The innate immune system is the first line of defence against invading pathogens. It involves soluble and cellular mediators, such as macrophages, which detect microbial products (e.g. lipopolysaccharide - LPS) via Toll-like Receptors (TLRs). TLR stimulation of macrophages triggers a rapid change in gene expression, leading to the production of cytokines/chemokines and antimicrobial proteins. The histone deactetylase (HDAC) family of enzymes, which deacetylate lysine residues on target proteins, are important regulators of macrophage functions through their capacity to control signalling and gene expression.
HDAC6 is predominantly cytoplasmic and interacts with several proteins, among which alpha tubulin, HSP90 and others, demonstrating a role beyond histone modifications. One recently identified substrate is mitofusin (MFN) 1 that regulates mitochondrial dynamics. Mitochondria constantly shift between a fragmented state and a more tubular state, modulating several physiological aspects in the cell, but the actual functions of this cellular process in immune contexts are still unclear, as are the roles of HDAC6. Furthermore, since mitochondria is one of the main drivers of metabolism and that HDAC6 has been shown to target some enzyme of the TCA cycle, I hypothesised that HDAC6 could play an important, yet still unknown, role in immunometabolism.
This project addresses two health societal needs: it identifies new ways to control mitochondrial function via the manipulation of its dynamics. Indeed, mitochondria are involved in many inflammatory disorders, in particular neuroinflammation. My research also shows that modulating mitochondrial dynamics via HDAC6 inhibition enhances antimicrobial activity. Thus, my results could contribute to the development of novel antimicrobial treatment strategies as alternatives to antibiotics. Indeed, a UK review on Antimicrobial Resistance estimated that by 2050, if nothing is done, up to 10 million people could die annually from AMR. During the course of the project, I have made several contacts within the industry world and, in the future, will strive for translational opportunities in the healthcare and livestock industries
This MSCA-IF project had three major goals: a) to investigate the role of HDAC6 in macrophages, the importance of its catalytic domains and how it can modulate mitochondria and immunometabolism. To answer these questions, I joined the group of Prof. Patrick Matthias– world expert on HDACs, in particular HDAC6 – at the Friedrich Miescher Institute for Biomedical Research (FMI) in Basel, Switzerland.
