Effect of short chain fatty acids on the function of type 3 innate lymphoid cells: involvement of the FFAR2 receptor in this process

Author(s)

Laís Passariello Pral

• Document type: Master's Dissertation
• Press: Campinas, SP.
• Institution: Universidade Estadual de Campinas (UNICAMP). Instituto de Biologia
• Defense date: 2020-06-16

Examining board members

Marco Aurélio Ramirez Vinolo; Denise Morais Fonseca; Renata Sesti Costa

• Advisor: Marco Aurélio Ramirez Vinolo

Abstract

The ILC3 are innate lymphoid cells found mainly along the intestinal mucosa. These cells play a fundamental role in the direct and indirect interactions between the local microbiota, and the host cells. Our hypothesis is that these cells are modulated by the action of products of the bacterial metabolism in the intestinal microbiota, the so-called short-chain fatty acids (SCFAs). First, we used wild (WT) or deficient (KO) mice of the FFAR2 protein to demonstrate the relevance of this receptor in maintaining the profiles of innate lymphoid cells. In the absence of the receptor, there was a reduction in the number of ILC1, ILC2 and ILC3 in the lamina propria of the small intestine. Despite this phenotype observed in animals that do not express the SCFAs receptor, strategies that alter the amount of SCFAs systemically did not have any effect on the amount of ILC3 in adult C57BL6 animals in the absence of inflammation. Next, we evaluated in vivo the functions of ILC3s in mice with specific FFAR2 deletion in cells that express the RORyt transcription factor, which includes the ILC3 (FFAR2?Rorc) and its litter controls (FFAR2fl/fl). For this purpose, we used the C. difficile infection model, in which it is known that ILC3 have a relevant role. In these experiments, we observed that the FFAR2 receptor is very important for the function of the ILC3 since in its absence the animals developed a disease much more serious than the controls. Associated with this, we observed that there was a reduction in the numbers of ILC1, ILC2 and, mainly, ILC3 present in the intestinal lamina propria of these animals, and functional impairment of ILC3 (reduction of ILC3 IL-22+, ILC3 il-17+ and the proliferation of these cells). Together, the data show that the FFAR2 receptor is relevant to the response of the ILC3, being essential for the maintenance of these cells in both homeostatic and inflammatory contexts. However, the functional effects of the absence of the receptor in the ILC3 are only relevant in an inflammatory context, when the production of key cytokines for resolution such as IL-22 and IL-17 is impaired, and the proliferation capacity of these cells is compromised (AU)

• FAPESP's process: 18/02208-1 - Effect of short chain fatty acids on the function of type 3 innate lymphoid cells: involvement of the FFAR2 receptor in this process
• Grantee: Laís Passariello Pral
• Support Opportunities: Scholarships in Brazil - Master