Immune Dysregulation Orchestrated by High-Salt Diet: Mechanistic Insights into Disease Pathogenesis

Introduction

Table salt is an essential component and an important ingredient in food. Salt can enhance the taste of food and increase its palatability. In Western countries, salt is often added to food and consumed in larger amounts than recommended. Numerous studies have shown that high salt intake is inversely correlated with human health,¹ leading to various conditions such as hypertension,² osteoporosis,³ colitis,⁴ kidney disease,⁵ gastric cancer,⁶ dementia,⁷ obesity,⁸ and more. High salt intake is a significant risk factor for numerous diseases and should be of great concern.

The immune system is a complex network of organs, cells, and proteins that protect the body from infection. This defense system is carried out by identifying and handling foreign objects. The network consists of the lymphatic system, complement system, spleen, thymus, bone marrow, and cells (white blood cells, B cells, T cells). Immune cells have a protective and preventive effect against pathogens that invade the host. The state of the immune environment is influenced by dietary factors. HSD has been shown to adversely affect autoimmune diseases by shifting immune cell balance to a pro-inflammatory state.^9,10 In addition to affecting effector T cells (Teff) responses, such as Th17 cells.^11,12 It has also been shown that HSD can also affect the function of regulatory T cells (Tregs).^13–17 Increased salt concentration favors the differentiation of CD4+T cells to pathogenic Th17 cells, which predispose to a variety of inflammatory diseases by regulating the immune environment.¹⁸ In addition, high salt interferes with the mitochondrial respiration of Tregs, leading to the dysfunction of Tregs, and the “downtime” of Tregs increases the risk of many diseases.¹⁹ Therefore, immune imbalance due to excessive salt intake is a key factor in triggering diseases. Thus, immune imbalance plays a key role in HSD-induced disease development. There is a need to further summarize the data linking HSD, the immune environment, and disease.

To date, many reviews have focused on the role of sodium in modulating immune cell function. Examine studies by Nicola Wilck et al²⁰ that have demonstrated a role for high extracellular salt in modulating the differentiation and function of innate and adaptive immune cell populations. Western diets are rich in salt. However, there is still a lack of discussion of recent studies on the intestinal immune imbalance induced by HSD in disease and its corresponding mechanisms. Therefore, this paper aims to systematically summarize the characteristics of HSD-induced immune imbalance in disease and reveal the potential mechanisms of interaction in the HSD model. The following sections systematically illustrate the effects of HSD-mediated immune imbalance with various diseases such as hypertension, nephropathy, cancer, and IBD and their corresponding mechanisms.

Material and Methods

All data related to high salt in the immune field reported in this paper were found using the advanced search function of the WOS core collection in March 2023, and the language is limited to “English”. All data were analyzed using the local function of WOS. The potential search keywords are the following: TS = ((immune or immunity or inflammation) AND “high salt”).

Results

HSD-induced immunity is closely associated with kidney disease, hypertension, cancer, inflammatory bowel disease, and autoimmune diseases. Animal experiments and in vitro cell culture studies provided evidence that HSD mediates diseases development by affecting immune cells and their secreted cytokines (Figure 1).

Figure 1 HSD-induced immunity is closely associated with kidney disease, hypertension, cancer, inflammatory bowel disease, and autoimmune diseases.

Influences of HSD on Immunity Toward Kidney Disease

Renal damage in Dahl salt-sensitive (Dahl SS) hypertension is attributed to oxidative stress and inflammation within the kidneys.^21,22 Infiltration of immune cells in the kidneys plays a crucial role in the pathogenesis of hypertension and renal injury in Dahl SS rats.²³ Compared to Dahl SS rats on a low-salt diet, rats fed an HSD exhibit increased numbers of macrophages, T cells, and B cells in the kidneys, with the severity of hypertension and renal damage correlating with the presence of these immune cells.^24–27 High salt intake-induced T cell infiltration into the kidneys is significantly attenuated in RAG1-deficient rats, and the average arterial blood pressure and urinary albumin excretion rate are significantly lower in RAG1-null mutants than in SS rats. Furthermore, the glomerular and tubular damage in the kidneys of SS rats fed an HSD is also reduced in RAG1 mutants.²⁸ Experimental evidence demonstrates that treatment with immunosuppressive agents during high NaCl intake prevents T-cell infiltration in the kidneys and alleviates SS hypertension and renal injury in Dahl SS rats.^25,26,29,30 The current study suggests that T lymphocytes that infiltrate the kidney can participate in the development of SS hypertension and kidney disease in Dahl SS rats by increasing levels of free radicals in the kidney,²⁹ and oxygen radical scavengers can mitigate the progression of salt-induced hypertension and related kidney damage.³¹ In kidney tissue from Dahl SS rats fed HSD, there was an association between increased T-cell infiltration, increased oxidative stress, and increased expression of NADPH oxidase.²⁹ Dahl SS rats (SSP 67 Phox) inhibited NADPH oxidase by p 67 Phox mutation, improving salt-induced hypertension, kidney damage, and kidney immune cell infiltration.³² Long-term administration of immunosuppressants during periods of high salt intake reduces T lymphocyte infiltration, reduces the oxidative status and kidney expression of the NADPH oxidase subunit P67 Phox, and improves hypertension and kidney disease.²⁹ In addition, Antioxidant therapy administered to rats with Dahl SS resulted in a reduction of kidney inflammatory cytokines and chemokines, kidney immune cells, NF-kB, as well as arterial pressure, and improved kidney function and damage.³³

