Specifying macrophage responses to sterile versus microbe-induced tissue injury

Project Overview

A key function of our immune system is to maintain the body's integrity. If we become infected our immune system fights the infection, and if we injure ourselves it repairs the wound. These two very different processes (defence versus repair) are, surprisingly controlled by the same immune cells, receptors and signalling pathways, but how such a system directs a response that is tailored to its inducer is currently poorly understood. Macrophages, key sentinels of tissue injury, are particularly well suited to adapt to the local microenvironment and provide specific responses (1). We have recently described how macrophages integrate signals from cytokines (soluble mediators that report on tissue injury) with signals from microbial and tissue-damage sensors to direct a response that is tailored to a specific pathophysiologic situation (2,3). The goal of the project is to characterize function of a novel class of cytokine-regulated signalling adapters and their role in shaping immune responses to sterile and microbial tissue injury. Better understanding of how is inflammatory response initiated will allow us to design therapies to facilitate wound repair yet prevent/treat chronic inflammatory diseases caused by sterile injury (e.g. arthritis, gout, pulmonary fibrosis) without compromising the patient's antimicrobial defences.

Training Opportunities

The Kennedy Institute is a world-renowned research centre and is housed in a brand new state-of-the-art research facility. The project presents excellent training opportunities in a broad spectrum of immunological and biochemical approaches and in the use of the cutting edge technologies. Program will start with 20 lectures in year 1 to set the theoretical foundation in immunology and inflammation. Building on that foundation, we will use a combination of next generation sequencing transcriptome analyses (e.g. RNASeq), cell biology and imaging techniques (e.g. confocal microscopy), immunological assays (e.g. FACS, ELISA) and new mouse models to investigate and compare responses elicited by infectious agents (e.g. bacteria or fungi), dead cells or dead cells carrying an infectious agent in vitro and in vivo. Extensive collaborations with other research groups inside and outside of the Kennedy Institute will be developed. Student will attend weekly supervision and laboratory meetings, and departmental seminars. Student will also attend and present at external scientific conferences..

Relevant Publications

1. Udalova IA, Mantovani A, Feldmann M. Macrophage heterogeneity in the context of rheumatoid arthritis. Nature Reviews Rheumatology. 2016 Aug;12(8):472-85.
2. Bezbradica, J. S., et al & Medzhitov, R. (2014). A role for the ITAM signaling module in specifying cytokine-receptor functions. Nature immunology, 15: 333-342.
3. Bezbradica, J. S., & Medzhitov, R. (2009). Integration of cytokine and heterologous receptor signaling pathways. Nature immunology, 10: 333-339.

Scientific Themes

Immunology; Infection & immunity; Cell Signalling

Further information

Dr Jelena Bezbradica Mirkovic, Kennedy Institute, University of Oxford
jelena.bezbradica@kennedy.ox.ac.uk