Pflugers Arch - Eur J Physiol (2015) 467:543–550
DOI 10.1007/s00424-014-1659-z
INVITED REVIEW
Sodium chloride, SGK1, and Th17 activation
Katrina J. Binger & Ralf A. Linker & Dominik N. Muller &
Markus Kleinewietfeld
Received: 16 October 2014 / Revised: 19 November 2014 / Accepted: 20 November 2014 / Published online: 4 December 2014
# Springer-Verlag Berlin Heidelberg 2014
Abstract The incidence of autoimmune diseases in Western
civilizations is increasing rapidly, suggesting an influence of
environmental factors, such as diet. The pathogenesis of sev-
eral of these autoimmune diseases is characterized by aberrant
activation of T helper 17 (Th17) cells. Recent reports have
shown that the differentiation of Th17 cells is sensitive to
changes in local microenvironments, in particular salt (NaCl)
concentrations, in a molecular mechanism centered around the
serum- and glucocorticoid-inducible kinase 1 (SGK1). In this
review, we summarize the recently disclosed mechanisms by
which salt has been shown to affect SGK1 and, subsequently,
Th17 activation.
Keywords Salt . SGK1 . T cells . Autoimmunity
Introduction
Incidence and prevalence of human autoimmune diseases
such as multiple sclerosis (MS), psoriasis, and type 1 diabetes
K. J. Binger : D. N. Muller
Experimental and Clinical Research Center, an institutional
cooperation between the Charité Medical Faculty and the
Max-Delbrueck Center for Molecular Medicine, Berlin 13125,
Germany
R. A. Linker
Friedrich-Alexander-University of Erlangen-Nuremberg,
Erlangen 91054, Germany
D. N. Muller (*)
Max-Delbrueck Center for Molecular Medicine, Berlin 13125,
Germany
e-mail: dominik.mueller@mdc-berlin.de
M. Kleinewietfeld
Translational Immunology, Medical Faculty Carl Gustav Carus, TU
Dresden, 01307 Dresden, Germany
(T1D) in Western societies are increasing rapidly, but the
underlying cause for this has not been elucidated [4, 74].
MS and psoriasis are both relapsing and remitting autoim-
mune diseases, accompanied by increased hypertension and
cardiovascular risk. Genome-wide association studies have
demonstrated that genetic factors predispose to the develop-
ment of autoimmune diseases [48, 52, 64]. Environmental
factors may also be important triggers for these diseases, as
there is a relatively low concordance rate between monozy-
gotic twins for most of these diseases [8]. The “Western diet,”
high in saturated fatty acids and salt, has long been postulated
as one potential environmental cause for the increasing inci-
dence of autoimmune diseases in developed countries where
processed and fast food consumption is more common.
Differentiation of Th17 cells
Helper T lymphocytes play an essential role in combatting
infection. During active inflammation, naïve T cells differen-
tiate into various T helper cell types (e.g. Th1, Th2, Th17),
depending on the local cytokine milieu. Th1 cells typically
produce interferon (IFN)-γ and tumor necrosis factor-α, while
Th2 cells produce interleukin (IL)-4 and 13, and Th17 cells
release IL-17, IL-21, and IL-22; cytokines which are pivotal in
the defense against bacteria and fungi. Besides Th17 cells, IL-
17 is also produced by γδ T cells, natural killer cells, and
natural killer T cells [60]. The differentiation of inflammatory
Th17 cells, required for host defense and autoimmunity, can
occur with a number of different cues. These include stimula-
tion with TGF-β3 in combination with IL-23 [39], IL1β, and
IL-6 or IL-23 [27], where, in both cases, IL-17A single-
positive cells are converted into IL-17A/interferon (IFN)-γ
double-positive cells. Additionally, IL-1β has been shown to
induce the differentiation of inflammatory Th17 cells by
repressing IL-10 production (a cytokine with potent anti-
544
inflammatory and regulatory properties) in human Th17 cells
[78]. Although it was initially thought that Th17 cells are
exclusively inflammatory, there has been recent accumulating
evidence of a ‘regulatory’ IL-17 producing Th17 subset. In
this setting, it was demonstrated that with combined TGF-β1
and IL-6 signaling, or by dedicated mechanisms in the small
intestine in vivo, subsets of Th17 cells are generated which
produce high levels of IL-10 [23, 44]. Taken together, the
inflammatory potential of Th17 cells seems to be determined
by the cytokine milieu and local environment by which these
cells face.