Macrophage accumulation plays a key role in kidney injury.^34–36 In Liu’s study, 5/6 NX rats receiving HSD exhibited strongly enhanced macrophage infiltration and activation in kidney tissue, accompanied by worsening kidney inflammation.³⁷ Emerging evidence indicates that high salt intake can independently stimulate the immune activation of macrophages via STAT1 and exacerbate renal inflammation, leading to kidney damage.³⁷ In the Dahl SS model, the addition of dietary salt has been shown to promote the conversion of kidney macrophages to the pro-inflammatory phenotype M1,²⁷ increase the production of pro-inflammatory cytokines (IL-6, TNF-α, IL-β), and the expression of chemokines (MCP-1, CXCL1, and CCR2).³⁷ Research has demonstrated that administering anti-IL-6 antibodies to Dahl SS rats attenuates the development of salt-sensitive hypertension and ensuing kidney damage,³⁸ indicating that an HSD potentially induces hypertension and associated renal damage by eliciting the release of the pro-inflammatory cytokine IL-6 from macrophages. In addition, IL-6 can produce intercellular adhesion molecule-1 (ICAM-1) by activating vascular endothelial cells, however, Takahashi’s research shows that HSD rapidly increases leukocyte adhesion through overexpression of the ICAM-1.³⁹ Prostacyclin and nitric oxide are potent inhibitors of white blood cells, and levels of vasodilators such as prostacyclin and nitric oxide have been reported to be reduced, and levels of vasoconstrictors are elevated in Dahl SS rats. Increased leukocyte adhesion in prehypertensive prehypertension is responsible for subsequent kidney injury in rats with Dahl SS. In addition, an imbalance between endothelial cell adhesion, vasodilation, and vasoconstrictor substances may be responsible for early angiotensin-II-independent leukocyte adhesion.^40–43 It has been reported that Dahl SS rats are susceptible to angiotensin-induced kidney damage. Thus, the rapid increase in leukocyte adhesion caused by HSD may be associated with the high sensitivity of the renin-angiotensin system in Dahl SS rats.⁴⁴

Neutrophils are the main immune effector against pyelonephritis.⁴⁵ The innate immune defense of urinary tract infections (UTIs) relies on neutrophils, which clear Urinary tract pathogenic E. coli (UPEC) through phagocytosis, as well as mononuclear phagocytes, such as macrophages or dendritic cells, which attract and activate neutrophils by chemokines and cytokines.^46–48 It has been shown that HSD suppresses intrarenal neutrophil NFAT5 by altering the local microenvironment (osmotic gradient of urea) and systemic glucocorticoid-mediated immunity. However, HSD does not enhance the response of neutrophils; rather, it systematically damages the antibacterial activity of neutrophils by changing hormones and metabolism.⁴⁵

Influences of HSD on Immunity Toward Hypertension

Antigen-presenting cells (APCs), mainly including dendritic cells (DCs), monocytes (macrophages), and T cells, are the first responders to hypertension stimulation and drive T cell proliferation through antigen-MHC receptor interactions.⁴⁹ High salt, as a strong stimulus of inflammatory activation and oxidative stress, can activate APCs,^50–53 and indirectly activate T cells, leading to hypertension by damaging blood vessel and kidney function.

