The role of tryptophan metabolism and tolerogenic dendritic cells in maintaining immune tolerance: Insights into celiac disease pathogenesis

Abstract

Background: In mammals, amino acid metabolism has evolved to control immune responses. Tryptophan (Trp) is the rarest essential amino acid found in food and its metabolism has evolved to be a primary regulatory node in the control of immune responses. Celiac disease (CeD) is a developed immunological condition caused by gluten intolerance and is linked to chronic small intestine enteropathy in genetically predisposed individuals. Dendritic cells (DCs), serving as the bridge between innate and adaptive immunities, can influence immunological responses in CeD through phenotypic alterations.

Objective: This review aims to highlight the connection between Trp metabolism and tolerogenic DCs, and the significance of this interaction in the pathogenesis of CeD.

Results: It is been recognized that various DC subtypes contribute to the pathogenesis of CeD. Tolerogenic DCs, in particular, are instrumental in inducing immune tolerance, leading to T-reg differentiation that helps maintain intestinal immune tolerance against inflammatory responses in CeD patients and those with other autoimmune disorders. T-regs, a subset of T-cells, play a crucial role in maintaining intestinal immunological homeostasis by regulating the activities of other immune cells. Notably, Trp metabolism, essential for T-reg function, facilitates T-reg differentiation through microbiota-mediated degradation and the kynurenine pathway.

Conclusion: Therefore, alterations in Trp metabolism could potentially influence the immune response in CeD, affecting both the development of the disease and the persistence of symptoms despite adherence to a gluten-free diet.

Keywords: celiac disease; glutens; tolerogenic dendritic cells; tryptophan metabolite.

Figure 1

Pathophysiology of celiac disease. 1—Undigested Gliadin peptides move through paracellular and transcellular pathways and enter the intestinal submucosa. 2—In the lamina propria, tissue transglutaminase (tTG) deamidates Gliadin peptide. 3—Antigen‐presenting cells (APCs), which subsequently recognize deamidated Gliadin by their HLA‐DQ2 or HLA‐DQ8 molecules, inducing an immunological response. 4—As a result, Th1 and Th2 inflammatory pathways are activated. 5—CD8 and NK cells are stimulated by Th1 cells, and use the Fas/FasL system to induce apoptosis in the enterocytes. 6—B cells are stimulated by Th2 cells to develop into antibody‐producing plasma cells (anti‐tTG and anti‐Gliadin). Extracellular tTG and anti‐tTG interaction can result in further damage to the epithelium tissue.

Figure 2

l‐Typthophan metabolism. The metabolic pathways of tryptophan involve the generation of bioactive metabolites through either the kynurenine pathway or the serotonin pathway in host organisms. Within gut microbes, tryptophan undergoes metabolic processes leading to the formation of indole and its derivatives. 3‐HAO, 3‐hydroxyanthranilate 3,4‐dioxygenase; ACMSD, alpha‐amino‐beta‐carboxymuconate‐epsilon‐semialdehyde decarboxylase; IDO, indoleamine 2,3‐dioxygenase; KMO, kynurenine monooxygenase; KYNU, kynureninase; TDO, tryptophan 2,3‐dioxygenase, TPH1, tryptophan hydroxylase.

Figure 3

Trp metabolism and IDO. As a result of Trp metabolism, ligands of AhR are produced via KP and microbially induced breakdown that affects T‐reg development. The release of Kyn and consumption of Trp are caused by IDO activity in APCs. Immune suppression and tolerance are caused by the effects of such metabolic cues on T‐reg and effector T cells through the release of Kyn, and the consumption of Trp (via GCN2 and mTOR, as two amino acid sensors) as well. APC, antigen‐presenting cell; IDO, indoleamine 2,3‐dioxygenase; mTOR, mechanistic target of rapamycin.

Figure 4

Mechanics of T‐reg cells control the immune response. T‐reg cells use multiple mechanisms, including (I) inhibition by immunoregulatory cytokines; (II) inhibition by cytolysis of effector cells; (III) inhibition by metabolic interruption; and (IV) modulation of dendritic cell function and maturation.