Effects of mitochondrial dynamics on macrophage inflammatory and effector responses within a trained immunity model

• Grant number: 24/17833-0
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Start date: February 01, 2025
• End date: January 31, 2026
• Field of knowledge: Biological Sciences - Immunology - Cellular Immunology
• Principal Investigator: Pedro Manoel Mendes de Moraes Vieira
• Grantee: Enzo Triozzi
• Host Institution: Instituto de Biologia (IB). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
• Associated research grant: 20/16030-0 - Immunometabolic adaptation of tissue resident macrophages in health and disease, AP.TEM

Abstract

Innate immunity has a pivotal role in ensuring homeostasis, acting both on tissue repair and on the defense against pathogens. Recently, the discovery of innate immune memory, also termed trained immunity, has been growing in notoriety for its capability to increase the intensity of inflammatory responses and therefore provide a protective effect against multiple pathogens. For this reason, there has been an increase in efforts towards a better understanding of the processes underlying the establishment of trained immunity, aiming to make the induction of this cell profile possible, which would in turn allow for more analyses on its possible therapeutic applications in bacterial and viral infections, for example, to be conducted. It is well described that metabolic reprogramming and epigenetic alterations are important for macrophage training, causing an increase in cytokine secretion and antimicrobial effects; however, the alterations on macrophage mitochondrial dynamics during the establishment of the trained immunity profile and, furthermore, on the following effector responses are still unexplored. It is, therefore, imperative that more research is conducted in this field, since the findings contribute towards the development and testing of novel clinical applications. It is known that macrophage activation with beta-glucan and CpG deoxynucleotide increases mitochondrial fission. We hypothesize that mitochondrial fission events following beta-glucan and CpG stimuli are necessary in order to achieve the trained immunity profile on macrophages. Our goal is to determine the processes of mitochondrial dynamics on trained macrophages. By modulating the mitochondrial dynamics with gene silencing techniques, we expect to uncover quantitative differences on macrophage inflammatory and effector capabilities after priming, with either CpG or beta-glucan. This finding would contribute towards the discovery of yet undescribed pathways involved in the establishment of trained immunity in macrophages and, consequently, to future research concerning the application of mitochondrial dynamics as a therapeutic target for immune response modulation in many medical conditions.