The effects of DCs and hypertension are bidirectional, DCs not only aggravate hypertension, but hypertension enhances the activity and activation of DCs. Neoantigens produced by mechanical trauma of hypertension can activate DCs,^54,55 which are presented by DCs to T cells, and induce the production of pro-inflammatory cytokines and ROS,^54–57 further aggravating hypertension. Isolevuglandins (IsoLGs) are highly active products of lipid oxidation that form covalent bonds with lysine residues, resulting in post-translational modification of protein.⁵⁸ Related studies have shown that IsoLGs play an important role in promoting the activation of T cells and hypertension.⁵⁹ Transfer of isoketal-activated DCs into wild-type mice was shown to increase blood pressure,⁵⁹ and removal of IsoLGs reduces T-cell activation and prevents hypertension and end-organ damage.⁵⁹ It was demonstrated that in a murine model, elevated Na+ is a potent stimulus for the formation of IsoLGs adducts in DCs.⁶⁰ High salt intake increases the epithelial sodium channel (ENaC)-mediated sodium entry into DCs and exchanges with calcium (Ca2+) via Na+/Ca2+ exchangers. Ca2+ enters the activating protein kinase C (PKC), which in turn phosphorylates the NADPH oxidase subunit P47 phox.⁶⁰ This leads to NADPH oxidase activation, increased superoxide, and derived ROS.⁶⁰ The production of ROS leads to the formation of IsoLGs, the presentation of costimulatory factor CD86, and the secretion of pro-inflammatory factors IL-6, IL-1β, and IL-23.⁶¹ Activated DCs promote T cell activation by accumulating IsoLGs and presenting them to T cells via MHC-II cell surface receptors, stimulating the production of IFN-γ and TNF-α (from CD8+ and CD4+Th1) and IL-17A (from γδ-T cells and CD4+Th17), resulting in vascular and renal dysfunction and salt-sensitive hypertension.^59,60 Van Bethescom et al demonstrated that salt can activate DCs through serum glucocorticoid kinase 1 (SGK1) and that the loss of SGK1 in DCs reduces salt-sensitive hypertension.⁶² Mice lacking SGK1 expression in T cells are protected from ANGII infusion and DOCA salt-induced hypertension and eliminate hypertension-induced renal and vascular inflammation and end-organ damage.⁶³ IL-17 is a marker of inflammation produced by Th 17 cells. Studies have found that IL-17 acts on endothelial cells and leads to eNOS Thr 495 phosphorylation, which is mediated by RhoA/Rho kinases and leads to reduced NO production and reduced NO-mediated vasodilation,⁶⁴ leading to hypertension. Deletion of SGK1 in T cells eliminates an increase in the frequency of spleen Th 17 cells in response to ANGII infusion.⁶³ In addition, studies have shown that HSD can induce the production of Th 17 cells by reducing lactobacilli, resulting in hypertension in mice and humans.⁶⁵

High-salt-activated monocytes/macrophages have a dual role in regulating vascular function and blood pressure. High sodium concentrations are recognized by macrophages as chemotactic stimuli in a dose-dependent manner.⁶⁶ Macrophages can sense high sodium concentrations via the sodium-calcium exchanger 1 (NCX 1), leading to macrophage activation followed by activation of the osmoprotective transcription factor nuclear factor of T cell 5 (NFAT5).⁶⁷ NFAT5 leads to increased NO production by nitric oxide synthase (NOS)-2 and the production of pro-inflammatory cytokines such as IL-1β, IL6, and TNF-α, which are released in high-salt reactions.⁵⁰ In addition, NFAT 5 triggers the secretion of vascular endothelial growth factor (VEGF)-C.^67,68 VEGF-C signaling, in turn, leads to VEGF receptor (VEGFR)3-dependent hyperplasia of the lymphatic capillary network, which enhances interstitial sodium clearance by improving drainage of interstitial fluid and electrolytes into the vascular ventricle. VEGF-C also stimulates the expression of endothelial nitric oxide synthase (eNOS) via VEGFR2 receptors, increases NO production, and acts as a direct compensatory vasodilation mechanism to buffer blood pressure increases due to excess extracellular volume.⁶⁸ In addition, disturbances in macrophage infiltration or VEGF-C signaling can increase blood pressure in rats on HSD.⁶⁸ Macrophages cause vascular dysfunction and hypertension by releasing ROS and pro-inflammatory cytokines in different tissues, including the vasculature, kidneys, and brain⁶⁹ In addition, Mahnik et al observed that high-salt treated rats acquired a pro-inflammatory macrophage(M1) response and also exhibited fluid retention, leading to hypertension.⁷⁰ Figure 2 shows the mechanism of HSD-induced immune disorders in kidney disease and Hypertension.

Figure 2 Influences of HSD on immunity toward hypertension and kidney disease: High salt intake increases sodium entry into dendritic cells through ENaC-mediated transport and exchanges with Ca2+ via the Na+/Ca2+ exchanger. This leads to NADPH oxidase activation, increased O2- production, and generation of ROS, ultimately promoting the secretion of pro-inflammatory cytokines. Activated dendritic cells accumulate IsoLGs and present them to T cells via MHC-II cell surface receptors, thereby facilitating T cell activation and stimulating the production of IFN-γ, TNF-α, and IL-17A, resulting in vascular and renal dysfunction, as well as salt-sensitive hypertension. Furthermore, high levels of sodium activate macrophages through NCX1, subsequently activating NFAT5. NFAT5 triggers the secretion of VEGF-C and NOS-2, increasing the production of NO as a compensatory vasodilatory mechanism to mitigate the resulting increase in blood pressure.

