Udalova Group | Genomics of Inflammation

Inflammation is a normal and self-limiting physiological response to infection and injury but if sustained can lead to extensive tissue damage and disability, manifested in a variety of chronic inflammatory disorders, ranging from autoimmune diseases to atherosclerosis, Alzheimer’s and cancer. It is driven by changes in the tissue microenvironment, the activation of tissue-resident cells, such as macrophages, and the infiltration of effector myeloid effector cells, such as monocytes, neutrophils. Our aim is to understand the heterogeneity of the myeloid cells in inflammatory tissue microenvironment and the transcriptional circuits that control their phenotype and function.

1. Molecular control of the innate immune response in inflammatory disease

Our research at the forefront of the molecular and genomic control of the innate immune response. Using a state-of-the art genomic and computational pipelines and unique in vivo models, we study how distinct repertoires of transcription factors orchestrate the development and function of specific innate immune cell populations in inflammation, with a direct impact on the pathophysiology of inflammatory diseases. We are translating our exciting new findings in to the human disease settings in collaboration with our clinical colleagues.
We have identified the transcription factor IRF5 as a master regulator of innate immune cells establishing a new paradigm for macrophage regulation and function. This substantial body of work has firmly established IRF5 as a therapeutic target in inflammatory disease. Our current research is focused on dentification of novel upstream activators of IRF5 with an aim to expand therapeutic targets, and in collaboration with chemistry colleagues, of a new series of inhibitory compounds and their mechanism of action.
Our focus is on decoding the logic of transcriptional control of neutrophils, led to the first transcriptional blueprint of neutrophils, previously considered transcriptionally inactive, identifying novel transcriptional regulators and opening up new therapeutic avenues for targeting specific neutrophil functions. Our current interest is directed towards unravelling TF networks controlling neutrophil functional states and their interaction with the tissue and vascular microenvironment. We are also exploring the functional relevance of very distinct process of neutrophil nuclear segmentation.

2. Biophysical regulation of immune cell development and function

While the influence of biochemical signals on the acquisition of macrophage phenotype and function in tissue has been extensively studied, the impact of biophysical forces remains largely unexplored. By investigating the impact of mechanical stimulation by joint movement and during mechano-inflammatory pathologies on the function of tissue-resident synovial macrophages, we identified a novel subset of embryonically derived macrophages localised at the mechanically strained areas of the joint, whose maintenance was dependent on a healthy mechanical load. Furthermore, their proliferation was expedited in mechano-inflammatory pathologies and critical for the formation and integrity of synovial lining. Our current focus on the mechanisms and signalling pathways behind the function of these macrophages and their presence and function in other mechano-stimulated organs. We are also extending these concepts to other immune cells.