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Autoimmunity

Rubbing salt in the wound

Nature volume 496, pages 437439 (25 April 2013) | Download Citation

The ability of sodium chloride to induce enzymatic activity that leads to the generation of pathogenic TH17 immune cells implicates salt as a possible factor that might exacerbate autoimmune disease. See Letters p.513 & p.518

The role of the immune system is to protect our bodies from viral, bacterial, fungal and parasitic infections. But, sophisticated as this system is, it can go awry. One consequence is autoimmunity, a diverse collection of disorders in which the immune system turns against the host. Genetics and gender undoubtedly play key parts in the susceptibility to autoimmune diseases, but environmental factors are also important. In this issue, Kleinewietfeld et al.1 (page 518) and Wu et al.2 (page 513) provide provocative data implicating a novel component in this mix: salt*.

The stories focus on a crucial orchestrator of immune responses — the CD4+, or 'helper', T cells. These cells regulate immune responses through their ability to differentiate into distinct classes of cell according to the nature of the offending pathogen. In the past decade, increasing attention has focused on a subset of CD4+ T cells, commonly known as T helper 17 (TH17) cells3,4,5,6, which secrete molecules belonging to the IL-17 group of cell-signalling compounds called cytokines. Cells that produce IL-17 are prominent in the gut, where they influence its barrier function and help to protect against extracellular pathogens and fungi. However, these helpers can also be traitors — TH17 cells are important drivers of autoimmune disease, and have inflammatory properties.

The present studies tell their stories in different ways, but both show that an elevated sodium chloride (NaCl) concentration (40–80 millimolar) in an otherwise isotonic culture medium promotes the differentiation of CD4+ T cells into TH17 cells in vitro. Perhaps the most provocative experiments relate to an in vivo correlate of this finding. The authors demonstrate that a high-salt diet accelerates neuropathology in experimental autoimmune encephalomyelitis (EAE), a mouse model of the autoimmune disease multiple sclerosis. They used inhibitors, interfering RNA molecules and knockout mice to test the role of cellular signalling pathways in these processes, and link the regulation of NaCl and TH17 differentiation with the transcription factor NFAT5 and the protein-kinase enzymes p38 and SGK1 (Fig. 1). This makes sense, because p38 is an evolutionarily conserved kinase that is activated by changes in cellular osmolarity, and NFAT5 and SGK1 are both substrates of p38.

Figure 1: SGK1 and the differentiation of TH17 cells.
Figure 1

a, Kleinewietfeld et al.1 and Wu et al.2 provide evidence that a high-salt diet can enhance the differentiation of a class of immune cell called TH17 cells, and exacerbate disease in a mouse model of multiple sclerosis called experimental autoimmune encephalitis (EAE). They also show that mice whose T cells lack the enzyme SGK1 (T-cell SGK−/−) display reduced disease severity and are protected from NaCl-exacerbated EAE. b, The authors demonstrate that extracellular NaCl concentration and signalling through the IL-23 receptor both influence the activity of SGK1 to drive expression of pathogenic TH17-cell characteristics, which include the production of the cytokines IL-17A and IL-17F and enhanced expression of the IL-23 receptor (IL-23R) and the transcription factor RORγT (encoded by Rorc). However, this finding must be considered in the context of other environmental factors, such as oxygen and nutrient provision. These influence signalling pathways and glycolytic metabolism in ways that regulate not only TH17-cell differentiation, but also that of other classes of T cell.

The authors also find that SGK1 is expressed in TH17 cells and is induced by NaCl, and show that mice lacking this kinase in their T cells have impaired expression of IL-17-family cytokines and of a receptor for another cytokine molecule, IL-23. When they tested these knockout mice in the EAE model, they found that the lack of SGK1 also leads to reduced neuropathology. SGK1 has been implicated in inflammatory pathways before: it is known to inactivate the transcription factor Foxo1. Accordingly, Foxo1-deficient T cells have higher levels of IL-17 and IL-23-receptor expression.

