritoneal damage induced by chronic exposure to peritoneal dialysis fluids.22
T-cell function is also affected by sodium concentration. Increasing NaCl concentration by ≈40 mmol/L boosts IL-2 expression and T-cell proliferation. Furthermore, hypertonic saline added to the culture media may help restore the function of inhibited T cells.23 In addition to stimulating T-cell proliferation, salt suppresses anti-inflammatory activity. Hernandez et al24 reported that increasing NaCl impairs regulatory T cell (Treg) function in association with heightened IFN-γ (interferon-γ) secretion both in vivo and in vitro. These authors reported that SGK1 mediates both the loss of Treg function and the increased IFN-γ secretion.
Salt also modulates the mononuclear phagocyte system, resulting in promotion of inflammation. The best known of the salt–macrophage interactions is the one related to the buffering of the blood pressure effects of salt retention. Macrophage responses to hyperosmolarity represent a critical element in the regulation of blood pressure and salt homeostasis by inducing TonEBP and VEGFC (vascular endothelial growth factor C)/VEGFR3 (VEGF receptor 3)–mediated modification of lymphatic capillary network that clears electrolytes accumulated in the interstitial fluid.25,26 Of interest, activation of skin macrophages by the increment in interstitial sodium content also promotes antimicrobial defense.27 In addition to the effects on salt homeostasis, salt modifies the balance between proinflammatory and anti-inflammatory macrophages. The concept of 2 macrophage phenotypes has gained general acceptance: the classical proinflammatory M1-type macrophage induced by IFN-γ in T helper–type responses and the M2-type macrophage, induced by Th2 cytokines (IL-4 and IL-13), with activity directed to suppress inflammation and tissue repair.28 In experiments with lipopolysaccharide-induced lung injury, high salt has been found to induce a proinflammatory M1 type in macrophages by a novel mechanism that involves activating p38/cFos or Erk1/2 (extracellular signal-regulated kinases 1/2)/cFos pathways.29 In addition to stimulating M1 macrophages, high-salt diet suppresses anti-inflammatory M2 macrophages by a mechanism involving a reduction in glycolysis and mitochondrial metabolic output, coupled with blunted AKT and mTOR (mammalian target of rapamycin) signaling. The suppression of M2 macrophages contributes to the proinflammatory immune imbalance driven by the stimulation of M1 macrophages.30
There is also an interaction between high sodium concentrations with dendritic cells. Dendritic cells are the prototype of antigen-presenting cells in which sodium may gain intracellular access via amiloride-sensitive α and γ subunits of the epithelial sodium channel and the sodium hydrogen exchanger 1. Intracellular sodium increase triggers activation of the Na-Ca exchanger, calcium influx, and assembly of the NADPH oxidase with superoxide generation and subsequent formation of immunogenic IsoLG (isolevuglandin)-protein adducts. Dendritic cells activated by excess sodium produce increased IL-1β and promote T-cell production of IL-17A and IFN-γ.31
There are limited but suggestive data that high salt may affect other immune cells, including splenic B cells,32 neutrophils,33 and basophils.34
Finally, proinflammatory changes induced by high sodium are not restricted to immune cells. Studies in rats have shown that a high-salt diet increases the sulfation of heparan sulfate in the kidney, resulting in an increased ability to bind sodium and orchestrate proinflammatory responses.35

Salt and Autoimmunity

Preliminary reports also suggest an association between high-salt diet and autoimmune disease. The severity of experimental autoimmune encephalitis, for example, is increased in the setting of a high sodium intake, and the effect is sex-specific and genetically controlled.36 Experimental colitis induced in mice by trinitrobenzene-sulfonic acid or dextran sulfate is also exacerbated by high salt intake. Activated mononuclear cells in intestinal lamina propria increase the production of IL-17A, IL-23R, TNF-α, and Ror-γT (RAR-related orphan receptor gamma) when exposed to a high salt concentration.37