Myeloid-derived suppressor cells (MDSCs) are a group of immature myeloid cells that inhibit T cell activation as well as Th17 and Th1 cells,^71,72 MDSCs by inhibiting inducible nitric oxide synthase (iNOS), ROS, and peroxynitrite inhibit T cells function.⁷¹ In addition, MDSC cells can induce the differentiation of Tregs by producing IL-10.⁷²

The impact of the immune system on cardiovascular health includes not only hypertension, but macrophages have been shown to play a key role in the pathogenesis of atherosclerosis, acute myocardial infarction, and heart failure, highlighting the importance of myeloid cells for cardiovascular disease.⁷³ In addition, DCs are also involved in cardiovascular remodeling,⁷⁴ and the elimination of DCs prevents the development of cardiac hypertrophy and perivascular fibrosis. Neutrophil gelatinase-associated lipocalin (NGAL) produced by DCs may play a key role in adaptive immune activation, leading to cardiovascular fibrosis caused by excessive mineralocorticoid hormone.

Influences of HSD on Immunity Toward Cancer

Chronic inflammation is a key hallmark of cancer development and progression.⁷⁵ The microenvironment of chronic inflammation can be induced by reactive oxygen/nitrogen species (ROS/RNS),⁷⁶ paracrine factors, or tumor-infiltrating cells, leading to sustained cell proliferation, DNA damage, or cancer transformation.⁷⁷ Inflammatory cytokines^78,79 and chemokines^80–82provide beneficial signals that promote cancer cell proliferation^78,83 and tumor angiogenesis.⁸⁴ High salt intake serves as an effective inducer of pro-inflammatory states. In a high-salt environment, the immune balance between Th17 cells and Treg cells is disrupted. High salt intake induces the differentiation of Th17 cells and the production of inflammatory cytokines such as IL-1, IL-6, and IL-23, as well as inflammatory mediators including prostaglandins, leukotrienes, transforming growth factor (TGF), and iNOS.⁸⁵ iNOS is a recognized inflammatory marker and its upregulation has been associated with various cancers, including breast cancer.⁸⁶ Existing research suggests that IL-17 has both tumor-suppressive and tumor-promoting effects.⁸⁷ High salt intake has been shown to accelerate breast cancer growth, promote lung metastasis, and increase the levels of Th17 cells.⁸⁸ The elevated levels of Th17 cells, potentially through the secretion of IL-17F, can activate the MAPK signaling pathway in breast cancer cells, thereby promoting breast cancer growth.⁸⁸

HSD can disrupt the balance of immune cells, promoting the induction of pro-inflammatory cells (such as helper Th17 cells and M1-like macrophages), while impairing the function of anti-inflammatory cells (such as M2-like macrophages and Tregs).^6,50,65 Current research indicates that high salt intake activates a pro-inflammatory Th17 phenotype in CD4+ T cells and polarizes anti-inflammatory CD4+FOXP3+Tregs towards an inflammatory Th1 phenotype.^13,89 This polarization is accompanied by the secretion of pro-inflammatory cytokine IFN-γ,^13,90,91 induction of M1,⁹² and exertion of anti-tumor effects. Figure 3(a) shows an anti-tumor effect of HSD in the early stages of tumors. Myeloid-derived suppressor cells (MDSCs) play a pivotal role in tumor-induced immune tolerance.^93,94 Upon entering the tumor environment, M-MDSCs rapidly differentiate into tumor-associated macrophages (TAMs), leading to increased IL-10 secretion and impaired T-cell responses.^95,96 HSD may inhibit the production of Treg cells through the function of MDSC, thus activating anti-tumor immune surveillance and inhibiting tumor growth in mice.⁹⁷

Figure 3 Influences of HSD on immunity toward cancer. (a) HSD exerts anti-tumor effects in the early stages of tumors: In the early stages of tumors, HSD activates CD4+ T cells to promote the pro-inflammatory Th17 phenotype and leads to the polarization of anti-inflammatory Tregs into an inflammatory Th1 phenotype. This results in the secretion of inflammatory cytokines such as IFN-γ, inducing the expression of pro-inflammatory M1 macrophages, and exerting an anti-tumor effect; (b) Protumor effects of HSD-mediated immunomodulation in the tumor microenvironment: In the later stages of tumor progression, HSD promotes the differentiation of macrophages into the M2 phenotype and induces the pro-inflammatory Th17 phenotype. This leads to increased secretion of pro-angiogenic VEGF, resulting in enhanced tumorigenicity and metastasis.

