three-dimensional-cell-culture-models-to-investigate-epithelial

Three-Dimensional Cell Culture Models to Investigate the Epithelial Barrier in Eosinophilic Esophagitis

The squamous epithelium of the esophagus is directly exposed to the environment, continuously facing foreign antigens, including food antigens and ...

University of Basel

Autoimmune/inflammatory intestinal diseases, such as Crohn's disease and ulcerative colitis, infectious gastrointestinal diseases, and gastrointestinal cancers, such as colorectal cancer, are worldwide a significant health problem. Intercellular communication and direct contact with the environment as the microbiota colonizes the gastrointestinal surface facilitates these diseases. Cytokines mediate the intercellular communication to maintain the equilibrium between host and environment and to regulate immune responses. One cytokine family that exchange information between immune cells and epithelial cells is the IL-20 cytokine family which includes the cytokines IL-19, IL-20, IL-22, IL-24, and IL-26. These cytokines share common receptor subunits and signaling pathways. IL-22 is the most intensively studied cytokine within this family in contexts of gastrointestinal disease, but the importance of other family members is more and more appreciated. In this review, the potential function of IL-20 cytokines concerning gastrointestinal conditions is discussed.

The Interleukin-20 Cytokines in Intestinal Diseases.

Single-nucleotide polymorphisms in the gene encoding G protein-coupled receptor 35 (GPR35) are associated with increased risk of inflammatory bowel disease. However, the mechanisms by which GPR35 modulates intestinal immune homeostasis remain undefined. Here, integrating zebrafish and mouse experimental models, we demonstrate that intestinal Gpr35 expression is microbiota dependent and enhanced upon inflammation. Moreover, murine GPR35 colonic macrophages are characterized by enhanced production of pro-inflammatory cytokines. We identify lysophosphatidic acid (LPA) as a potential endogenous ligand produced during intestinal inflammation, acting through GPR35 to induce tumor necrosis factor (Tnf) expression in macrophages. Mice lacking Gpr35 in CX3CR1 macrophages aggravate colitis when exposed to dextran sodium sulfate, which is associated with decreased transcript levels of the corticosterone-generating gene Cyp11b1 and macrophage-derived Tnf. Administration of TNF in these mice restores Cyp11b1 expression and intestinal corticosterone production and ameliorates DSS-induced colitis. Our findings indicate that LPA signals through GPR35 in CX3CR1 macrophages to maintain TNF-mediated intestinal homeostasis.

Lysophosphatidic Acid-Mediated GPR35 Signaling in CX3CR1 Macrophages Regulates Intestinal Homeostasis.

The gastrointestinal tract is the largest compartment of the body's immune system exposed to microorganisms, structural components and metabolites, antigens derived from the diet, and pathogens. Most studies have focused on immune responses in the stomach, the small intestine, and the colon, but the esophagus has remained an understudied anatomic immune segment. Here, we discuss the esophagus' anatomical and physiological distinctions that may account for inflammatory esophageal diseases.

Immune system and microbiome in the esophagus: implications for understanding inflammatory diseases.

Goblet cells secrete mucin to create a protective mucus layer against invasive bacterial infection and are therefore essential for maintaining intestinal health. However, the molecular pathways that regulate goblet cell function remain largely unknown. Although GPR35 is highly expressed in colonic epithelial cells, its importance in promoting the epithelial barrier is unclear. In this study, we show that epithelial Gpr35 plays a critical role in goblet cell function. In mice, cell-type-specific deletion of Gpr35 in epithelial cells but not in macrophages results in goblet cell depletion and dysbiosis, rendering these animals more susceptible to Citrobacter rodentium infection. Mechanistically, scRNA-seq analysis indicates that signaling of epithelial Gpr35 is essential to maintain normal pyroptosis levels in goblet cells. Our work shows that the epithelial presence of Gpr35 is a critical element for the function of goblet cell-mediated symbiosis between host and microbiota.

Epithelial GPR35 protects from Citrobacter rodentium infection by preserving goblet cells and mucosal barrier integrity.

Disruption of the epithelial barrier plays an essential role in developing eosinophilic oesophagitis (EoE), a disease defined by type 2 helper T cell (Th2)-mediated food-associated and aeroallergen-associated chronic inflammation. Although an increased expression of interleukin (IL)-20 subfamily members, IL-19, IL-20 and IL-24, in Th2-mediated diseases has been reported, their function in EoE remains unknown.

Article	Year
The Interleukin-20 Cytokines in Intestinal Diseases. Frontiers in immunology\| PubMed ID: 29967613	2018
Lysophosphatidic Acid-Mediated GPR35 Signaling in CX3CR1 Macrophages Regulates Intestinal Homeostasis. Cell reports\| PubMed ID: 32755573	2020
Immune system and microbiome in the esophagus: implications for understanding inflammatory diseases. The FEBS journal\| PubMed ID: 34213831	2022
Epithelial GPR35 protects from Citrobacter rodentium infection by preserving goblet cells and mucosal barrier integrity. Mucosal immunology\| PubMed ID: 35264769	2022
IL-20 subfamily cytokines impair the oesophageal epithelial barrier by diminishing filaggrin in eosinophilic oesophagitis. Gut\| PubMed ID: 35613844	2023

Tanay Kaymak

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