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) and plays an important role in tissue inflammation, pathology and remodelling (Weiss et al, PNAS 2015; Dalmas et al, Nat Medicine 2015; Byrne et al, Mucosal Immunology 2017). Our recent work has focused on the critical role of IRF5 in defining intestinal pathogenic macrophage signature in colitis.
Our current research is focused on decoding the logic of IRF5-controlled monocyte adaptation to the tissue microenvironment 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.
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. 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. We are currently validating the function of these transcription factors and unravelling the regulatory blueprint of neutrophil states in the signal-driven microenvironment. We are also translating our exciting new findings in to the human disease settings in collaboration with our clinical colleagues.
- An unexpected repair function for neutrophils
- Likely culprits causing blood vessel lesions in vasculitis identified
- Understanding of inflammatory bowel disease moves a step closer
- Joint cell discovery offers new hope for people with rheumatoid arthritis
- COVID-19 research at the Kennedy Institute