Role of the HIF1¿/AhR axis in regulatory T cells mitochondrial dynamics during Inflammatory Bowel Disease using an autologous organoid co-culture model.

• Grant number: 24/21710-0
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date: December 01, 2024
• End date: November 30, 2026
• Field of knowledge: Biological Sciences - Immunology - Cellular Immunology
• Principal Investigator: Niels Olsen Saraiva Câmara
• Grantee: Marcella Cipelli
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated research grant: 23/07482-2 - Sensing extra and intracellular stressors by renal and immune cells: new insights into signal reception and transduction, and their relevance for understanding renal diseases, AP.TEM

Abstract

Inflammatory Bowel Disease (IBD), which includes Crohn's Disease (CD) and Ulcerative Colitis (UC), is characterized by chronic intestinal inflammation resulting from complex interactions between genetic, environmental, microbial, and immune factors. In addition to affecting the gastrointestinal tract, IBD can involve other organs, with up to 50% of patients exhibiting extra-intestinal manifestations, such as chronic kidney disease (CKD), which may affect 5-15% of patients. The pathological mechanisms of IBD are related to microbial dysbiosis and impaired integrity of the intestinal barrier. In UC, tissue disruption activates antigen-presenting cells (APCs), which induce differentiation of CD4+ T cells into pathogenic subtypes (Th2, Th9, Th17) or regulatory T cells (Tregs). In CD, the activation of Th1 and Th17 cells is mediated by cytokines such as IL-12, IL-6, IL-23, TNF¿, and members of the IL-1 family. In IBD patients, there is an increase in CD4+ IL-17+Foxp3+ cells, a distinct population of "inflammatory" Tregs, which, despite suppressing the proliferation of effector T cells (Teff) and cytokine production, have insufficient suppression to prevent disease progression. The presence of these cells is elevated compared to healthy individuals, but their suppressive function in vitro is reduced. In healthy individuals, Tregs play a crucial role in intestinal homeostasis, contributing to tissue repair, epithelial cell differentiation, and microbiota regulation. Thus, the paradox of increased Tregs in inflammatory tissues along with ongoing inflammation remains a focus of research to understand their role in the pathogenesis of IBD and potential therapeutic approaches. Furthermore, immune cells utilize various mechanisms to respond to environmental and metabolic signals. Recent studies have highlighted the roles of two related proteins: the aryl hydrocarbon receptor (AhR) and hypoxia-inducible factor 1¿ (HIF1¿). AhR, activated by ligands found in diet, pollution, and microorganisms, influences Treg differentiation. HIF1¿, active under low oxygen conditions, regulates cellular responses to hypoxia and metabolism. Both factors influence Tregs and promote Th17 differentiation, stimulating IL-17 and IL-22 production. HIF1¿ also induces glycolysis and the expression of ROR¿t, a characteristic of Th17 cells. Studies show that AhR plays an important role in maintaining mitochondrial homeostasis in response to stress induced by TCDD, with AhR translocating to the cell nucleus and also localizing in mitochondria. HIF1¿ positively regulates DRP-1, facilitating mitochondrial fragmentation. Mitochondrial dysfunction and oxidative stress are recognized as features of IBD, being considered factors that affect the redox balance of the intestinal mucosa, the integrity of the intestinal barrier, and the immune system. Therapeutic approaches targeting mitochondrial function, especially in IL-17+ Tregs in intestinal epithelial cells, emerge as a promising strategy with potentially significant benefits.