Inflammasomes: mediators of immune defence but culprits in inflammatory disease

Inflammasome and caspase activation mechanisms and cellular programs

Inflammasomes activate caspase family proteases, and thereby trigger caspase-dependent cellular programs, such as cytokine maturation and secretion, pyroptotic cell death and apoptotic cell death. We aim to understand precisely how inflammasomes control the activity of caspases, and the proteolytic cascades that control cellular programs such as unconventional protein secretion.

Inflammasome inhibition by cellular pathways and small molecules

Inflammasomes are potent drivers of inflammatory responses, and are thus important for microbial clearance. But uncontrolled or inappropriate inflammatory responses are responsible for a wide variety of human diseases (e.g. septic shock, gout, diabetes, neurodegenerative diseases, various cancers). We are characterising cellular mechanisms of inflammasome inhibition, of key importance to maintaining human health. We are also characterising new pharmacological approaches for inflammasome inhibition, with broad potential for the treatment of human inflammatory and neurodegenerative diseases.

Inflammasome function in neutrophils

Neutrophils are innate immune cells with key functions in antimicrobial host defence, but their ability to signal via pattern recognition receptor pathways is poorly characterised. We are characterising new roles for neutrophils in inflammasome signalling in vivo, and seek to understand how cell identity shapes neutrophil immune signalling pathways.

Host-pathogen interactions.

The inflammasome pathway is an important part of the host defence response to infection, and so microbes have evolved various mechanisms to evade this response. We are defining how inflammasomes detect microbes, and the microbial strategies employed to avoid this antimicrobial response.

Inflammasome function in humans.

Immunological research often uses the laboratory mouse to understand human disease. Inflammasome research is no exception, and previous studies in mice have revealed important mechanisms of immune signalling. But the immune responses of humans and mice are not identical, in part because of gene differences between these species. Recent technological advances (e.g. CRISPR/Cas9 gene editing) give us unprecedented precision in approaches for characterising inflammasome signalling in human cells.

We collaborate nationally and internationally, and across research fields.

Major collaborators include:

• Prof Matthew Sweet (innate immunity, IMB)
• Prof Jenny Stow (cell biology, IMB)
• Prof Alpha Yap (epithelial defence, IMB)
• Prof Matthew Cooper (anti-inflammatory drug design, IMB)
• Prof Ben Hankamer (structural biology, IMB)
• Assoc Prof Trent Woodruff (neurodegenerative disease, The University of Queensland)
• Assoc Prof Katryn Stacey (inflammasomes and cell death, The University of Queensland)
• Dr James Vince (cell death, The Walter and Eliza Hall Institute)
• Dr Seth Masters (auto-inflammatory diseases, The Walter and Eliza Hall Institute)
• Prof Geoff Farrell (liver disease, The Canberra Hospital)
• Prof Vojo Deretic (autophagy, University of New Mexico)
• Dr Jelena Bezbradica (sterile inflammation, University of Oxford)
• Prof Luke O’Neill (inflammatory signalling, Trinity College Dublin).

Please view the full list of publications.