Autoimmune diseases and Th17 cells
Th17 cells are prominent in peripheral tissues, in particular the
gut, where the production of IL-17 is important for the re-
cruitment of other immune cells and the production of other
factors to promote pathogen clearance [reviewed by 34].
However, Th17 cells are also linked to the development of
several autoimmune diseases, and, in this context, their aber-
rant activation can be considered pathogenic. The develop-
ment of autoimmune diseases such as multiple sclerosis, pso-
riasis, type I diabetes, primary Sjögren’s syndrome, asthma,
and rheumatoid arthritis are all shown to involve Th17-driven
inflammation [reviewed by 1, 40, 57].
What causes Th17 cells to become pathogenic and drive
these diseases is unclear. Generally, the formation of Th17
cells is dependent on TGFβ signaling in combination with IL-
6 or other pro-inflammatory cytokines. TGFβ is also essential
for the formation of regulatory T cells (Treg), in this case with
co-stimulation with IL-2 or IL-10 [41]. Tregs are generally
considered to prevent autoimmunity, and thus, it is striking
that with the same primary stimulus (TGFβ), Th17 and Treg
cells adopt such different fates. Understanding the conditions
by which Th17 cells are enhanced and if these can be con-
verted or dedifferentiated into Tregs are the focus of much
recent work. Retinoic acid (RA; a vitamin A metabolite) was
one of the first molecules described to affect Th17-Treg dif-
ferentiation. Here, RA was shown to blunt IL-6 stimulation
and to promote Treg formation [46]. Along this same line,
cellular metabolism is emerging as a key feature defining the
difference between Th17 and Treg cells [56], which when
modulated, can promote the formation of one or the other cell
type. Th17 cells are characterized by glycolytic metabolism,
controlled by HIF1α, which when deleted results in the for-
mation of Treg [56]. In contrast, Treg cells depend on lipid
oxidation and mitochondrial oxidative phosphorylation. The
modulation of Th17 cellular metabolism from glycolysis to
oxidative phosphorylation with chemicals such as Rapamycin
[18, 56], or biomolecules such as Soraphen A [6], also pro-
motes differentiation into Treg. These studies further highlight
the sensitivity of Th17 cells to their microenvironment.
Pflugers Arch - Eur J Physiol (2015) 467:543–550
Role of Th17 cells in atherosclerosis and hypertension
As mentioned above, the differentiation of inflammatory
Th17 cells greatly depends on the cytokine milieu and local
microenvironment [reviewed by 61], which may be particu-
larly relevant to cardiovascular disease. Atherosclerosis, a
chronic inflammatory arterial disease dependent on both in-
nate and adaptive immunity, is most likely the best-studied
cardiovascular disease with regard to the immune system.
However, research on the contribution of Th17 cells in pro-
moting the pathogenesis of atherosclerosis is conflicting [61].
IL-17 has been shown to directly promote the production of
pro-atherogenic cytokines from macrophages [15]. However,
studies to block IL-17 have not been promising [reviewed by
[61]. It may be that some of this confusion is due to the
influence of confounding factors, such as effects from the
method used to block IL-17 and dietary composition or feed-
ing duration directly regulating the immune response. It has
also been shown that reducing Th17 can promote the number
of Th1 cells. These are important considerations as atheroscle-
rotic plaque size correlates with the Th1 cytokine IFN-γ, and
thus, enhancement of Th1 responses is associated with in-
creased lesion size. Conversely, a reduction in IFN-γ produc-
ing cells correlates with a reduction in plaque size [12, 67].
The role of IL-17 in hypertension is similarly controversial.
Madhur et al. showed that angiotensin II infusion increases IL-
17 production from T cells and IL-17 protein in the aortic
media layer. However, the initial hypertensive response to
angiotensin II infusion was similar with IL-17 knockout and
C57BL/6 J wild-type control mice, while 4 weeks after infu-
sion, hypertension was not sustained in IL-17 knockout mice.