The effect of high salt on tumors may change with different stages of tumor growth. Salt exerts anti-tumor effects by activating the immune system leading to tumor elimination in the early stages, and then antagonizes these effects and has pro-tumor effects through immune exhaustion in the later stages.⁹⁸ During the initial stages of tumor growth, salt promotes tumor elimination through immune surveillance, whereas continued high-salt treatment can lead to the failure of CD4+ T cells.⁹⁹ Long-term in vitro treatment of human monocytes with high salt has resulted in M2 macrophage phenotypic switching, which is both anti-inflammatory and pro-tumor.¹⁰⁰ Long-term HSD may inhibit the formation of MDSCs in the tumor microenvironment, and when MDSCs are depleted, HSD plays a pro-tumor role.¹⁰¹

Tumor neo-angiogenesis is essential for tumor metastasis. VEGF induces tumor angiogenesis through activation of cancer-specific PI3K/Akt signaling mechanisms.¹⁰² Inflammation-induced cellular stress induces the release of several growth factors, which induce neointima formation in tumors. Cancer cells metastasize to various parts of the body through these newly- formed blood vessels.⁸⁴ It has been shown that high salt induces an anti-inflammatory M2 phenotype in the tumor microenvironment,¹⁰⁰ M2 phenotype secretes pro-tumor IL-10 and VEGF.⁸⁴ In addition, high salt synergistically induces cancer cell proliferation, and RNS/ROS release and promotes angiogenic VEGF secretion with IL-17,^103,104 enhancing cancer cell metastasis.¹⁰⁵ Figure 3(b) shows the pro-tumor effects of HSD-induced immunomodulation in the tumor microenvironment.

Influences of HSD on Immunity Toward Inflammatory Bowel Diseases

IBD is a chronic, recurrent disorder that typically presents with ulcerative colitis (UC) and Crohn’s disease (CD).¹⁰⁶ IBD is a high-risk factor for colorectal cancer and a serious threat to human health worldwide. Although its etiology is currently unknown, the findings of available studies suggest that IBD is a complex process involving genetics, environment, and immunity.^107–110 The results showed that HSD could exacerbate DSS and TNBS-induced colitis, leading to increased mortality in mice.^111,112

Innate and adaptive immune cells play different roles in the pathogenesis of IBD. A large number of studies have shown that Th17, Th1, Tregs, and macrophages play an important role in the pathogenesis of IBD. For example, the number of Th17 cells in the lamina propria (LP) of the mucosa in colitis patients is significantly increased, resulting in IL-17, which causes mucosal damage and enhances disease activity.^113,114 Th1 polarization is associated with colon inflammation by inducing the production of IFN-γ and TNF-α, while different tendencies to develop colitis are associated with an inherent tendency of the immune system to produce Th1 or Th17/Treg responses.¹¹⁵ Tregs are very important Tregs, highly expressing IL-10 in IBD and inhibiting inflammation.¹¹⁶ In colitis patients, macrophages in the intestinal mucosa secrete cytokines TNF-α, IL-1, and IL-6.¹¹⁷ Intestinal macrophages are the main population of APCS in the intestinal mucosa, and they determine the type of response of T cells to luminal antigens.¹¹⁸ Excess salt leads to monocyte- and T-cell-driven inflammation, as well as parallel loss of immunoregulatory mechanisms involving the Th17 axis, M2 macrophages, and Tregs.¹¹⁹

Sodium chloride mediates the inflammatory effects of immune cells, which is very important for IBD. In one study, high salt content induced pro-inflammatory factor production by enhancing the signaling pathways of LPS-induced macrophage activation p38 and ERK1.⁵³ High NaCl pro-inflammatory factors in LPS and IFN-γ-activated laminar propria monocytes (LPMCs) rely on upregulation of the p38 mitogen-activated protein kinase (p38/MAPK) axis, and inhibition of p38/MAPK can effectively inhibit the production of inflammatory mediators.¹²⁰ HSD activates Th17 cells in vitro and in vivo by activating the p38/MAPK/NFAT 5 pathway and the SGK1 pathway of T cells.¹² In one study, exposing human LPMCs to high concentrations of NaCl enhanced TNF-α and IL17A release in a p38-dependent manner, and feeding mice a salt-rich diet exacerbated experimental colitis.¹²¹ In addition, high NaCl enhances the expression of M1 proinflammatory gene in LPS-activated peritoneal macrophages, and colitis caused by high NaCl level may be the result of polarization of M1 macrophages. Therefore, HSD may enhance LPS and IFN-γ through activation, enhance M1 macrophage polarization, upregulate the p38/MAPK axis, and induce the production of pro-inflammatory factors, thereby aggravating colitis. In addition, in mouse DCs, excess sodium increases IL-1β production, which promotes the production of pro-inflammatory cytokines such as IL-17A and IFN-γ by T cells.¹¹⁹ Therefore, HSD-induced colitis is associated with the promotion of NaCl-promoting M1 macrophage polarization and IL-1β production in DCs, which in turn promotes Th17 polarization and the production of pro-inflammatory factors. Figure 4 shows the mechanism by which HSD mediates inflammation in IBD by inducing immune disorders.

Figure 4 Influences of HSD on immunity toward IBD: HSD promotes the polarization of macrophages into the M1 phenotype and induces the production of IL-1β in DCs, thereby promoting the polarization of Th17 cells and the secretion of pro-inflammatory cytokines IL-17A and IL-17F, leading to the development of IBD.

