Store-Operated Calcium Entry Controls Innate and Adaptive Immune Cell Function in Inflammatory Bowel Disease

Abstract

Objective: Inflammatory bowel disease (IBD) is characterized by dysregulated intestinal immune responses and constitutes a major clinical challenge in need of new treatment modalities to improve patient care. Store-operated Ca2+ entry (SOCE) is the predominant Ca2+ influx pathway in T cells and other immune cells, regulating many of their functional properties. It is currently unknown whether the pharmacologic blockade of SOCE represents a suitable drug-target for IBD treatment. Design: Using mass and flow cytometry the effects of SOCE inhibition on lamina propria (LP) immune cells of patients with ulcerative colitis (UC) and Crohn's disease (CD) were investigated.Primary organoid cultures served to study the impact of SOCE inhibition on the function, differentiation and survival of intestinal epithelial cells (IEC). T cell transfer models of colitis were applied to examine how the genetic or pharmacologic ablation of SOCE affects the clinical course of IBD in mice. Results: We observed that the LP of IBD patients is characterized by an enrichment of innate lymphoid cells (ILC), CD4+ and CD8+ effector- as well as T regulatory cells producing IL-17 and TNFα. The pharmacologic inhibition of SOCE attenuated the production of pathogenic cytokines including IL-2, IL-4, IL-6, IL-17, TNFα and IFNγ by human colonic T cells and ILC, reduced the production of IL-6 by B cells and the production of IFNγ by myeloid cells, without affecting the viability, differentiation and function of primary IEC. T cell-specific genetic deletion of the SOCE signaling components Orai1, Stim1 or Stim2 revealed that the magnitude of SOCE correlates with the function of T cells and intestinal inflammation in mice. Moreover, the pharmacologic inhibition of SOCE alleviated the clinical course of colitic mice. Conclusion: Our data suggest that SOCE inhibition may serve as a new pharmacologic strategy for treating IBD.

Targeting CRAC channels in inflammatory bowel disease

“…Inflammatory bowel disease (IBD) is a collective term for inflammatory diseases of the human gastrointestinal (GI) tract that are characterized by perturbations in the intestinal immune responses. In their study, Letizia et al (2022) found an enrichment of CD4 + effector T cells, interferon gamma (IFNc) producing CD8 + T cells, regulatory T cells, and innate lymphoid cells (ILC) in the lamina propria (LP) of IBD patients. In these cells, pharmacological inhibition of store-operated calcium entry (SOCE) reduced cytokine production.…”

“…In their recent study, Letizia et al (2022) show that per se SOCE is required to induce colitis in a murine model. So far, characterization of immune cell composition within the LP of IBD patients has been limited.…”

“…To test whether BTP2 alters the function of intestinal epithelial cells, Letizia et al (2022) tested BTP on murine and human colonic organoids and 2D monolayers and found no impairment of viability, differentiation, and barrier function of the epithelial cells. These findings suggest that CRAC channel targeting in IBD specifically reduces inflammation without affecting healthy epithelial cells.…”

HDAC7 controls anti-viral and anti-tumor immunity by CD8+ T cells

“…We have previously demonstrated that Store-operated Calcium Entry (SOCE) mediated by stromal interaction molecule (STIM)1, STIM2 as well as ORAI proteins, regulates effector functions of cytotoxic CD8 + T cells upon TCR activation such as the production of IFNγ, TNFα as well as the degranulation of toxic vesicles 9,10 . Additionally, SOCE is required for the differentiation, maintenance and re-activation of CD8 + T mem cells during anti-viral response in lymphocytic choriomeningitis virus (LCMV) infected Stim1 fl/fl Stim2 fl/fl Cd4-Cre mice 11 .…”