Vessels from IL-17 knockout mice displayed a preserved
vascular function, decreased superoxide production, and re-
duced T cell infiltration in response to angiotensin II [42].
While a reduction in blood pressure only during late phase
points towards Th17 cells having an indirect effect in the
pathogenesis of hypertension, a recent study of Amador
et al. in rats demonstrated an immediate decrease in blood
pressure after the injection of neutralizing anti-IL-17 antibod-
ies [2]. In contrast, Marko et al. did not observe any lowering
of blood pressure upon anti-IL-23 or anti-IL-17 antibody
treatment [43]. This latter study is in agreement with a report
by Krebs et al., which showed that genetic disruption of the
IL-23/IL-17 axis does not alter hypertension after angiotensin
treatment in the presence of excess mineralocorticoids [35].
One alternative explanation for this inconsistency in de-
scribing the role of IL-17 in atherosclerosis and hypertension
could be due to a lack of characterization of the gut
microbiome in these studies. Commensal intestinal bacteria
influence multiple metabolic and physiological functions in
the host, and thus have the potential to profoundly affect the
host immune system [63]. Ivanov et al. observed that inbred
C57BL/6 mice obtained from Taconic Biosciences Inc.
Pflugers Arch - Eur J Physiol (2015) 467:543–550
developed a higher Th17-responsive phenotype compared to
mice obtained from Jackson Laboratories, indicating that the
Taconic environment/diet increased the levels of gut-
associated Th17 cells [31, 32]. This has, as yet, not been
deduced in the setting of atherosclerosis or hypertension.
Regulation of SGK1 expression and activity
and SGK1-regulated functions
High dietary salt (sodium chloride; NaCl) is an environmental
risk factor newly postulated to be linked to autoimmune dis-
eases [16, 25, 28, 45, 58]. A molecule important for sensing and
responding to changes in extracellular Na+ is the serum- and
glucocorticoid-inducible kinase (SGK1), which was cloned as a
gene regulated by the hydration state of a cell [71, reviewed by
26]. SGK1 is a downstream target of tonicity-responsive en-
hancer binding protein (TonEBP; also known as Nuclear factor
of activated T cells 5 (NFAT5)) [14]. Under physiological
conditions, SGK1 is expressed at low levels but is significantly
increased under glucocorticoid or mineralocorticoid excess,
hyperglycemia, ischemia, inflammation and hypertonicity, or
cell shrinkage [38]. Upon stimulation with insulin and growth
factors such as TGF-β, SGK1 is phosphorylated within mi-
nutes via signaling pathways involving phosphatidylinositide-
3-kinase, 3-phosphoinositide-dependent kinase, and the mam-
malian target of Rapamycin [50]. TGFβ stimulation also
upregulates SGK1 gene expression [37, 72]. In contrast, aldo-
sterone upregulates SGK1 solely on the genomic level via the
mineralocorticoid receptor [62]. Altogether, non-genomic or
genomic activation of SGK1 leads to the increased activity of
a variety of ion channels including the epithelial Na+ channel
ENaC [70], the voltage gated Na+ channel SCN5A [7], the
transient receptor potential channels TRPV4-6 [7, 38], the Ca2+
release activated Ca2+ channel Orai1/STIM1 [24], the K+ chan-
nel ROMK [30], the voltage gated K+ channels KCNE1/
KCNQ1 [22] and cystic fibrosis transmembrane regulator
[70], several ion carriers (including Na+/Cl− NCC, Na+/K+/
2Cl− NKCC2 cotransporter, Na+/H+ exchangers NHE1 and
NHE3, Na+/glucose symporter SGLT1) [38], as well as Na+/
K+-ATPase [54]. Furthermore, SGK1 affects the activity of
several molecules; it increases the phosphorylation of ubiquitin
ligase Nedd4-2 [19] and glycogen synthase kinase-3 [47],
negatively regulates transcription factors such as forkhead tran-
scription factor 3a [9, 20] and beta-catenin [20], and enhances
the activity of the transcription factor nuclear factor kappa B
[59].
SGK1, hypertension, and cardiovascular organ damage
The phenotype of SGK1 knockout mice is mild, and these
mice show normal blood pressure [66]. Thus, SGK1 is
545
apparently dispensable for basic cellular and organ function.
