Summary
Edwin Chilvers is Professor of Medicine, and Head of the National Heart and Lung Institute (NHLI), at Imperial College London. His research interests are in inflammatory cell biology, in particular the intracellular signals that regulate the activation and survival of neutrophils and eosinophils. This has translational relevance to a range of inflammatory lung diseases including chronic obstructive pulmonary disease (COPD), asthma and acute lung injury. He has a particular interest in the signalling mechanisms regulating NADPH oxidase function in neutrophils, and the control of neutrophil and eosinophil survival by hypoxia and inflammatory cytokines. His research has received continuous MRC and Wellcome Trust support for the past 25 years.
Edwin graduated from Nottingham University Medical School and following junior posts at the Hammersmith, St Thomas’, NHNN, Queen Square and Royal Brompton Hospitals and Registrar posts at the Hammersmith Hospital, he undertook an MRC Research Training Fellowship with Professor Steve Nahorski at Leicester and Professor Peter Barnes FRS at the NHLI, to study the role of phosphoinositide signalling in airways smooth muscle. He then took up a Lectureship at Edinburgh, working with Professor Chris Haslett, and subsequently a Wellcome Trust Senior Clinical Research Fellowship and Hon Consultant Physician at the Royal Infirmary Hospital, where he focused on the role of PI3-kinase signalling in neutrophil priming and apoptosis.
Professor Chilvers was Professor of Respiratory Medicine at Cambridge from 1998-2018 prior to taking up his current post, where he helped develop the academic Respiratory Medicine Division within the Department of Medicine and specialist clinical services at Addenbrooke’s Hospital. He also served as NED at the Royal Papworth Hospital and was involved in their decision to relocate to the Cambridge Biomedical Campus. He was elected a Fellow of the Academy of Medical Sciences in 2007, serving on Council between 2013-16, and was President of the British Thoracic Society in 2016-17. He is a Trustee of the British Lung Foundation and Chair of its Research Committee.
research
Edwin’s research has a particular focus on the role of phosphoinositide 3-kinase and HIF-alpha in regulating human and murine neutrophil function. His interest in cell signalling developed during his MRC Training Fellowship with Professor Nahorski in Leicester where using bovine trachealis as a model system he provided the first direct pharmacological proof of an inositol 1,4,5-trisphosphate (Ins(1,4,5)P3) receptor in smooth muscle and demonstrated the importance of agonist-stimulated Ins(1,4,5)P3 metabolism in generating the rapid and transient Ins(1,4,5)P3 ‘spike’ seen following contractile-agonist stimulation. During this work he also identified a novel pathway for Ins(1,4,5)P3 metabolism to Ins(4,5)P2 and helped develop the first radio-receptor assay for measuring Ins(1,4,5)P3 and PtdIns(4,5)P2 mass.
Following his move to Edinburgh he applied his training in lipid-derived second messengers to investigate the mechanisms linking the processes of granulocyte priming, activation and apoptosis. Edwin’s group at Cambridge University revealed for the first time that neutrophil priming is reversible and that these cells can participate in a complete cycle of priming, de-priming and re-priming. This observation refuted the view that innate immune cell priming is a terminal event and suggested that neutrophils primed in vivo might be retained in the pulmonary circulation and allowed to de-prime before re-entering the circulation. This was confirmed using single cell optic stretching of neutrophils, which reveals fast and active de-priming induced by repetitive stretch. These concepts have been progressed to understand human neutrophil and eosinophil trafficking in vivo using autologous Tc-99m and In-111-labelled cells. This has allowed the complete but transient retention of primed neutrophils in the lung to be studied, using 3-D SPECT/CT, and the development of a non-invasive method to measure ‘whole-lug’ neutrophil uptake.
In collaboration with Professors Walmsley and Condliffe (University of Cambridge, Sheffield and Edinburgh) Edwin’s group has also demonstrated the capacity of innate immune cells to sense and respond to changes in environmental oxygen tension relevant to the inflamed site, and that hypoxia has a profound effect on neutrophil longevity, secretion and NADPH-dependent bacterial killing.
