Store-operated Calcium Entry (SOCE) controls immune cell function and activation in inflammatory bowel disease

Ulcerative colitis (UC) and Crohn’s disease (CD) are two forms of chronic inflammatory bowel disease (IBD) representing major clinical challenges in need of new treatment modalities to improve patient care. Store-operated calcium entry (SOCE) is the predominant calcium influx pathway in immune cells regulating many of their functional properties. However, it is currently unknown whether the pharmacologic inhibition of SOCE is a suitable drug target in IBD.

Using murine T cell transfer models of colitis, in which the SOCE signaling components STIM1, STIM2 or ORAI1 were conditionally deleted, we observed that pro-inflammatory T cells depend on high levels of SOCE-activity to induce colitis in mice, whereas regulatory T cells require a lower threshold of SOCE signaling strength for their differentiation and function. By applying mass cytometry, we furthermore investigated how a gradual pharmacologic inhibition of SOCE affects the activation and pro-inflammatory functions of various immune cell subsets obtained from colon resectates of patients with UC and CD, which were characterized by the accumulation of CD4+ effector T cells, IFNγ-producing CD8+ T cells and IL-17-producing innate lymphoid cells (ILCs) compared to non-inflamed resectates. Remarkably, inhibition of SOCE attenuated the production of pathogenic cytokines including IL-2, IL-4, IL-6, IL-17, TNF-α and IFNγ byT cells and ILCs, reduced the activation of B cells and decreased the production of IL-6 by myeloid cells and B cells without affecting the viability, differentiation and barrier-function of primary human epithelial cells.

Taken together our data suggest, that inhibition of SOCE might serve as a new drug target in IBD arguing in favor of a therapeutic window, in which pro-inflammatory cells can be suppressed by SOCE-blockade while the development and function of anti-inflammatory Treg cells are preserved.

Publication History

Article published online:
07 September 2021