Clinical Studies

Clinical studies on the role played by salt intake in the immune function are limited. Luo et al38 studied 15 healthy volunteers and found that a high-salt diet did not modify peripheral blood total B cell counts or percentages, or CD3+, CD4+, or CD8+ T-cell subsets. However, Th17 and Treg showed progressive changes during high-salt feeding. Specifically, high-salt diet initially decreased Th17 counts between days 3 and 4, and then they gradually increased up to day 17 of the high-salt diet. In contrast, Treg counts increased on day 4 and then decreased throughout the whole high-salt period. The Th17/Treg ratio significantly increased from day 4 to day 10 and then decreased gradually to baseline during the following week. Although the explanation for these changes is presently unknown, the findings in the first week are consistent with those of experimental animal data.38 In another recently published pilot study, a moderate high-salt challenge in humans reduced intestinal survival of Lactobacillus spp. and increased Th17 cells and blood pressure, suggesting the participation of intestinal microbiota in salt-induced immune changes.39
Yi et al40 studied 6 healthy humans receiving 12, 9, and 6 g of NaCl per day and found changes in the peripheral leukocyte phenotypes. A higher number of monocytes were found when the subjects were on the 12 g salt/day diet, whereas a lower salt intake was associated with reduced production of IL-6 and Il-23 levels and enhanced production of the anti-inflammatory cytokine, IL-10. In another study, 20 healthy volunteers were administered a high-salt diet (≥15 g NaCl/day; 256 mmol sodium/day) for 7 days, followed by switching to a low-salt diet (≤5 g NaCl/day; 85.5 mmol sodium/day) for 7 days. The high-salt diet resulted in CD14++ monocyte activation and a rapid expansion of CD14+ CD16+ monocytes, in association with a reciprocal decrease in the percentages of the CD14+ CD16 subsets. These changes were reversed after switching to a low-salt diet.41
There is also epidemiological evidence in humans linking salt with immune disease. Specifically, a cross-sectional study of 18 555 individuals (mean age 38 years; 60% women, including 392 with self-reported rheumatoid arthritis) found that the adjusted risk of rheumatoid arthritis was increased by 50% in subjects ingesting higher sodium intake (the upper fourth quartile) estimated by history.42

Very Low Salt Intake and Inflammation

The complexity of the relation between salt intake and immunity is shown by investigations that have also found that a very low salt intake may also be proinflammatory. For example, Mallamaci et al43 examined the effect of salt restriction on biomarkers of innate immunity. In a crossover study, 32 uncomplicated essential hypertensive patients were randomized to receive for 2 weeks either a 10 to 20 mmol sodium diet plus sodium tablets (180 mmol/day) to achieve a 200 mmol sodium intake per day or the same diet plus placebo tablets. Procalcitonin and TNF-α increased, whereas adiponectin decreased during the very low–sodium diet, suggesting a proinflammatory response to severe salt restriction.43 In a separate study, Fernandez-Fernandez et al44 compared the effects of a low sodium intake (Na=60 mmol/day) to a control, high-sodium diet (Na=160 mmol/day) and found that the low-sodium diet was associated with higher C-reactive protein, TNF-α and IL-6 concentrations, activation of the renin–angiotensin–aldosterone system, and evidence for insulin resistance.45 These results are not totally unexpected, given the known proinflammatory effects of both angiotensin II and aldosterone, which are activated in states of low salt intake.44

Research Needs

The relationship between dietary salt intake and the immune response as it relates to cardiovascular and autoimmune diseases needs further investigation. Although potential benefits of modifying salt intake may be evident in healthy individuals and subjects with uncomplicated hypertension, studies in specific high-risk subpopulations may be required to explore the potential benefit of modifying salt intake in addition to drug treatments of established value. An example of the potential usefulness of such studies is the demonstration of a synergistic reduction in proteinuria when salt restriction is associated with angiotensin receptor blockers.46