Together, these studies have provided novel insights into the roles of Ins(1,4,5)P3 in pharmaco-mechanical coupling and PI3-kinase and hypoxia in neutrophil priming and survival; this work has provided the basis to develop myeloid restricted PI3-kinase-gamma and the hypoxia-PHD-HIF-1alpha inhibitors as pharmacological targets to modulate granulocytic inflammation.
Selected Publications
Journal Articles
Lok LSC, Dennison TW, Mahbubani KM, et al., 2019, Phenotypically distinct neutrophils patrol uninfected human and mouse lymph nodes, Proceedings of the National Academy of Sciences of the United States of America, Vol:116, ISSN:0027-8424, Pages:19083-19089
Toepfner N, Herold C, Otto O, et al., 2018, Detection of human disease conditions by single-cell morpho-rheological phenotyping of blood, Elife, Vol:7, ISSN:2050-084X
Cowburn AS, Macias D, Summers C, et al., 2017, Cardiovascular adaptation to hypoxia and the role of peripheral resistance, Elife, Vol:6, ISSN:2050-084X
Sadiku P, Willson JA, Dickinson RS, et al., 2017, Prolyl hydroxylase 2 inactivation enhances glycogen storage and promotes excessive neutrophilic responses, Journal of Clinical Investigation, Vol:127, ISSN:0021-9738, Pages:3413-3426
Sowerby JM, Thomas DC, Clare S, et al., 2017, NBEAL2 is required for neutrophil and NK cell function and pathogen defense, Journal of Clinical Investigation, Vol:127, ISSN:0021-9738, Pages:3259-3264
Farahi N, Paige E, Balla J, et al., 2017, Neutrophil-mediated IL-6 receptor trans-signaling and the risk of chronic obstructive pulmonary disease and asthma, Human Molecular Genetics, Vol:26, ISSN:0964-6906, Pages:1584-1596
Thomas DC, Clare S, Sowerby JM, et al., 2017, Eros is a novel transmembrane protein that controls the phagocyte respiratory burst and is essential for innate immunity, Journal of Experimental Medicine, Vol:214, ISSN:0022-1007, Pages:1111-1128
Thompson AAR, Dickinson RS, Murphy F, et al., 2017, Hypoxia determines survival outcomes of bacterial infection through HIF-1 alpha-dependent reprogramming of leukocyte metabolism, Science Immunology, Vol:2, ISSN:2470-9468, Pages:1-12
Juss JK, House D, Amour A, et al., 2016, Acute respiratory distress syndrome neutrophils have a distinct phenotype and are resistant to phosphoinositide 3-Kinase inhibition, American Journal of Respiratory and Critical Care Medicine, Vol:194, ISSN:1073-449X, Pages:961-973
Cader MZ, Boroviak K, Zhang Q, et al., 2016, C13orf31 (FAMIN) is a central regulator of immunometabolic function, Nature Immunology, Vol:17, ISSN:1529-2908, Pages:1046-1056
Cowburn AS, Crosby A, Macias D, et al., 2016, HIF2 alpha-arginase axis is essential for the development of pulmonary hypertension, Proceedings of the National Academy of Sciences of the United States of America, Vol:113, ISSN:0027-8424, Pages:8801-8806
Angulo I, Vadas O, Garcon F, et al., 2013, Phosphoinositide 3-Kinase δ Gene Mutation Predisposes to Respiratory Infection and Airway Damage, Science, Vol:342, ISSN:0036-8075, Pages:866-871
Cowburn AS, Takeda N, Boutin AT, et al., 2013, HIF isoforms in the skin differentially regulate systemic arterial pressure, Proceedings of the National Academy of Sciences of the United States of America, Vol:110, ISSN:0027-8424, Pages:17570-17575
Farahi N, Singh NR, Heard S, et al., 2012, Use of 111-Indium-labeled autologous eosinophils to establish the in vivo kinetics of human eosinophils in healthy subjects, Blood, Vol:120, ISSN:0006-4971, Pages:4068-4071