Inflammatory bowel disease (IBD) is characterized by chronic inflammation of the gastrointestinal
system and its incidence is rising worldwide.
1
Current concepts of the pathogenesis of IBD suggests that IBD is predominantly triggered
by environmental factors in genetically susceptible individuals, ultimately resulting
in impaired immune cell homeostasis and deterred intestinal epithelial barrier functions
by enterocytes and goblets cells.2, 3, 4 Current treatment of IBD consists of tumor
necrosis factor blockers, integrin inhibitors, JAK-inhibitors, and interleukin 12/23
blocking antibodies, which predominantly inhibit immune cell activation and function.
5
In contrast, no treatment is currently available that would effectively improve epithelial
barrier functions in intestinal inflammation by targeting epithelium intrinsic pathways.
As a large proportion of patients with IBD does not sufficiently respond to available
biologics, new treatment concepts are urgently required. To date, the molecular pathways
regulating the differentiation, function, and survival of enterocytes and goblet cells
are incompletely understood and deeper insights into mechanisms controlling apoptosis
in intestinal epithelial cells (IEC) during chronic inflammation are lacking. In this
issue of Cellular and Molecular Gastroenterology and Hepatology, Liang et al
4
provide evidence that the stromal interaction molecule (STIM), which controls Store-operated
Ca2+ entry (SOCE), may be a pertinent molecule to target in epithelial cells.
SOCE, mediated by calcium release activated channels (CRAC) and STIM proteins, represents
the predominant Ca2+ influx pathway in lymphocytes but can also be observed in a large
variety of other cells including enterocytes and goblet cells.
4
,
6
,
7
Activation of SOCE can be detected on agonist stimulation of various surface receptors
on the plasma membrane of cells, such as the T cell receptor on T cells
7
or the acetylcholine receptor on neural cells
8
inducing a phospholipase C–dependent production of inositol 1,4,5-trisphosphate (IP3).
Subsequently, IP3 binds to and opens the IP3 receptors located on the membrane of
the endoplasmic reticulum (ER), resulting in a transient release of Ca2+ from the
ER into the cytoplasm.
9
The consecutive decrease in ER Ca2+ concentrations is sensed by N-terminal EF-hand
motifs of ER-based STIM1 and STIM2 proteins,
10
inducing their oligomerization and translocation to the plasma membrane, where they
bind to ORAI1-CRAC channels resulting in sustained influx of extracellular Ca2+ into
the cytoplasm.
11
SOCE not only controls the activation of transcription factors, such as NFAT, but
also regulates multiple cellular functions including mitochondrial activation, apoptosis,
and trafficking of cellular vesicles.
6
,
7
The importance of SOCE is highlighted by patients with loss-of-function mutations
in STIM1 or ORAI1, who suffer from immunodeficiency, muscular hypotonia, and impaired
enamel formation.12, 13, 14
Liang et al
4
now identify the SOCE-signaling component STIM1 as an important modulator of intestinal
epithelial barrier functions during intestinal inflammation. Thus, the authors showed
that STIM1 expression is increased in IEC of inflamed tissues from patients with IBD.
The authors next developed mice with a conditional genetic deletion of Stim1 in IEC
to investigate the impact of decreased SOCE-activity on IEC function. Remarkably,
the deletion of STIM1 in IEC had no impact on epithelial differentiation and gut homeostasis
at steady state.
4
In contrast, on induction of acute or chronic dextran sulfate sodium colitis, Stim1
ΔIEC
mice displayed reduced disease severity, decreased inflammation, and improved epithelial
regeneration. This effect could be traced back to reduced loss of goblet cells during
the inflammatory phase of dextran sulfate sodium colitis and, subsequently, to faster
epithelial reconstitution. Remarkably, increased protection of the epithelial barrier
in STIM1-deficient mice under inflammatory conditions was paralleled by an increased
expression of tight junction proteins. Furthermore, Liang et al
4
observed an augmented survival of goblet cells in the acute phase of dextran sulfate
sodium, caused by decreased levels of intracellular Ca2+ and reduced ER stress, leading
to an increased production of mucin by goblet cells and an enhanced thickness of the
intestinal mucus layer, ultimately reducing the translocation of commensal bacteria
in Stim1
ΔIEC
mice.
Because Liang et al
4
detected increased expression of STIM1 in IEC and in lamina propria mononuclear cells
in inflamed tissue of patients with IBD, one may anticipate a beneficial dual effect
of the pharmacologic blockade of SOCE in IBD. On the one hand, blocking SOCE might
decrease the decay of goblet cells by reducing ER stress under inflammatory conditions,
stabilize the inner mucus layer, and prevent bacterial translocation.
4
On the other hand, inhibition of SOCE might suppress effector functions of proinflammatory
lymphocytes in IBD. Thus, STIM1-deficient T cells display impaired production of interleukin-17,
tumor necrosis factor-α, and interferon-γ and fail to induce colitis in mice.
15
In regard of ongoing clinical trials testing the SOCE-inhibitor Auxora in the treatment
of overwhelming immunity in COVID-19 and its promising safety profiles,
16
the application of SOCE-inhibitors might represent a new concept for treating IBD.