In contrast, various experimental and clinical studies have
demonstrated that excessive SGK1 expression and activity
increases the pathogenesis of several disorders including hy-
pertension, obesity, diabetes, thrombosis, stroke, fibrotic dis-
eases, infertility, and tumor growth. A SGK1 gene variant in
exon 6 (I6CC) and 8 (E8CC/CT) with a prevalence of 3–5 %
in Caucasians and about 10 % in Africans is associated with
hypertension [11, 69], QT interval alterations [11], stroke [17],
obesity, and type 2 diabetes [53]. It was also shown that
increased SGK1 activity promotes pulmonary vascular re-
modeling [5] and macrophage activation in the development
of pulmonary arterial hypertension [76]. In addition, SGK1
may play a decisive role in promoting fetal programming of
hypertension induced by prenatal protein restriction. Follow-
ing prenatal protein restriction, the weight gain in offspring of
wild-type mothers was slower and associated with higher
blood pressure after birth. In contrast, prenatal protein restric-
tion of SGK1 knockout mothers had no effect on postnatal
weight gain and blood pressure [51]. SGK1 knockout mice
infused with angiotensin II [77] or mineralocorticoid excess
with high salt [66] did not show an altered progression of
hypertension although cardiac hypertrophy, renal damage, and
cardiac and renal fibrosis were markedly reduced. In addition,
SGK1 can promote cardiac remodeling and development of
heart failure following an excessive pressure overload [68].
Taken together, the role of SGK1 in the development of
hypertension and cardiovascular disease remains ambiguous,
suggesting the existence of unknown mechanisms.
Role of sodium, SGK1 in Th17 polarization
and autoimmunity
Two recent studies have shed new light on the role of sodium,
SGK1, and the differentiation of naïve T cells to Th17 cells
[33, 75]. Wu et al. performed genome-wide messenger RNA
(mRNA) profiling to identify molecular mechanisms by
which naïve T cells develop into Th17 cells. Surprisingly,
SGK1 was one of the top-ranked genes whose transcriptional
regulation was clearly associated with IL-23 signaling and
highly induced with Th17 differentiation. Interestingly,
SGK1 was not equally expressed in other T cell subsets
(Th0, Th1, or Th2). TGF-β-induced regulatory T cells
(iTreg) had weak SGK1 expression [29, 75]. IL-23 was shown
to specifically induce and maintain the expression of SGK1 in
Th17 cells [75]. Utilizing a curated database of protein-protein
interaction analysis, the authors further identified the tran-
scription factor forkhead box O (FOXO) 1 as one of the
highest-ranking nodes downstream of SGK1. FOXO1 is
known to direct or fine-tune multiple biological functions that
are crucial for metabolism and differentiation of cells, includ-
ing cell cycle, apoptosis, oxidative stress response, enzyme
546
Th17 polarizing
Naive conditions
T cell NaCl-induced
hypertonicity
Fig. 1 The induction of Th17 cells is augmented by salt via SGK1-dependent mechanisms
activities, or DNA damage repair [10, 13, 65]. Interestingly, di
Pietro et al. showed that SGK1 promotes adipocyte differen-
tiation by regulating FOXO1 phosphorylation and thus re-
vealed a potentially important function for this kinase in the
control of body fat mass and function [21]. Upon FOXO1
phosphorylation, FOXO is deactivated and translocates from
the nucleus to the cytoplasm. In SGK1-deficient T cells, IL-23
stimulation leads to a compromised nuclear phosphorylation
of FOXO1 leading to an increase of its own mRNA and
protein expression [75]. Regarding Th17 cell differentiation,
Wu et al. suggested that SGK1-deficient cells have enriched
FOXO1 binding to the IL-23 receptor (IL-23r) promoter,
providing an explanation for the increased suppression of
IL-23r transcription. Vice versa, IL-23-induced SGK1 phos-
phorylation led to reduced FOXO1 activity and increased IL-
23r expression and induction of retinoic-acid-receptor-related
orphan receptor γt (RORγt), a master regulator of Th17
development (Fig. 1). In the same paper, Wu et al. demon-
strated that SGK1 deletion in CD4+ or IL-17-specific T cells
resulted in a milder disease course in an experimental model
of multiple sclerosis due to the differentiation of less patho-
genic Th17 cells [75].