Empirical evidence supports the notion that the consumption of HSD exerts a stimulatory effect on the Th17 immune response via the activation of caspase-1 in macrophages.^112,122 Th17 cells are present in the entire LP of the intestine,¹²³ and emerging evidence suggests that Th17 cells and related molecules play a critical role in the pathogenesis of IBD.^114,124,125 Existing research indicates that HSD promotes the activation of Th17 cells in the LP and exacerbates experimental colitis in mice.^112,121 The upregulation of IL-17A and IL-17F has been implicated in the development of IBD.^{112,114,121,124,125} In animal models, knockout of the IL-17 receptor gene in mice prevents the development of IBD.¹²⁴ The orphan nuclear receptor (RORγt) is a key transcription factor that drives the development of CD4+ T cells to Th17 cells,^123,126 and we found that HSD significantly increased the expression of RORγt in SILP CD4+TCRβ+ cells. RORγt has been reported to control the production of IL-17A and IL-17F, thereby regulating the pathogenicity of mouse models of IBD.^112,114 As immunosuppressive cells, Tregs secrete a variety of cytokines, including anti-inflammatory factors represented by TGF-β and IL-10, which are crucial in maintaining intestinal homeostasis.¹²⁷ Studies have shown that HSD significantly inhibits IL-10 secretion and inhibitory function of Treg cells.^68,112 In β7-deficient mice treated with DSS, colonic Tregs are depleted, and the upregulation of ICAM-1 between colonic epithelial cells leads to excessive infiltration of macrophages in the colon, which promotes the expression of pro-inflammatory cytokines and aggravates DSS-induced colitis.¹²⁸ Disruption of balance may allow T cells to proliferate in an increased manner, thereby contributing to the development of chronic intestinal inflammation,¹²⁹ and HSD may increase the risk of IBD by impairing the intestinal Th17/Treg balance.

In a cross-sectional study examining dietary intake patterns among 67 patients with remission-ending CD, it was observed that salt intake exceeded recommended levels in all study cohorts. Notably, both male and female individuals with Crohn’s disease exhibited higher salt consumption compared to their respective control groups.¹³⁰ However, in a comprehensive women’s health study investigating dietary habits and lifestyles, there was no clear evidence supporting a causal link between dietary salt intake and the occurrence of CD events.¹³¹ Consequently, further human-based research endeavors are imperative to gain a more comprehensive understanding of the potential role of HSD in IBD.

Influences of HSD on Immunity Toward Autoimmune Disease

Autoimmune diseases, such as multiple sclerosis (MS), systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and IBD, showcase a strong association with HSD-induced immune dysregulation. In our earlier discussion, we elucidated the intricate mechanisms linking HSD-mediated immune disturbances with the pathogenesis of IBD. Moving forward, we aim to delve into the precise mechanisms through which HSD influences immunity in the context of multiple sclerosis, SLE, and RA.

MS is a chronic, inflammatory, autoimmune disease of the central nervous system (CNS)¹³² characterized by the destruction of myelin sheath by autoreactive T cells and axons crossing the blood-brain barrier (BBB).^133,134 It is a disease that currently has no cure and causes motor, sensory, and cognitive deficits. In genetically predisposed individuals, environmental factors play an important role in the pathogenesis of MS.¹³⁵ High intake of sodium chloride is currently considered a potentially important factor in the onset of MS. EAE is one of the most commonly used animal models for MS, and it can be induced by active immunity of myelin peptides or passive transfer of myelin-responsive T cells.¹³⁶ More recently, in experimental autoimmune myelitis models (EAEs), increased NaCl intake has been shown to promote the development of Th 17 cells via the MAPK/P38 pathway¹² or by altering MAPK signaling in macrophages, promoting pro-inflammatory macrophage polarization, and exacerbating CNS autoimmunity.¹³⁷ In mouse studies, HSD altered the development of different cytokine-producing T-helper cell types, and HSD-aggravated EAE mice showed enhanced peripheral-induced pathogenic Th17 cell infiltration in CNS.^12,35 Sodium intake enhances the polarization of naive Th17 cells to pathogenic Th 17 cells lymphocytes by activating the p38/MAPK and SGK1 signaling pathways and drives the development of multiple sclerosis-like pathologies.^35,138 Studies have shown that excessive dietary sodium intake can induce an increase in the frequency of pro-inflammatory Th17 and Th1, as well as impaired function of Treg cells to affect autoimmunity.¹³⁹ It is generally believed that the autoimmune basis of MS stems from an imbalance between pro-inflammatory Th 1 and Th 17 cells and anti-inflammatory Tregs.¹⁴⁰ The role of the gut microbiota in this process was highlighted in one study, supplementing Lactobacillus murine to blunt salt-induced pathogenic Th17 cells and improving EAE deterioration.⁶⁵ DCs are specialized APCS that present antigens to T cells and initiate adaptive immunity.^141,142 However, in autoimmune neuroinflammation, evidence suggests that the effects of high salt on T cells are applied directly, rather than mediated by DCs.¹⁴³ This suggests that different immune cell subtypes respond differently to NaCl and that the production of a salt-induced pro-inflammatory environment involves a specific effect on immune cells rather than nonspecific activation of all lymphocytes and APCs.

