Targeting SOCE in Intestinal Epithelial Cells: A New Treatment Concept for Inflammatory Bowel Disease?

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 al⁴ 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 cells⁷ or the acetylcholine receptor on neural cells⁸ 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 al⁴ 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 al⁴ 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 al⁴ 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.