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.

Keywords: Crohn’s disease; chemosensing; colorectal neoplasia; inflammation; inflammatory bowel disease; intestine; tuft cells; ulcerative colitis.

Figure 1

Tuft cell (TC) anatomy. Illustration of a TC located in the intestinal epithelium with its long apical microvilli (the “tuft”) extending into the gut lumen. Within the cell these microvilli associate with microtubules and microfilaments that extend towards the nucleus connecting to the perinuclear rough endoplasmic reticulum and Golgi apparatus. Intermediate filaments, such as cytokeratin-18 (CK18) and neurofilaments, contribute to the cytoskeletal make-up. At the nucleus level, cytoplasmic (or lateral interdigitating) spinules extend from the lateral TC border reaching the nuclei of neighboring cells. The basal part of TCs contains vesicles, unlike the neuropod-like protrusions extending towards the basal membrane.

Figure 2

Tuft cell (TC) signaling. Illustration of TC signaling including input, output, and second messengers. Apical signaling involves luminal G-protein coupled receptors including succinate receptor 1 (SUCNR1), taste receptors (Tas1R/Tas2R), and receptor tyrosine kinases (RTK). Cell depolarization and IP3/DAG activity leads to increased intracellular calcium levels stimulating intracellular synthesis of effector molecules such as interleukin (IL)-25, acethylcholine (ACh), and eicosanoids. Activated arachidonic acid (AAA) is metabolized by cyclooxygenase enzyme (COX)-1/2, hematopoietic prostaglandin D synthase (hPGDS), and arachidonate 5-lipoxygenase (ALOX5) into prostaglandin E₂ (PGE₂), prostaglandin D₂ (PGD₂), and cysteinyl leukotriene C₄ (LTC₄), respectively. Basolateral secretion of IL-25 and ACh occurs through yet unknown mechanisms, whereas secretion of PGE₂ and PGD₂ is facilitated through the prostaglandin transporter (PGT), and LTC₄ possibly through the multidrug resistance protein 1 (MRP1). Basolateral signaling involves GABAA (ligand-gated chloride channel) and GABAB (G-protein coupled) receptors. Stimulation initiates cell repolarization mediated by GABA receptors.

Figure 3

Cyclooxygenase 1 (COX-1) positive tuft cells (TC) of the human colon. Illustration of colonic TCs from healthy human sigmoid biopsies (controls). Orange arrows indicate TCs, while white arrows indicate what could be interpreted as subepithelial/pericryptal fibroblasts. Adapted from “Possible predisposition for colorectal carcinogenesis due to altered gene expressions in normal appearing mucosa from patients with colorectal neoplasia” by Petersen et al. (126).

Figure 4

Tuft cells (TC) as potential therapeutic targets. Illustration of hypothetical beneficial effects on mucosal integrity when stimulating TCs. Left and right side show intestinal mucosa before and after TC stimulation, respectively. Upon stimulation, TCs increase secretion of interleukin (IL)-25 and cysteinyl leukotriene C₄ (LTC₄) which in turn stimulate lamina propria immune cells such as, type 2 innate lymphoid cells (ILC2), natural killer T cells and nuocytes to produce and release type 2 inflammatory cytokines (e.g. IL-4, IL-5 and IL-13). This initiates differentiation of T helper type 2 cells (T_h2), recruitment of eosinophils and stimulation of intestinal stem cells leading to tuft cells and goblet cell differentiation and hyperplasia.