Unravelling Inflammatory Caspases Co-regulation

The innate immune is the body first line of defence against pathogens.

One key pathway of the innate immune system, called the inflammasome, activates signalling proteases named inflammatory caspases.

Inflammatory caspases are cleaving important proteins in the cells to orchestrate the innate immune responses and protect the body.

However, dysregulation of caspases activity is harmful and leads to various immune conditions like sepsis, rheumatoid arthritis, and gout and have been involved in other conditions with inflammatory components like diabetes and ageing. Humans have three inflammatory caspases, caspase-1, -4 and -5. The canonical inflammasome activates caspase-1 whereas by the non-canonical inflammasome activates caspase-4 and -5.

Despite their crucial roles in innate immunity, inflammatory caspases regulatory mechanism are poorly described.

Here, we will study how human inflammatory caspases activity is regulated and how two inflammatory caspases, caspase-1 and -4, fine-tuned each other activity to impact immune responses.

Our exciting preliminary data suggest that caspase-4 can be activated on the canonical inflammasome, challenging the current dogma.

Using a combination of cell biology and biochemical approaches, we aim to understand how caspase-1 and 4 regulate each other during human immune responses.

Ultimately, the fundamental knowledge gain through this project will guide the development of caspase inhibitors for inflammasome-related diseases.