Store-operated calcium entry controls innate and adaptive immune cell function in inflammatory bowel disease.

Inflammatory bowel disease (IBD) is characterized by dysregulated intestinal immune responses. Using mass cytometry (CyTOF) to analyze the immune cell composition in the lamina propria (LP) of patients with ulcerative colitis (UC) and Crohn's disease (CD), we observed an enrichment of CD4+ effector T cells producing IL-17A and TNF, CD8+ T cells producing IFNγ, T regulatory (Treg) cells, and innate lymphoid cells (ILC). The function of these immune cells is regulated by store-operated Ca2+ entry (SOCE), which results from the opening of Ca2+ release-activated Ca2+ (CRAC) channels formed by ORAI and STIM proteins. We observed that the pharmacologic inhibition of SOCE attenuated the production of proinflammatory cytokines including IL-2, IL-4, IL-6, IL-17A, TNF, and IFNγ by human colonic T cells and ILCs, reduced the production of IL-6 by B cells and the production of IFNγ by myeloid cells, but had no effect on the viability, differentiation, and function of intestinal epithelial cells. T cell-specific deletion of CRAC channel genes in mice showed that Orai1, Stim1, and Stim2-deficient T cells have quantitatively distinct defects in SOCE, which correlate with gradually more pronounced impairment of cytokine production by Th1 and Th17 cells and the severity of IBD. Moreover, the pharmacologic inhibition of SOCE with a selective CRAC channel inhibitor attenuated IBD severity and colitogenic T cell function in mice. Our data indicate that SOCE inhibition may be a suitable new approach for the treatment of IBD.

Histone Deacetylases in the Inflamed Intestinal Epithelium-Promises of New Therapeutic Strategies.

The intestinal epithelium is a complex, dynamic barrier that separates luminal contents from the immune compartment while mediating nutrient absorption and controlled passage of antigens to convey oral tolerance. A compromised epithelial barrier often leads to inflammation because immune cells in the lamina propria come into direct contact with luminal antigens. Defects in epithelial cell function were also shown to be involved in the etiology of inflammatory bowel diseases. These are severe, chronically relapsing inflammatory conditions of the gastrointestinal tract that also increase the risk of developing colorectal cancer. Despite major efforts of the scientific community, the precise causes and drivers of these conditions still remain largely obscured impeding the development of a permanent cure. Current therapeutic approaches mostly focus on alleviating symptoms by targeting immune cell signaling. The protein family of histone deacetylases (HDACs) has gained increasing attention over the last years, as HDAC inhibitors were shown to be potent tumor cell suppressors and also alleviate morbid inflammatory responses. Recent research continuously identifies new roles for specific HDACs suggesting that HDACs influence the cell signaling network from many different angles. This makes HDACs very interesting targets for therapeutic approaches but predicting effects after system manipulations can be difficult. In this review, we want to provide a comprehensive overview of current knowledge about the individual roles of HDACs in the intestinal epithelium to evaluate their therapeutic potential for inflammatory conditions of the gut.

HDAC inhibitors promote intestinal epithelial regeneration via autocrine TGFß1 signalling in inflammation.

Intact epithelial barrier function is pivotal for maintaining intestinal homeostasis. Current therapeutic developments aim at restoring the epithelial barrier in inflammatory bowel disease. Histone deacetylase (HDAC) inhibitors are known to modulate immune responses and to ameliorate experimental colitis. However, their direct impact on epithelial barrier function and intestinal wound healing is unknown. In human and murine colonic epithelial cell lines, the presence of the HDAC inhibitors Givinostat and Vorinostat not only improved transepithelial electrical resistance under inflammatory conditions but also attenuated the passage of macromolecules across the epithelial monolayer. Givinostat treatment mediated an accelerated wound closure in scratch assays. In vivo, Givinostat treatment resulted in improved barrier recovery and epithelial wound healing in dextran sodium sulphate-stressed mice. Mechanistically, these regenerative effects could be linked to an increased secretion of transforming growth factor beta1 and interleukin 8, paralleled by differential expression of the tight junction proteins claudin-1, claudin-2 and occludin. Our data reveal a novel tissue regenerative property of the pan-HDAC inhibitors Givinostat and Vorinostat in intestinal inflammation, which may have beneficial implications by repurposing HDAC inhibitors for therapeutic strategies for inflammatory bowel disease.