Role of neutrophil extracellular traps in the pathogenesis of inflammatory bowel disease

• Grant number: 22/16903-9
• Support Opportunities: Scholarships in Brazil - Doctorate
• Start date: June 01, 2023
• End date: March 31, 2025
• Field of knowledge: Biological Sciences - Pharmacology
• Principal Investigator: Fernando de Queiroz Cunha
• Grantee: Anderson dos Santos Ramos
• Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Associated research grant: 13/08216-2 - CRID - Center for Research in Inflammatory Diseases, AP.CEPID

Abstract

Inflammatory bowel diseases (IBD), including Crohn's disease (CD) and ulcerative colitis (UC), are chronic and complex inflammatory diseases that affect the gastrointestinal tract. They are characterized by chronic remitting intestinal inflammation. The pathogenesis of IBD is related to the patient's genetic susceptibility, dysregulated immune response, impairment of the epithelial barrier and environmental factors. The dysregulated immune response occurs, partially, in response to the marked translocation of luminal antigens to the lamina propria of the intestine, activated in the exacerbated activation of inflammatory pathways. Among the various immune cells implicated in IBD, neutrophils are the first to infiltrate and there is evidence that they can compromise the epithelial barrier, tissue destruction by various mechanisms, including oxidative and enzymatic damage, and the perpetuation of inflammation by the release of inflammatory cytokines and chemokines. In addition to basic effector mechanisms such as phagocytosis and chemotaxis, neutrophils can also release extracellular traps (NETs), which are made up of a mesh-like structure - which contains chromatin (DNA+histones) associated with enzymes such as MPO and NE. Recent evidence has demonstrated the presence of NETs in intestinal samples from patients with UC and CD. In murine models, including DSS and TNBS-induced colitis, which mimic the histological and immunological findings of UC and CD, respectively, NETs are present in colonic homogenate samples. However, the mechanisms by which NETs may contribute to disease progression have not been investigated, providing an opportunity to better understand the pathogenesis of IBD. Thus, this project will seek to investigate whether NETs have a dual effect on the pathogenesis of IBD, that is, on the one hand, due to their microbicidal role, they have a protective role, due to microbial translocation from the intestinal lumen to the submucosa. And on the other hand, if they have a deleterious effect, due to their cytotoxic and inflammatory role, directly participating in tissue lesions and/or in the genesis of the deregulated immune response. It also intends to determine the mechanisms involved in the release of NETs during IBD. Initially, we will seek to understand the kinetics of NETs production in the DSS-induced acute colitis model to better understand the appropriate time for intervention with anti-NET pharmacological therapy (GSK-484 and/or Pulmozyme). We will investigate whether the gasdermin D protein regulates the release of NETs in acute colitis. We will seek to understand the impact of NETs depletion on bacterial translocation and on the activity of gamma delta, Th1 and Th17 lymphocytes. In addition, this project will also seek to understand the role of NETs in the clinical remission phase of the disease, in an attempt to understand whether the repair phase is delayed by NETs. Finally, we will determine the involvement of NETs in intestinal fibrosis using a chronic colitis model. Thus, this project will provide a set of evidence for a better understanding of the pathogenesis of IBD, which will be of paramount importance for identifying new targets for therapy.