Kennedy Trust Prize Studentships
Regulation of the inflammasome pathway in tissue macrophages
- Project No: KTPS-NC-6
- Intake: 2021 KTPS-NC
Chronic inflammation is the biggest risk factor for most modern-day diseases, from neurodegeneration to cancer and chronic diseases affecting joints and gut. Our research goal is to elucidate mechanisms that control the initiation and duration of inflammatory responses. To accomplish this goal, we study innate sensing and signalling in myeloid cells, as these cells typically initiate the inflammatory response. Our group investigates how innate cells integrate signals from cytokines (which report on infection or tissue injury) with signals from microbial and tissue-damage sensors to direct the most appropriate effector response. We also study how myeloid cells communicate with other effector cells to instruct their effector responses.
The NLRP3 inflammasome is a critical sensor of cell and tissue homeostasis that becomes activated in myeloid cells in response to pathogen- or tissue-derived danger signals. Activated NLRP3 inflammasome drives the secretion of proinflammatory cytokines IL-1 and IL-18 to initiate the downstream inflammatory responses, and at the same time it induces the proinflammatory form of cell death to eliminate infected or damaged cells. While activation of the NLRP3 inflammasome is beneficial during infections, excessive and uncontrolled NLRP3 activity contributes to the development of several chronic inherited and acquired inflammatory diseases such as Cryopyrin-Associated Periodic Syndromes (CAPS), Alzheimer’s, Parkinson’s, Colitis, arthritic diseases and aging associated inflammation and functional decline. Thus, we study how NLRP3 activity is naturally ‘turned on and off’ in healthy individuals, to be able to harness this knowledge for therapeutic interventions. We recently described one mechanism that naturally limits the inflammasome pathway activity in healthy macrophages. We also described how inflammatory responses elicited by the inflammasome pathway differ in microbe-induced versus sterile inflammation.
Most research so far investigated inflammasome pathway in vitro, in bone marrow- or blood derived-macrophages. This remains an important step in understanding the basic principles of inflammasome biology. But as a result, very little is known about how the inflammasome pathway is regulated in tissue, where the damage, or infection, are first sensed. Recently a subset of inflammatory macrophages expressing high level of inflammasome components was described in the inflamed arthritic joints from mice and patients. So, this project will combine studies of inflammasome biology in vitro with the arthritis disease models in vivo to investigate how the inflammasome pathway is naturally tuned on and off in tissue macrophages, and how this pathway contributes to local inflammation and development of arthritic diseases.
NLRP3 Inflammasome, Macrophages, Inflammation, Arthritis.
Training will be provided in techniques including biochemistry, confocal microscopy, immunological techniques such as flow cytometry and in vitro functional assays, and disease specific techniques such as induction of arthritis. You will attend regular seminars within the department and in the University. You will be present data at lab meetings, departmental progress report seminars and conferences. You will be trained by a unique team of basic scientists and clinicians, covering basic biology of macrophages (Dr Bezbradica Mirkovic), and disease specific biology of arthritis (Prof Coles and Buckley). A set of lectures is offered in the first term to provide a solid foundation in a broad range of subjects including musculoskeletal biology, inflammation, translational immunology, data analysis, statistics and the microbiome.
The Kennedy Institute is a world-renowned research centre, housed in a brand new, state-of-the-art facility at the University of Oxford. Kennedy Institute has one of the best imaging facilities in UK and is an ideal place for this project. Bezbradica Mirkovic lab consists currently of 1 postdoc, 2 DPhll students and 1 research assistant. We have a close collaboration (including a collaborative grant and a co-supervised DPhil student) with Prof Coles and Prof Buckley and their teams in Oxford and Birmingham. Thus, environment is set up, friendly and ready to go for this work.
- Boucher, D., Monteleone, M., Coll, R.C., Chen, K.W., Ross, C.M., Teo, J.L., Gomez, G.A., Holley, C.L., Bierschenk, D., Stacey, K.J., Yap, A.S., Bezbradica, J.S., Schroder, K. Caspase-1 self-cleavage is an intrinsic mechanism to terminate inflammasome activity(2018) Journal of Experimental Medicine, 215 (3), pp. 827-840.
- Bezbradica, J.S., Coll, R.C., Schroder, K. Sterile signals generate weaker and delayed macrophage NLRP3 inflammasome responses relative to microbial signals (2017) Cellular and Molecular Immunology, 14 (1), pp. 118-126.
- Buckley, C.D.Macrophages form a protective cellular barrier in joints (2019) Nature 572 (7771), pp. 590-592.
- Croft, A.P., Campos, J., Jansen, K., Turner, J.D., Marshall, J., Attar, M., Savary, L., Wehmeyer, C., Naylor, A.J., Kemble, S., Begum, J., Dürholz, K., Perlman, H., Barone, F., McGettrick, H.M., Fearon, D.T., Wei, K., Raychaudhuri, S., Korsunsky, I., Brenner, M.B., Coles, M., Sansom, S.N., Filer, A., Buckley, C.D. Distinct fibroblast subsets drive inflammation and damage in arthritis (2019) Nature 570 (7760), pp. 246-251.
Contact: Dr Jelena Bezbradica Mirkovic, Kennedy Institute, University of Oxford