First person – Tara Gleeson

Tara Gleeson

Who or what inspired you to become a scientist?

I don't think that there was any one person who specifically inspired me to pursue a career in science; rather, my interest has grown as I've grown up. I always had an interest in biology from a young age and growing up on a farm probably added to this. There have been so many different people who influenced and nurtured my interest in science over the years, from teachers in school, to lecturers in university to my colleagues here in Manchester – it's been a continuous path of inspiration and learning, and I'm sure that it will continue for many more years to come.

What is the main question or challenge in disease biology you are addressing in this paper? How did you go about investigating your question or challenge?

Our paper revolves around understanding the source and role of interleukin 18 (IL-18) in the macrophage activation syndrome (MAS). Clinically, IL-18 is used as a marker of disease; therefore, we were interested in establishing the role of inflammasomes and, more specifically NLRP3, in disease pathogenesis. To do this we used an established mouse model in which MAS is induced through repetitive stimulation of the Toll-like receptor 9 (TLR9) by using the CpG oligonucleotide. This model recapitulates a number of clinical features observed in MAS, including splenomegaly, hyperferritinemia and cytokine storm. To determine whether the NLRP3 inflammasome is involved in pathogenesis and IL-18 production in these hyperinflammatory mice, we used the inflammasome inhibitors MCC950 and VX-765 to determine the effects on IL-18 in the blood. We found that inhibition of the NLRP3 inflammasome reduced blood plasma levels of IL-18 but did not alleviate clinical features of MAS in mice.

How would you explain the main findings of your paper to non-scientific family and friends?

Hyperinflammatory disease is characterised by an abnormal or ‘over-the-top’ inflammatory response of the body. The cause of this abnormal response can be a result of infection (such as that observed following severe infection with COVID-19), autoimmune disorders, cancer and/or cancer treatment, although the factors leading to this abnormal response are poorly understood. What we do know is that patients with this disease present with abnormally high inflammatory markers in their blood, as well as with enlarged organs. Moreover, if left untreated, hyperinflammatory disease can result in organ failure and, in some cases, death. There are two inflammatory proteins that are associated with disease – interferon gamma (IFNG) and IL-18. Both of these proteins can promote an inflammatory environment in the body and further worsen the disease. Understanding the mechanisms driving disease is becoming ever-more important, as more personalised treatments become available. Current treatment options point to a potential role of inflammasomes, i.e. multi-protein complexes that are responsible for the production of inflammatory proteins, such as IL-18. Prior to this study, the role of inflammasomes in hyperinflammatory disease had not been described. For our research, we used mice to model the human disease and understand the mechanisms underpinning the disease. This mouse model of hyperinflammation mirrors a number of the clinical symptoms of hyperinflammation, including enlarged organs and elevated inflammatory markers. We then took this model and used drugs that specifically target inflammasome function, to establish whether the source of IL-18 in hyperinflammatory disease is, in fact, inflammasome-dependent. We were specifically interested in a certain inflammasome complex known as the NLRP3 inflammasome. This is why we used well-characterised inhibitors of this NLRP3 inflammasome protein complex to study its role in hyperinflammatory disease. We found that inhibition of the NLRP3 inflammasome significantly reduced IL-18 levels in the blood but did not prevent an increase of other inflammatory markers or of organ enlargement. This was an interesting finding, as it suggests that IL-18 is dependent on inflammasome activity in hyperinflammation but that this inflammatory marker is not essential for the development of the disease. Our study sheds light on the mechanisms driving MAS disease and indicates that targeting the NLRP3 inflammasome in patients may be beneficial in reducing IL-18 levels in the blood.

What are the potential implications of these results for disease biology and the possible impact on patients?

Our results enhance our understanding of the complex disease landscape observed in hyperinflammatory disease. Inflammasomes appear to be involved in the disease process but, perhaps, to a lesser extent than we had anticipated, because inhibition of the NLRP3 inflammasome significantly reduced the concentration of IL-18 in the blood plasma but did not prevent other features of the disease, including hyperferritinemia and cytokine storm. This indicates that the NLRP3 inflammasome is activated in hyperinflammatory disease and is crucial for the production of IL-18 that, as mentioned previously, is a characteristic manifestation of disease observed clinically. However, by using the mouse model of MAS, we established that IL-18 and the NLRP3 inflammasome are not essential for a number of the clinical observations associated with hyperinflammatory disease. This may be due to the fact that we used young healthy mice for this study, which did not have underlying inflammatory conditions. However, our study suggests that IL-18 production in hyperinflammatory disease is inflammasome dependent and that inhibition of inflammasomes in patients may be an effective target for treatment of disease.

Why did you choose DMM for your paper?

Disease Models and Mechanisms is a peer-reviewed, open-access and scientifically rigorous journal – all of which are key characteristics of a journal we like to publish in. The subject area of the journal also fits well with our paper as we were investigating a rodent model of hyperinflammatory disease to decipher the role of the NLRP3 inflammasome in the disease process. DMM was, therefore, the obvious choice!

Given your current role, what challenges do you face and what changes could improve the professional lives of other scientists in this role?

It seems that the biggest challenge for early-career researchers is the instability of a career in academia. Constantly applying for grants and the availability of short-term positions are a cause of uncertainty. The lack of security in academia is definitely a struggle for early career researchers. I believe that a change in the academic framework – with more permanent roles available – would really improve the professional lives of anyone in the sector.

What's next for you?

I am currently in the final year of my PhD at the University of Manchester and, as I approach the end of my studies, I hope to continue inflammasome research. I am hoping to find a postdoctoral research opportunity following submission of my thesis early next year.