Udalova Group | Genomics of Inflammation
Our research focuses on how myeloid cells - key components of our immune system - affect inflammatory diseases to contribute to more effective therapies for these conditions.
Inflammation is a normal and self-limiting physiological response to infection and injury but if sustained can lead to extensive tissue damage and disability. Pathological consequences of chronic inflammatory responses include a wide variety of diseases with huge social impact ranging from autoimmune diseases to atherosclerosis, Alzheimer's and cancer.
Myeloid cells are critical components of host defence. They sense microbial components and damaged tissue, eliminate bacteria and activate adaptive immune cells via the release of cytokines and chemokines. But under certain circumstances the same cells can be major contributors to pathology. The exact nature of the myeloid cells in various inflammatory diseases is thus a topic of major interest, as it will not only provide clues about pathogenesis, but also contribute towards more effective therapeutics.
1. Role of IRF5 in the pathogenesis of autoimmune and inflammatory diseases
We have discovered that transcription factor IRF5, linked by genetic-association to many autoimmune diseases, is a major factor defining inflammatory macrophages (Krausgruber et al Nat Immunology 2011). It activates the majority of key inflammatory cytokines and chemokines (Saliba et al, Cell Reports 2014), promotes Th1/Th17 immune response and plays important role in tissue remodelling. Mice lacking IRF5 are resistant to lethal endotoxic shock and pristane-induced model of lupus. They are also protected from insulin resistance in diet-induced model of obesity (Dalmas et al, Nat Medicine 2015) and show a significant reduction in knee swelling and pathology in inflammatory arthritis (Weiss et al, PNAS 2015). Our current research is focused on understanding the heterogeneity of IRF5-expressing immune cells and their functions in various inflammatory disease models. We also search for the regulators of IRF5 activation, with the goal of designing selective therapeutic strategies, which might be useful in a wide spectrum of inflammatory diseases.
2. IFN-lambda: novel biologics for controlling neutrophil-mediated pathology in rheumatic diseases?
Type III interferons - IFN-λ1, IFN-λ2 and IFN-λ3 - are best known for their antiviral activity but have broader roles in autoimmune and inflammatory disease than previously appreciated. We found that that IFN-λ2 (IL-28A) treatment resulted in abrogation of disease and reversal of joint damage in mice with collagen-induced arthritis (CIA) by having a major effect on neutrophils, i.e. inhibiting neutrophil IL-1β production and neutrophil migration (Blazek et al, J Exp Med 2015). We currently investigate the cellular and molecular mechanisms behind this suppression and examine the translational potential of our finding.