Udalova Group | Genomics of Inflammation
Work in the Udalova is focused on understanding how the inflammatory response is controlled on the molecular level.
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 pathogenic inflammatory monocyte/macrophage responses: IRF5
Tissue resident and inflammatory monocytes and monocyte-derived macrophages cooperate in the inflamed tissue to guide the recruitment of neutrophils. Interferon regulatory factor 5 (IRF5) is a key regulator of inflammatory monocyte-derived macrophages (Udalova et al, Nat Rev Rheumatology, 2016). We demonstrated that it orchestrates the inflammatory cytokine and chemokine gene programme (Saliba et al, Cell Reports 2014), promotes Th1/Th17 immune response (Krausgruber et al Nat Immunology 2011), plays an important role in tissue inflammation, pathology and remodelling (Weiss et al, PNAS 2015; Dalmas et al, Nat Medicine 2015; etc) and defines monocyte adaptation to the tissue microenvironment during the inflammatory response (Corbin et al Sci Immunology 2020).
Our current research is focused on decoding the logic of IRF5-controlled myeloid cell biology throughout various stages of the inflammatory response: initiation, peak and resolution. We have assembled an integrative pipeline of the state-of-the-art single cell genomic, functional validation approaches and unique in vivo models to tease out this issue. We also work on functional validation of the recently identified by us novel regulators of IRF5 activation, and explore whether the inhibitors of these regulators may be used in the therapies for specific inflammatory diseases (Ryzhakov et al, Nat Communications 2021).
2. Molecular control of pathogenic neutrophil responses: novel transcriptional regulators.
Neutrophils are pathogenic in many inflammatory and autoimmune diseases, including rheumatoid arthritis, vasculitis, and lupus, with marked abnormalities in phenotype and function and extended lifespan (Wang et al, JCI Insights 2020). We and others demonstrated that suppressing neutrophil infiltration into the synovium in mouse models of RA resolves joint inflammation (Blazek et al, J Exp Med 2015; Weiss et al, PNAS 2015). The molecular control of pathogenic neutrophil responses is largely unknown. We have developed a state-of-the-art genomic platform to reveal transcriptional circuits that control neutrophil function and identified novel putative regulators of neutrophil activation (Khoyratty et al, Nat Immunology 2021). We are currently validating the function of these transcription factors and unravelling the regulatory blueprint of neutrophil states in the signal-driven microenvironment (Ballesteros et al, cell 2020). We are also translating our exciting new findings in to the human disease settings in collaboration with our clinical colleagues.