Impact of the interaction between macrophages and intestinal epithelial cells on the development of intestinal inflammation

• Grant number: 24/09768-3
• Support Opportunities: Scholarships in Brazil - Doctorate
• Start date: May 01, 2025
• End date: June 30, 2028
• Field of knowledge: Biological Sciences - Immunology - Cellular Immunology
• Principal Investigator: Vinicius de Andrade Oliveira
• Grantee: Laura de Quadros Pereira
• Host Institution: Centro de Ciências Naturais e Humanas (CCNH). Universidade Federal do ABC (UFABC). Santo André , SP, Brazil
• Associated research grant: 19/14755-0 - Shaping gut microbiota and immune system by the intestinal epithelial cells: from tissue homeostasis to diseases, AP.JP

Abstract

Ulcerative colitis (UC) is currently the most common type of inflammatory bowel disease (IBD), with a prevalence of 5 million cases worldwide. Characterized by a dysregulated immune response, microbiota imbalance and damage to the intestinal epithelium, UC affects the colon and rectum. Macrophages are crucial for orchestrating immune responses in the intestinal epithelium and ensure intestinal homeostasis. In UC, it is known that macrophages have a profile like the M1 phenotype, being considered more inflammatory. Enteroendocrine cells (EECs) are glandular epithelial cells specialized in transepithelial signal transduction and respond to luminal nutrients through the secretion of peptide hormones. Among the hormones released by EECs, GIP (Gastric inhibitory polypeptide) and GLP-1 (Glucagon-like polypeptide 1) stands out, recognized as incretins due to their insulinotropic capacity. Sitagliptin is a drug that inhibits dipeptidyl peptidase-4 (DPP-4), the enzyme responsible for the cleavage of incretins, increasing their bioavailability. In addition to the pharmaceutical importance, evidence demonstrates anti-inflammatory effects of sitagliptin in in vitro and in vivo treatment in different inflammatory contexts. In previous work, we demonstrated that treatment with sitagliptin in vitro was capable of exacerbating the polarization of the M2 phenotype, however, the mechanisms by which it exerts these effects are not yet completely elucidated, including the influence and action on macrophages in in vivo models. In this sense, PPAR³ (peroxisome proliferator-activated receptor gamma) appears to play an important role in polarizing macrophages towards an M2 profile, and thus contributing to an anti-inflammatory profile, emerging as a possible mechanism by which sitagliptin could be acting on these cells. In view of the above, it is of great biological relevance to investigate the effects of sitagliptin in vivo in an experimental colitis model, elucidating the impact that the treatment has on intestinal macrophages and the modulation of the immune response, paving the way for the development of new therapeutic approaches. for inflammatory conditions like UC.