Tuft Cells and Their Role in Intestinal Diseases

Abstract

The interests in intestinal epithelial tuft cells, their basic physiology, involvement in immune responses and relevance for gut diseases, have increased dramatically over the last fifteen years. A key discovery in 2016 of their close connection to helminthic and protozoan infection has further spurred the exploration of these rare chemosensory epithelial cells. Although very sparse in number, tuft cells are now known as important sentinels in the gastrointestinal tract as they monitor intestinal content using succinate as well as sweet and bitter taste receptors. Upon stimulation, tuft cells secrete a broad palette of effector molecules, including interleukin-25, prostaglandin E2 and D2, cysteinyl leukotriene C4, acetylcholine, thymic stromal lymphopoietin, and β-endorphins, some of which with immunomodulatory functions. Tuft cells have proven indispensable in anti-helminthic and anti-protozoan immunity. Most studies on tuft cells are based on murine experiments using double cortin-like kinase 1 (DCLK1) as a marker, while human intestinal tuft cells can be identified by their expression of the cyclooxygenase-1 enzyme. So far, only few studies have examined tuft cells in humans and their relation to gut disease. Here, we present an updated view on intestinal epithelial tuft cells, their physiology, immunological hub function, and their involvement in human disease. We close with a discussion on how tuft cells may have potential therapeutic value in a clinical context.

BMP signaling in the intestinal epithelium drives a critical feedback loop to restrain IL-13–driven tuft cell hyperplasia

“…Specifically, we find that key cytokines associated with different modes of immunity influence developmental pathways to guide changes in epithelial composition. In recent years, tuft cells have been identified as regulators of intestinal health in general (9), and have taken center stage in the defense against helminth infections specifically (29). They express receptors that help them detect helminths, which together with type 2 cytokines result in their expansion (30,31).…”

“…Of note, tuft cells are not only important in immunity to helminth infections; activation of tuft cells by succinate is protective in a murine model of colitis, and reduced tuft cell numbers are found in patients with Crohn’s disease that have more severe inflammation ( 8 ). Thus, tuft cells have been gaining interest as important regulators of intestinal diseases ( 9 ), and the discovery of regulatory mechanisms used by tuft cells could have clinical ramifications.…”

Sirtuin 6 maintains epithelial STAT6 activity to support intestinal tuft cell development and type 2 immunity

“…So, the decreased intestinal tuft cell frequency we observed in naive IEC-KO mice or vehicle-treated IEC-KO organoids is unlikely caused by the changes in STAT6 activity. POU2F3 is a master regulator and an absolute requisite for tuft cell differentiation from epithelial crypt progenitor cells 44 . Pou2f3 -/- mice completely lack intestinal tuft cells and have defective mucosal type 2 immune responses to helminth infection 13 .…”

The potential roles of interleukin-25 in infectious diseases

“…The infection induced by a protozoan parasite can reduce IL-25 expression while the administration of rIL-25 protein can help control amebiasis in mice (63). Similar to the helminth infection, IL-25 recruits ILC2, which mediates the clearance of protozoan parasites (64). In addition, IL-25 was downregulated in mice infected with Plasmodium berghei (P. berghei), and the incidence of parasitemia in the Il-25 depleted mice were higher than that in the wild-type mice (65).…”