Mechanisms involved in neutrophils recruitment to the lung post-treatment with a ketogenic diet

• Grant number: 21/15168-0
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate
• Effective date (Start): May 30, 2022
• Effective date (End): April 30, 2023
• Field of knowledge: Biological Sciences - Immunology - Cellular Immunology
• Principal Investigator: Denise Morais da Fonseca
• Grantee: Marina Caçador Ayupe
• Supervisor: Timothy Wesley Hand
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Research place: University of Pittsburgh (Pitt), United States
• Associated to the scholarship: 19/12691-4 - Gut-lung axis: contribution of diet and intestinal microbiota to the regulation of lung mucosa-associated immune system, BP.DR

Abstract

Mucosal tissues are endowed with a specialized immune system designed to respond to an enormous range of regional challenges while maintaining tissue homeostasis. Our research group has been working to understand and integrate the mechanisms that act not only in maintaining tissue homeostasis but also in the communication between barrier tissues, such as the intestine and the lung. The communication of bacteria, metabolites and cells between the gut and lung, called the 'gut-lung axis', contributes to both the development and protection from disease, depending upon the context. In the intestine, dietary components are essential for the proper functioning of the gut-associated immune system often by influencing the resident microbiota, but little is known about how diet impacts distal mucosal sites and their resident microbiomes. Here, we hypothesized that the usage of an unbalanced carbohydrate-deficient ketogenic diet may cause long-term consequences for the lung immunity, by interfering in the gut-lung axis. We found that the feeding mice with a ketogenic diet was associated with the presence of a persistent neutrophilic infiltrate in the lung vasculature that was dependent on increased recruitment of IL-17A-producing T³´ lymphocytes. This effect was dependent on IL-6 production by inflammatory monocytes, possibly driven by diet-induced changes in the lung resident microbiota. As a consequence, mice fed a ketogenic diet became susceptible to immune-mediated lung diseases, such as allergic asthma and COVID-19. We propose to study how a ketogenic diet changes the composition of the lung microbiota and the traffic of IL-17-producing TCR³´ cells from the gut, to affect lung inflammation. This proposal is part of one of the specific aims of the JP-2 project recently granted to our research group and will consolidate the collaborative studies between our group and Dr Hand's research team. (AU)