Conclusions

Accumulating evidence supports the role of salt intake in the interaction between immunity and hypertension. Our understanding of the relationship between increased salt intake and the immune system is in its infancy. There is currently evidence that high salt intake can promote abnormal leukocyte–endothelial cell interactions, stimulate proinflammatory cytokines, and modulate immune cell (mainly macrophages and T cells) function. In addition, the relationship between increased blood pressure and immune cell infiltration (especially T cells) is probably bidirectional8,47 (Figure; Table). More studies are needed to harness the potential of the salt–autoimmunity relationship in the design of novel therapeutic approaches to hypertension, renal, and cardiovascular diseases.
Table. Impact of High-Salt Diet on Immune Cell Function
Macrophages
 Promotes macrophage infiltration in diverse tissues17,25,26,48
 Promotes proinflammatory M1 macrophage activation27,29
 Depresses anti inflammatory M2 macrophage activation30
T cells
 Increased T-cell infiltration, proliferation, and activation49
 Promotes Th17 activation
  Boosts the development of IL-17-producing CD4+ Th17 cells18,19,24,39
  Promotes Th17 activation via p38 MAPK-, NFAT-, and SGK1-dependent signaling18
 Negative impact on Tregs
  Impairs the function and development of regulatory forkhead box P3+ Tregs24,38
  Induces SGK1-signal transduction and promotes interferon release from Tregs which abrogates their suppressive effects19
Effects on other leukocytes
 Splenic B cells32
 Neutrophils33
 Basophils34
Effects on dendritic cells
 Increased sodium enters the dendritic cells via specific channels, and increased NADPH oxidase activity produces superoxide with subsequent formation of immunogenic isolevuglandin, promoting an autoimmune-like state leading to renal and vascular dysfunction and hypertension.42
IL indicates interleukin; MAPK, mitogen activated protein kinases; NFAT, nuclear factor of activated T cells 5; SGK1, serum and glucocorticoid-inducible kinase 1; Th17, T helper 17 cells; and Tregs, regulatory T cells.
Figure. High salt intake, immunity, and blood pressure.

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Affiliations

Baris Afsar
From the Department of Nephrology, Suleyman Demirel University School of Medicine, Isparta, Turkey (B.A.)
Masanari Kuwabara
Department of Medicine (M. Kuwabara, R.J.J.)
Department of Cardiology, Toranomon Hospital, Tokyo, Japan (M. Kuwabara)
Alberto Ortiz
Dialysis Unit, School of Medicine, IIS-Fundacion Jimenez Diaz, Universidad Autónoma de Madrid, Spain (A.O.)
Aslihan Yerlikaya
Department of Internal Medicine, Koc University School of Medicine, Istanbul, Turkey (A.Y.)
Dimitrie Siriopol
Department of Nephrology, Dialysis and Renal Transplant Center, “Dr C.I. Parhon” University Hospital, “Grigore T. Popa” University of Medicine and Pharmacy, Iasi, Romania (D.S., A.C.)
Adrian Covic
Department of Nephrology, Dialysis and Renal Transplant Center, “Dr C.I. Parhon” University Hospital, “Grigore T. Popa” University of Medicine and Pharmacy, Iasi, Romania (D.S., A.C.)
Bernardo Rodriguez-Iturbe
Division of Renal Diseases and Hypertension (B.R.-I.), University of Colorado Anschutz Medical Campus, Aurora, CO
Renal Service, Hospital Universitario, Universidad del Zulia and Instituto Venezolano de Investigaciones Científicas (IVIC)-Zulia, Maracaibo (B.R.-I.)
Richard J. Johnson
Department of Medicine (M. Kuwabara, R.J.J.)
Mehmet Kanbay
Division of Nephrology, Department of Medicine, Koc University School of Medicine, Istanbul, Turkey (M. Kanbay).

Notes

Correspondence to Mehmet Kanbay, Division of Nephrology, Department of Medicine, Koc University Hospital, Davupasa Caddesi, No. 4, 34510 Zeytinburnu, Istanbul, Turkey. E-mail [email protected]

Disclosures

None.

Sources of Funding

This research was partially funded by a grant of Ministry of Research and Innovation, CNCS–UEFISCDI (Cocsiliul National al Cercetarii Stiintifice–Unitatea Execuvita pentru Finantarea Invatamantului Superior, a Cercetarii, Dezvoltarii si Inovaii), project number PN-III-P4-ID-PCE-2016-0908, contract number 167/2017, within PNCDI III.

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  1. Maternal nutrition and offspring lung health: sex-specific pathway modulation in fibrosis, metabolism, and immunity, Food & Nutrition Research, 69, (2025).https://doi.org/10.29219/fnr.v69.11035
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  10. Somatic growth outcomes in response to an individualized neonatal sodium supplementation protocol, Journal of Perinatology, (2024).https://doi.org/10.1038/s41372-024-02141-9
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