SGK1 has also been shown to be important in the
differentiation of human T cells. Here, a Th17-promoting
cytokine cocktail (IL-1β, IL-6, IL-21, IL-23, and
TGF-β1), together with increased NaCl-concentrations,
substantially accelerated the induction of Th17 cells [33].
Th17 cells produced in this manner displayed an inflam-
matory phenotype, as indicated by the increased induction
of other pro-inflammatory cytokines like CSF2 (also called
GM-CSF). Surprisingly, the effect by which salt promoted
Th17 differentiation was dependent on Na+, as non-ionic
hypertonic osmolytes (such mannitol or urea) were not able
to promote the same degree of Th17 cell induction. Th1
and Th2 polarization was not affected by Na+-induced
hypertonicity, suggesting a specific effect of salt on Th17
differentiation. As described above, extracellular
Pflugers Arch - Eur J Physiol (2015) 467:543–550
IL-23r
p-p38
Th17
NFAT5 polarizing
1.
phospo-FOXO1
conditions Th17
SGK1
2.
phospo-FOXO1
4.
cells
3. RORγt
hypertonicity leads to cell shrinkage accompanied by the
influx of extracellular sodium via ENaC, NHE1, and
NKCC2 [36]. This adaptation to hypertonicity is controlled
in mammalian cells by multiple signaling pathways that
include p38 MAP kinase [55]. A direct outcome of p38
MAP kinase signaling upon hypertonicity is NFAT5 acti-
vation [3]. This has been shown to be important in vivo,
where macrophages utilize this signaling axis to regulate
whole-body sodium storage [73]. Downstream of this,
SGK1 is a direct target of NFAT5 [14]. Thus, under
Th17-polarizing conditions, blockade, or genetic knock-
down of either p38 MAP kinase, NFAT5 or SGK1
prevented Na+-mediated Th17 induction, thus identifying
the molecular mechanism by which excess salt enhances
Th17 differentiation [33]. Importantly, a high salt diet was
shown to accelerate the pathogenesis of experimental au-
toimmune encephalomyelitis (EAE), a mouse model of
multiple sclerosis, demonstrating an increased induction
of Th17 cells in vivo [33, 75]. Heightened EAE induction
was dependent on SGK1 expression, since the specific
deletion of SGK1 in CD4+ expressing cells prevented the
high-salt-induced effect [75].
Conclusion
Altogether, these recent studies demonstrated that SGK1
could play an important role in promoting the differentiation
of Th17 cells in vitro and in vivo [49]. Under elevated salt
concentrations, Na+-mediated hypertonicity accelerates a
SGK1 dependent signaling cascade, leading to an increased
induction of pro-inflammatory Th17 cells. Excess dietary salt
intake might therefore represent an environmental risk factor
for the development (or exacerbation) of autoimmune diseases
via the induction of pathogenic Th17 cells. Interestingly, a
recent observational study by Farez et al. reported that patients
with relapsing-remitting multiple sclerosis who consume high
Pflugers Arch - Eur J Physiol (2015) 467:543–550
levels of sodium have an increased risk of disease exacerba-
tion and clinical and radiological disease activity [25]. As
Th17 cells also contribute to the development of hypertension
and cardiovascular diseases, we thus speculate that the mech-
anisms related to heightened CNS autoimmunity may also be
applicable to these diseases.
Upon stimulation with Th17 polarizing conditions, p38
MAP kinase (p38) is phosphorylated, followed by an induc-
tion of NFAT5 and SGK1 (1). SGK1 itself then induces the
phosphorylation of FOXO1. Normally, FOXO1 acts as a
repressor of the IL-23 receptor (IL-23r) by directly binding
to the IL-23r promoter and inhibiting RORγt-mediated IL-23r
transactivation. Phosphorylation of FOXO1 leads to its deac-
tivation, resulting in its export from the nucleus to the cyto-
plasm (2), thereby promoting unopposed RORγt (3) mediated
IL-23r transcription (4). In summary, Th17 polarizing condi-
tions in combination with Na+-mediated hypertonicity accel-
erates this SGK1-dependent signaling cascade, leading to an
increased induction of pro-inflammatory Th17 cells.
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