Abstract
A link between high sodium chloride (salt) intake and the development of autoimmune diseases was previously reported. These earlier studies demonstrated exacerbation of experimental autoimmune encephalomyelitis and colitis by excess salt intake associated with Th17- and macrophage-mediated mechanisms. Little is known about the impact of dietary salt intake on experimental arthritides. Here, we investigated if salt restriction can exert beneficial effects on collagen-induced arthritis (CIA) and K/BxN serum transfer-induced arthritis (STIA). CIA depends on both adaptive and innate immunity, while STIA predominantly mimics the innate immune cell-driven effector phase of arthritis. In both models, low salt (LS) diet significantly decreased arthritis severity compared to regular salt (RS) and high salt (HS) diet. We did not observe an aggravation of arthritis with HS diet compared to RS diet. Remarkably, in STIA, LS diet was as effective as IL-1 receptor blocking treatment. Complement-fixing anti-CII IgG2a antibodies are associated with inflammatory cell infiltration and cartilage destruction. LS diet reduced anti-CII IgG2a levels in CIA and decreased the anti-CII IgG2a/IgG1 ratios pointing toward a more Th2-like response. Significantly less inflammatory joint infiltrates and cartilage breakdown associated with reduced protein concentrations of IL-1 beta (CIA and STIA), IL-17 (CIA), and the monocyte chemoattractant protein-1 (MCP-1) (CIA) were detected in mice receiving LS diet compared to HS diet. However, we did not find a reduced IL-17A expression in CD4+ T cells upon salt restriction in CIA. Analysis of mRNA transcripts and immunoblots revealed a link between LS diet and inhibition of the p38 MAPK (mitogen-activated protein kinase)/NFAT5 (nuclear factor of activated T-cells 5) signaling axis in STIA. Further experiments indicated a decreased leukodiapedesis under LS conditions. In conclusion, dietary salt restriction ameliorates CIA and STIA, indicating a beneficial role of LS diet during both the immunization and effector phase of immune-mediated arthritides by predominantly modulating the humoral immunity and the activation status of myeloid lineage cells. Hence, salt restriction might represent a supportive dietary intervention not only to reduce cardiovascular risk, but also to improve human inflammatory joint diseases like rheumatoid arthritis.
Highlights
Rheumatoid arthritis (RA) is a chronic autoimmune disease in which complex interactions of adaptive and innate immune cells cause chronic joint inflammation resulting in a destruction of cartilage and bone [1]
The NaCl concentrations ranged from 25 mM NaCl (LS0), 50 mM NaCl (LS25), 75 mM NaCl (LS50), 125 mM NaCl (LS100 corresponding to regular salt condition with 299 mOsm/kg) to 165 mM NaCl (LS140)
A significant reduction of TNF-alpha (Figure 1A) and IL-6 (Figure 1B) production was observed in monocytes cultured in LS0 medium compared to monocytes cultured in medium ≥LS50
Summary
Rheumatoid arthritis (RA) is a chronic autoimmune disease in which complex interactions of adaptive and innate immune cells cause chronic joint inflammation resulting in a destruction of cartilage and bone [1]. RA is linked to a higher risk for cardiovascular diseases (CVD) accompanied with increased mortality [5, 6]. The “Western diet”, containing high amounts of sodium chloride (NaCl, referred to as salt), represents an important risk factor in inflammatory autoimmune diseases [7]. A link between excess salt intake and exacerbated disease in murine experimental autoimmune encephalomyelitis (EAE) [8, 9] and colitis models was reported [8, 10, 11]. Salt-sensitive innate immune cells such as macrophages critically contribute to increased inflammation in EAE [8]
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