Analysis of the role of the FFAR2 receptor in neutrophil functionality and myelopoiesis

• Grant number: 21/09155-3
• Support Opportunities: Scholarships in Brazil - Doctorate
• Effective date (Start): March 01, 2022
• Effective date (End): August 31, 2026
• Field of knowledge: Biological Sciences - Immunology - Cellular Immunology
• Principal Investigator: Marco Aurélio Ramirez Vinolo
• Grantee: Sarah de Oliveira
• Host Institution: Instituto de Biologia (IB). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
• Associated research grant: 18/15313-8 - Investigation of the molecular mechanisms involved in the interaction between microbiota-derived metabolites and host cells during inflammation, AP.JP2
• Associated scholarship(s): 23/00393-4 - Role of the acetate-FFAR2 axis on granulopoiesis and IL-22 production by intestinal neutrophils, BE.EP.DR

Abstract

The intestinal microbiota plays a fundamental role in the modulation of hematopoiesis and consequently in the production of neutrophils. This modulation can occur due to microbial components or metabolites derived from the microbiota. Short-chain fatty acids (SCFAs), produced by the intestinal microbiota through the metabolism of non-digestible carbohydrates from the diet, are molecules that act as signals in microbiota-host interactions. These molecules activate G protein-coupled receptors, such as FFAR2, which is highly expressed in neutrophils, inducing their chemotaxis, and regulating their effector functions. Studies on the acetate-FFAR2 relation and intestinal inflammation with FFAR2 knockout (KO) mice indicate that receptor activation in neutrophils plays an important role in the development of inflammatory diseases. Our preliminary results show that acetate has a protective effect on colitis through activation of FFAR2 in neutrophils. However, the mechanisms behind this effect are not defined. The aim of this project is to analyze the mechanism behind the effect of acetate on neutrophils in colitis, as well as the impact of the acetate-FFAR2 relation on myelopoiesis, functionality and neutrophil heterogeneity in intestinal inflammation. For this, we will evaluate the neutrophil response profile in mice with conditional receptor deletion (S100A8Cre+Ffar2fl/fl), in which colitis will be induced through the administration of DSS in the drinking water. We will assess whether neutrophils directly or indirectly help the tissue repair process. The effect of acetate-FFAR2 activation on the production and maintenance of stem cells and myeloid precursors in bone marrow and neutrophil heterogeneity will also be characterized. With these data, we will establish how the connection between SCFAs and neutrophils occurs, especially the role of the FFAR2 receptor, and how this can modify the inflammatory response.