About our research interests
Our research group is focused on the molecular basis of inflammation, with a particular emphasis on innate immunity and immunometabolism. The field of immunometabolism is a rapidly growing area, investigating the intricate relationship between metabolism and the immune system. It explores how metabolic processes and signalling pathways regulate immune cell function and immune responses in health and disease.
Upon activation, immune cells undergo metabolic reprogramming to meet the increased energy and biosynthetic demands associated with their effector functions. This often involves shifts in metabolic pathways, such as Kreb’s cycle, oxidative phosphorylation, glycolysis, and fatty acid oxidation. Research in our laboratory and other research groups have shown that several metabolites, such as Succinate, Itaconate and Fumarate, and enzymes, such as PKM2 and GAPDH play specific roles in the immune response in macrophages. Itaconate, a metabolite produced from cis-aconitate by the enzyme ACOD1 and several derivatives of Itaconate, are key anti-inflammatory metabolites in the innate immune response. We have found Itaconate to activate the anti-inflammatory transcription factor NRF2. Also, Itaconate and in particular its derivatives such as 4-Octyl Itaconate target such proteins as JAK1 and NLRP3. Fumarate accumulation, and more specifically impairment in Fumarate Hydratase, leads to the release of mitochondrial double-stranded RNA, which is sensed by MDA-5 and RIG-I, promoting Type I interferon production.
Our research group is building on the findings we have made, and endeavours to provide a better understanding into the metabolic regulation of immune cell function and the innate immune system, with the aim of developing novel therapies to treat inflammatory diseases.
Our research is supported by Science Foundation Ireland and the European Research Council.
The lab has fully funded academic-industry collaborations with three pharma companies: Sitryx Therapeutics, Eli Lilly and Company and Sail Biomedicines. Working with industry partners is an effective way to translate our discoveries and developments into real-world applications, with the hope of ultimately benefitting patients with autoimmune and autoinflammatory diseases.
Ongoing projects include
The role of Itaconate in neutrophil function
In this project, we are investigating the role of itaconate in neutrophils function. We found that ACOD1-KO neutrophils produce less ROS and express higher amounts of complex IV in the mitochondria. Accordingly, we found that basal mitochondrial respiration was increased in ACOD1-KO neutrophils. To further investigate this, our next steps will include to evaluate complex IV activity and the impact of ACOD1 in neutrophils function, including phagocytosis and NET (neutrophils extracellular trap) production.
Effect of small molecule modulators of Complex III of the electron transport chain on cytokine production in macrophages
When macrophages are primed with the Gram-negative bacterial product Lipopolysaccharide (LPS), they show an M1 pro-inflammatory phenotype and aberrant macrophage activation can contribute to the pathogenesis of inflammatory diseases. We are exploring the role of the Electron Transport Chain (ETC) in shaping the macrophage immune response. M1 macrophages release multiple cytokines including the pro-inflammatory cytokines Interleukin (IL)-1β and Tumour Necrosis Factor (TNF)-α and the immunomodulatory cytokine Interleukin (IL)-10. In this project, we are exploring the link between the electron transport chain (ETC), specifically Complex III, and the innate immune response, with a focus on the mechanisms driving cytokine production.
Exploring the role of Itaconate on post-translational modifications in macrophages.
We are uncovering additional targets for itaconate, specifically in human macrophages, where there are important differences with mouse macrophages. Investigation into the exact role of itaconate in the modification of cysteines and the direct impact of this on the innate immune responses in macrophage biology is being explored in detail.
Exploring the role of Itaconate in Autophagy and Mitophagy
Autophagy is a well conserved process of self-degradation that involves the recycling of aged or damaged cellular contents for their reuse in repair and biogenesis. Mitophagy represents a specialised form of autophagy which involves the selective degradation of damaged or stressed mitochondria. Many labs have demonstrated a link between dysregulated mitophagy and metabolic disease, cancer, and neurodegenerative disease, highlighting the close relationship between dysfunctional mitophagy and disease. This project involves an investigation into the role of itaconate in the processes of autophagy and mitophagy in macrophages, with a particular focus on p62.
Investigating the mechanism of mitochondrial RNA release in response to Fumarate Hydratase Inhibition
Fumarate Hydratase (FH) deficiency induces the release of mitochondrial RNA (mtRNA) into the cytosol and activates nucleic acid sensing pattern recognition receptors to produce interferon-β (IFN-β). However, the mechanism of mtRNA release is still not defined. Small molecule inhibitors and knockdown of specific mitochondrial channels are being employed to assess possible mechanisms. We have found that sorting nexin 9 (SNX9) is required for mtRNA release and IFN-β production in macrophages. Voltage-dependent anion channel (VDAC) and Rab7 also participate in this process. FH inhibition therefore appears to trigger a process involving these proteins for the release of mtRNA and further research is required for a better understanding and potential treatment against certain diseases.