In considering these studies, it is appropriate to re-emphasize that IL-17 and TH17 cells are not always the villains; they also protect us from a universe of true villains. In the same vein, it should also be pointed out that not all TH17 cells are alike: although some IL-17-producing T cells mediate immune pathology, others do not. IL-23 is a key cytokine in generating pathogenic TH17 cells7, and the authors of both papers note that NaCl and SGK1 seem to contribute to the generation of TH17 cells that have pathogenic potential. However, many cells other than CD4+ T cells, including innate immune cells and γ/δ T cells, also produce IL-17 and related cytokines8. Although a high-salt diet may indeed worsen autoimmune disease, the data provided do not establish exactly which cells NaCl works on to achieve this.

An additional point is that autoimmune diseases are heterogeneous, and the benefit achieved by blocking IL-17 is variable. Inhibiting IL-17 is useful in treating psoriasis, but less so in inflammatory bowel disease; the jury is still out on whether targeting IL-17 will be of help in treating multiple sclerosis. It is also worth noting that the studies by Kleinewietfeld et al.1 and Wu et al.2 show that NaCl exacerbates an artificially created disease; there are no data indicating that dietary salt promotes or worsens spontaneous disease.

The complex interaction of the factors that regulate helper-T-cell differentiation must also be taken into account when considering these results (Fig. 1). SGK1 is a member of the AGC family of protein kinases, and is homologous to the enzyme Akt9. Akt has well-documented effects on cell survival, metabolism and helper-T-cell differentiation. Moreover, Akt and SGK1 share upstream activators, including the enzymes PI3K and PDK1, and downstream substrates. Key molecules, such as mTor and Foxo1, are also influenced by diverse factors and have complex effects on T-cell function10. Furthermore, helper T cells are influenced by nutrient availability and by the oxygen-sensitive transcription factor HIF-1α, which suggests a close link between metabolism and differentiation. Similarly, p38 is also a recognized regulator of helper T cells11. This is pertinent to the present studies, because the authors' results suggest that the functions of SGK1 and NaCl are not entirely congruent: SGK1 positively regulates IL-17, but negatively regulates the genes Ifng, Tbx21 Il4, Il13, Gata3, Il2 and Il9, whereas NaCl positively regulates IL-17, Ifng, Tbx21, Il2 and Il9.

Thus, dietary salt is just one of many factors that influence helper T cells; cytokines, the microbiota, diet, metabolism and other diverse environmental factors are all important too10,12,13. The bottom line is that these kinases and transcription factors represent key nodes for many receptors and signalling pathways that integrate a vast array of stimuli. So, although these are exciting and provocative data, it is clearly premature — as also pointed out by both sets of authors — to state that dietary salt influences autoimmune disease in humans and that this is mediated by T-cell-induced production of IL-17. However, the work should spur investigation of tangible links between diet and autoimmune disease in people. In doing so, it will be essential to conduct formal, controlled clinical trials. Fortunately, the risks of limiting dietary salt intake are not great, so it is likely that several such trials will be starting soon.

Notes

  1. 1.

    *This article and the papers under discussion1,2 were published online on 6 March 2013.

References

  1. 1.

    et al. Nature 496, 518–522 (2013).

  2. 2.

    et al. Nature 496, 513–517 (2013).

  3. 3.

    , , & Annu. Rev. Immunol. 25, 821–852 (2007).

  4. 4.

    , & Semin.Immunol. 19, 353–361 (2007).

  5. 5.

    & Immunity 21, 467–476 (2004).

  6. 6.

    & Nature Rev. Drug Discov. 11, 763–776 (2012).

  7. 7.

    et al. Nature 421, 744–748 (2003).

  8. 8.

    , & Eur. J. Immunol. 42, 2221–2231 (2012).

  9. 9.

    , , & Growth Factors 28, 394–408 (2010).

  10. 10.

    & Annu. Rev. Immunol. 30, 759–795 (2012).

  11. 11.

    , & Annu. Rev. Immunol. 20, 55–72 (2002).

  12. 12.

    & Nature Immunol. 13, 907–915 (2012).

  13. 13.

    , , & Semin. Immunol. 23, 99–105 (2011).

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  1. John J. O'Shea is in the Intramural Research Program, National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, Maryland 20892-1616, USA.

    • John J. O'Shea
  2. Russell G. Jones is at the Rosalind and Morris Goodman Cancer Research Centre, Department of Physiology, McGill University, Montreal, Quebec H3G 1Y6, Canada.

    • Russell G. Jones

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Correspondence to John J. O'Shea or Russell G. Jones.

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https://doi.org/10.1038/nature11959

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