Innate Lymphoid Cells as Regulators of Epithelial Integrity: Therapeutic Implications for Inflammatory Bowel Diseases

Abstract

The occurrence of epithelial defects in the gut relevantly contributes to the pathogenesis of inflammatory bowel diseases (IBD), whereby the impairment of intestinal epithelial barrier integrity seems to represent a primary trigger as well as a disease amplifying consequence of the chronic inflammatory process. Besides epithelial cell intrinsic factors, accumulated and overwhelmingly activated immune cells and their secretome have been identified as critical modulators of the pathologically altered intestinal epithelial cell (IEC) function in IBD. In this context, over the last 10 years increasing levels of attention have been paid to the group of innate lymphoid cells (ILCs). This is in particular due to a preferential location of these rather newly described innate immune cells in close proximity to mucosal barriers, their profound capacity to secrete effector cytokines and their numerical and functional alteration under chronic inflammatory conditions. Aiming on a comprehensive and updated summary of our current understanding of the bidirectional mucosal crosstalk between ILCs and IECs, this review article will in particular focus on the potential capacity of gut infiltrating type-1, type-2, and type-3 helper ILCs (ILC1s, ILC2s, and ILC3s, respectively) to impact on the survival, differentiation, and barrier function of IECs. Based on data acquired in IBD patients or in experimental models of colitis, we will discuss whether the different ILC subgroups could serve as potential therapeutic targets for maintenance of epithelial integrity and/or mucosal healing in IBD.

The Inflammatory Bowel Disease Transcriptome and Metatranscriptome Meta-Analysis (IBD TaMMA) framework

“…These results are well in line with most of the studies reporting these molecules as biomarkers of inflammation in patients with IBD 10 . Additionally, epithelium-and pro-angiogenicrelated biological processes, known to be altered during gut chronic inflammatory disorders [11][12][13][14] , were also found to be dysregulated in both UC and CD colon versus control colon, as well as in CD ileum versus control ileum (Supplementary Fig. 1d and 'Old evidence from the literature' tab at IBD TaMMA).…”

Epithelial Barrier: Protector and Trigger of Allergic Disorders

“…The role of type 1 and 2 ILCs (ILC1s and ILC2s, respectively) in the healthy gut is to date unclear. On the contrary, both subtypes are key cells to preserve epithelial barrier under pathogenic conditions [46,47].…”

Role of Goblet Cells in Intestinal Barrier and Mucosal Immunity

“…Type 3 Innate Lymphoid Cells (ILC3s) promotes goblet cell differentiation and the expression of MUC2 through the lymphotoxin (LT)-LTβR pathway during intestinal listeria infection. 10 , 97 DCs such as macrophages and dendritic cells provide processed, phagocytosed antigens for activating and instructing naïve CD4+ T cells to convert to type 2 helper (Th2) cells. 98 , 99 These cells are essential for the immune response against extracellular parasites and intracellular pathogens, resulting in the increased secretion of cytokines like IL-13, IL-9, IL-5, and IL-4.…”