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.

Keywords: ILC plasticity; colitis; cytokines; inflammatory bowel diseases; innate lymphoid cells; intestinal epithelium.

Figure 1

Distribution of murine and human ILCs along the intestine in steady-state and IBD patients. Heatmap summarizing the distribution of the classical helper ILC subsets in the lamina propria of the small and large intestine in both mice and humans. The frequency of ILCs is color-coded with the light green color indicating low frequencies and the dark green color representing high ILC percentages. Changes in local ILC frequencies in patients with ulcerative colitis (UC) and Crohn's disease (CD) are indicated by blue and orange arrows, respectively.

Figure 2

ILC-driven regulation of IECs in intestinal inflammation. Schematic depiction of the intestinal epithelium, consisting of goblet cells, tuft cells, enteroendocrine cells, and M cells dispersed throughout the enterocytes as well as transit-amplifying progenitor cells, paneth cells, and stem cells localized toward the crypt bottom. ILC1s, ILC2s, and ILC3s reside in the mucosa in close proximity to the epithelium or can be directly positioned in between IECs as intraepithelial ILCs, giving them prime positions to interact with IECs. While IECs are important activators of ILCs via the release of selective alarmins, ILCs can in return control the different IEC subtypes via the release of effector cytokines. With the secretion of IL-22 and lymphotoxin, ILC3s can drive stem and progenitor cell proliferation and differentiation. ILC3s can additionally drive mucus production by goblet cells and promote fucosylation of enterocytes. The effect of ILC3-derived IL-22, however, is largely dependent on the microenvironment. ILC2-driven IEC regulation is mainly based on their ability to release IL-13 and AREG, which can trigger stem and progenitor cells, goblet cells as well as robust tight junctions interconnecting enterocytes. Moreover, ILC1-derived TGF-β1, although not a classical type-1 cytokine, can drive stem cell proliferation and differentiation, while IFN-γ secreting ILC1s can weaken the epithelial stability.