Data from humans suggest that the effects of high salt on MS are controversial. One cohort study reported that high salt intake was associated with increased disease activity in MS.¹⁴⁴ Conversely, four other human studies found no association between HSD and MS progression.^145–147 In a randomized cross-intervention study on the effect of altering salt intake with human cytokines, high salt intake (or dietary changes) did not induce significant changes in any characteristic cytokines that controlled Th1, Th2, or Th17 polarization, nor were several other pro-inflammatory interleukins, chemokines, and growth factors affected by high salt intake, suggesting that clinically relevant changes in salt intake in humans do not reflect systemic concentrations of pro-inflammatory cytokines in the body.¹⁴⁸ In addition, a case-control study of MSin children and salt intake showed no strong association between dietary salt intake and the risk of developing MS in children, and salt intake may not play a significant role in susceptibility to MS among children.¹⁴⁶ Reasons for inconsistencies in clinical studies and studies using mouse models may include true species-specific differences in electrolyte metabolism and immune cell activation. In addition, the salt load used in mouse models and human HSDs is also significantly different, requiring high salt concentrations and exogenous Th-polarizing cytokines when human lymphocytes are polarized to the Th17 direction in a salt-absorbable manner in vitro.¹³

SLE is an autoimmune connective tissue disease characterized by increased production of various autoantibodies against autoantigens, mainly affecting women of childbearing age,^149–151 involving multiple systems. Lupus nephritis is one of the most serious organ manifestations of SLE. The data showed that HSD accelerated lupus progression and increased mortality in MRL/LPR mice (mouse models of SLE).^152,153 The proportion of Th17/Treg is significantly increased in MRL/LPR mice fed HSD,¹⁵³ and a higher proportion of Tfh cells is observed in the spleen. High NaCl promotes autoimmunity through Tet2-induced DNA demethylation and differentiation of Tfh (follicular T helper cell) cells, thereby accelerating the development of SLE in experimental MRL/LPR mouse models¹⁵² and demonstrating the key role of Tfh cells in autoantibody production and lupus pathogenesis.^154–158 In the lupus model, excess salt did not increase the number of DCs but significantly promoted the activation and maturation of DCs, increased antigen presentation of DCs, and the production of pro-inflammatory cytokines.¹⁵⁹ This enhancement of differentiation of various Th cell subsets, including Tfh cells, is subsequently achieved by modified DCs.¹⁵⁹ Furthermore, cells cultivated in high salt concentrations exhibited higher expression levels of the p38 gene.¹² The downstream target of the p38 gene is the nuclear factor that activates T cells, which triggers the production of IL-17.¹⁶⁰ IL-17 further enhances the production of pro-inflammatory mediators. According to studies, the intake of HSD speeds up the development of SLE by promoting immune activation in DCs via the p38/MAPK-STAT1 signaling pathway.¹⁵⁹

RA is a chronic inflammatory joint disease that can lead to cartilage, bone damage, and disability.¹⁶¹ Collagen-induced arthritis (CIA) and K/BxN serotransfer-induced arthritis (STIA) are mouse models of RA. CIA relies on both adaptive and innate immunity, while STIA mainly mimics the innate effector phase.¹⁶² CIA mice fed HSD showed more severe arthritis, a higher proportion of Th17 cells in spleen cells, and increased IL-17 expression in the synovial membrane and intestine.¹⁶³ A study recruiting patients with RA and SLE showed that limiting dietary salt intake suppressed the pro-inflammatory response in patients with autoimmune diseases.¹⁶⁴ Figure 5 shows the mechanism by which HSD induces immune disorders to produce autoimmune diseases.

Figure 5 Influences of HSD on immunity toward autoimmune diseases: HSD promotes the polarization of macrophages into the M1 phenotype and enhances the polarization of naive T helper cells towards pathogenic Th17 cells through the activation of the p38/MAPK/NFAT5 and SGK1 signaling pathways. This results in the production of pro-inflammatory cytokine IL-17, leading to the development of autoimmune diseases.

