Does membrane lipid chemistry control inflammatory cell death and tissue damage?

PROJECT OVERVIEW

Inflammatory cell death is an essential defence against infection, but when uncontrolled it becomes a major driver of tissue injury in diseases including sepsis, acute liver failure, ischaemia-reperfusion injury and acute respiratory distress syndrome. Although these diseases arise through very different mechanisms, they all share a common endpoint: catastrophic plasma membrane rupture, which releases inflammatory mediators that amplify tissue damage. Preventing this final rupture dramatically reduces disease severity, making it one of the most important yet least understood events in inflammatory disease.

Recent discoveries have identified the proteins that initiate inflammatory cell death by forming pores in the plasma membrane. Unexpectedly, these discoveries revealed that forming membrane pores is not enough to make a cell rupture. Instead, membrane pore formation and catastrophic plasma membrane rupture are distinct biological events, exposing one of the biggest unanswered questions in the field: What determines whether membrane pores progress to catastrophic plasma membrane rupture?

Current models explain the execution of inflammatory cell death almost entirely in terms of proteins. Yet these proteins ultimately act on the plasma membrane, whose lipid composition changes throughout life in response to ageing, inflammation, metabolism and diet. Whether these changes determine whether membrane pores are repaired or progress to catastrophic plasma membrane rupture remains unknown.

We hypothesise that membrane lipid chemistry controls whether membrane pores progress to catastrophic plasma membrane rupture. To test this idea, the student will use stable isotope-reinforced polyunsaturated fatty acids (D-PUFAs), which stabilise membrane lipids against oxidative damage, together with unique inducible cell death systems available in our laboratory that allow inflammatory signalling, membrane pore formation and catastrophic plasma membrane rupture to be studied independently.

The student will determine whether stabilising membrane lipid chemistry changes catastrophic plasma membrane rupture following direct activation of pyroptotic and necroptotic cell death pathways in mouse and human macrophages. This proof-of-concept evidence will then provide the foundation for a full DPhil integrating lipidomics, membrane biophysics, primary human immune cells and models of chronic inflammatory disease to understand how changing membrane composition regulates inflammatory cell death and downstream tissue injury.

Ultimately, this project asks a simple but fundamental question: do the changes that occur in our cell membranes during ageing, inflammation and in response to diet determine whether a dying inflammatory cell repairs membrane damage or catastrophically ruptures?

KEYWORDS

Inflammation, membrane damage, inflammatory cell death

TRAINING OPPORTUNITIES

The project will be undertaken at the Kennedy Institute of Rheumatology, University of Oxford, where all experimental work will be carried out. No overseas travel is required and the project is laboratory based.

The student will be jointly supervised by Professor Jelena Bezbradica Mirkovic (primary supervisor) and Professor Irina Udalova (co-supervisor), providing a unique opportunity to work at the interface of inflammatory cell death, innate immunity and membrane biology. Professor Bezbradica Mirkovic will provide day-to-day scientific supervision, project leadership and experimental guidance, while Professor Udalova will contribute complementary expertise in macrophage biology, inflammatory signalling and translational inflammation.

The student will receive close day-to-day support within the laboratory, with weekly meetings with the primary supervisor to review progress, discuss experimental design and interpret data, together with regular meetings with Professor Udalova to place the findings within the broader context of innate immunity and inflammatory disease.
The student will participate fully in the scientific life of both research groups through laboratory meetings, journal clubs, seminars and institute-wide research events, providing opportunities to present data, discuss new ideas and receive feedback from researchers with complementary expertise. The student will present their findings to both groups.

Working across two internationally recognised research groups will provide an exceptional interdisciplinary training environment spanning inflammatory cell death, innate immunity, membrane biology and translational inflammation. This collaborative environment will provide an outstanding foundation for a three-year DPhil and a future career in biomedical research.

KEY PUBLICATIONS

Kayagaki N, Kornfeld OS, Lee BL, Stowe IB, O'Rourke K, Li Q, et al. NINJ1 mediates plasma membrane rupture during lytic cell death. Nature. 2021;591(7848):131–136. doi:10.1038/s41586-021-03218-7.

Demarco B, Danielli S, Fischer FA, Bezbradica JS. How Pyroptosis Contributes to Inflammation and Fibroblast-Macrophage Cross-Talk in Rheumatoid Arthritis. Cells. 2022;11(8):1307. doi:10.3390/cells11081307.

Udalova IA, Mantovani A, Feldmann M. Macrophage heterogeneity in the context of rheumatoid arthritis. Nat Rev Rheumatol. 2016;12(8):472–485. doi:10.1038/nrrheum.2016.91.

THEMES

Immunity and Inflammation

CONTACT INFORMATION OF ALL SUPERVISORS

Jelena Bezbradica Mirkovic 

Irina Udalova