Influences of HSD on Immunity Toward Other Diseases

HSD disrupts immune homeostasis, provoking a pro-inflammatory milieu that underlies the pathogenesis of multiple diseases. In murine models, HSD not only facilitates the expansion of bone-derived Th17 cells but also impedes the development of anti-bone-derived Treg cells. These perturbations in the host immune system perturb the delicate equilibrium between Treg and Th17 cell populations, consequently exacerbating bone loss and compromising bone microstructure integrity,⁹¹ amplifying the risk of osteoporosis. In addition, HSD has been shown to inhibit the production of cerebral endothelial NO by inducing the synthesis of IL-17, the primary effector cytokine secreted by intestinal Th 17 cells. This effect results in cerebral hypoperfusion, neurovascular imbalance, and cognitive impairment in mice.¹⁶⁵ Furthermore, HSD can exacerbate ischemic stroke by reducing the expression of phagocytosis molecules expressed on triggering receptor expressed on myeloid cells 2a (TREM2) and inducing a pro-inflammatory phenotype in macrophages, leading to the delayed recovery of stroke lesions.¹⁶⁶ Additionally, HSD can worsen liver fibrosis by activating enterococcus-dependent macrophages, which can impair intestinal barrier function.¹⁶⁷ Studies have also shown that HSD can exacerbate food allergy in mice¹⁶⁸ and may be involved in the progression of atopic dermatitis by regulating the Th 2 response through sodium.¹⁶⁹ Therefore, it is crucial to further investigate the effects of HSD on various diseases and their underlying mechanisms to develop effective prevention and treatment strategies.

Discussion

This article highlights the potential role of HSD in triggering immune disorders that lead to various chronic diseases. The regulation of immune cell differentiation, activation, and function, induced by HSD, can ultimately contribute to the development of immune-mediated diseases like IBD, kidney disease, hypertension, cancer, and autoimmune diseases. This comprehensive review explores the intricate mechanisms underlying the impact of HSD on innate immune cells. It highlights the pivotal role of HSD in promoting macrophage differentiation and dendritic cell activation, enhancing their functionality as APCS. Furthermore, HSD exerts profound effects on T cells, driving their proliferation through antigen-MHC receptor interactions and influencing their differentiation towards Th17 cells. Concomitantly, HSD compromises the regulatory function of Treg cells, destabilizing immune homeostasis. This dysregulation is further accentuated by the upregulation of pro-inflammatory factors, including IL-17, and the concomitant decrease in anti-inflammatory factors such as IL-10. These intricate cellular and molecular processes collectively contribute to the altered disease development observed in response to HSD. Figures 2–5 elucidates the intricate interplay between HSD-mediated regulation of SGK1, NFAT5/TONEBP, and p38/MAPK signaling pathways, their impact on T cell differentiation, the delicate balance between Th17 and Treg cells, as well as the consequential release of pro-inflammatory and anti-inflammatory factors. The elucidated relationships provide valuable insights into the mechanistic underpinnings that drive the development and progression of various diseases.

Recent studies have highlighted the crucial role of the gut and gut microbiota in the adverse effects of high-salt conditions on immune cells.¹⁷⁰ Further investigation into the microbiome’s involvement in salt-induced colitis exacerbation in a mouse model of IBD has revealed a decline in lactobacilli and butyrate, a potent anti-inflammatory agent, and an aggravation of colitis in mice fed an HSD.⁴ Interestingly, this effect was absent in germ-free mice,⁴ indicating the involvement of gut microbiota in the exacerbation of colitis. Additionally, HSD-induced reduction in lactobacilli has been shown to induce the production of Th 17 cells, leading to hypertension in mice and humans.⁶⁵ Therefore, future research should focus on exploring the mechanisms underlying the gut microbiota’s response to high-salt conditions and its impact on immune function and disease pathogenesis. Such studies are essential in developing novel therapeutic strategies aimed at modulating the gut microbiota to prevent or treat salt-induced immune dysfunction and associated diseases.

While animal experiments suggest that HSD can lead to immune-mediated diseases, it is important to note that the impact of salt on immune cells may not always be pathogenic.¹⁷¹ The effects of HSD on humans are complex and variable, depending on the cellular environment in local tissues and the types and stages of diseases. Salt has an anti-tumor effect by activating the immune system in the initial stage of tumors, while it exerts antagonistic and pro-tumor effects through immune exhaustion in the later stages.⁹⁸ Moreover, increased mesenchymal salt concentrations at the site of skin infection have been shown to enhance the bactericidal response of macrophages through NFAT5-dependent mechanisms, thereby promoting host defenses.⁵⁰ Thus, it is crucial to call for further high-quality research to investigate the effects of HSD on immune cells and to determine the full range of its impact on human health. Future studies may focus on exploring the molecular pathways underlying the effects of HSD on gut microbes and their metabolites and investigating the development of effective interventions to prevent or treat immune-mediated diseases caused by HSD.

Conclusion

A high-salt diet is an environmental trigger for immune-mediated diseases that can increase tissue sodium concentrations, affect immune responses in the microenvironment, regulate the differentiation, activation and function of a wide range of immune cells, and thus influence the development of immune-regulatory disorders, including kidney disease, hypertension, cancer, inflammatory bowel disease, and some autoimmune diseases. The underlying mechanism may be related to gut microbes and their metabolites.