Joe Boyle and group work on macrophage differentiation in atherosclerosis. Our specific focus is on the responses of plaque macrophages to intraplaque hemorrhage. We are particularly interested in understanding protective pathways in order to help develop therapeutics and diagnostics for atherosclerotic cardiovascular disease. Our interests are extending from this niche to encompass inflammation-resolution and other routes by which to re-educate macrophages from being inflammatory and cytotoxic to protective, reparative and homeostatic.
Our main discoveries to date have been:
- Intraplaque hemorrhages in disrupted advanced atherosclerotic plaques are associated with macrophages that are adapted to reduce their adverse impact.
- metformin may suppress atherosclerosis in vivo via macrophage AMPK, rather than via an effect on blood glucose.
- normal resolution of tissue hemorrhage in vivo requires AMPK and ATF1; and their deficiency results in inflammation and oxidative stress. This is likely to apply to any hemorrhage including intraplaque hemorrhage and intracranial hemorrhage (Figure).
- chromatin remodelling mediated by the cardiovascular risk gene SMARCA4 contributes to the specificity of gene activation that distinguishes leukocyte resolution from erythrocyte resolution whilst they use related transcription factor binding sites (Figure).
We work on a plaque macrophage population (Mhem) that we first described. This population reacts to intraplaque hemorrhage and suppresses its pro-atherogenic effects. That is, the plaque is better off with Mhems than without. We next showed that Activating Transcription Factor 1 (ATF1) is a key driver for this phenotype. ATF1 in turn was activated by Adenosine Monophosphate Activated Kinase (AMPK). Then we showed that the AMPK-ATF1 pathway operates in vivo to induce Heme Oxygenase 1 (Hmox1) in normal hematoma resolution. It is required to suppress inflammation and oxidative stress and separately recycle iron and lipid. We showed that pharmacologically triggering this pathway by metformin in the therapeutic range may reduce atherosclerosis.
We then compared the responses of macrophages in erythrocyte resolution with leukocyte resolution. This is yielded very novel insights into gene regulation and translational pathways to reduce cardiovascular disease (Manuscript in Revision and forthcoming posting to Bioarxiv).
Guido de Meyer, Univ. Antwerp, Role of Atf1 in intraplaque hemorrhage in mice, 2018
Anna Randi, Imperial College London, Transcriptional control in inflammation, 2017
Claudio Raimondi, Imperial College London, Iron and inflammation, 2017 - 2027
Derek Gilroy, University College London, Anti-inflammatory pharmacology, 2017 - 2027
Graeme Birdsey, Imperial College London, Transcriptional control in inflammation, 2017 - 2027
Sian Harding, Imperial College London, Macrophage regulation of regeneration, 2017 - 2027
Prakash Punjabi, Imperial College London, Inflammation in heart failure, 2017
Niall Dillon, Imperial College London (MRC LMS), Gene regulation by chromatin modification, 2017 - 2022
Jan Nilsson, Isabel Goncalves, Universities of Malmo and Lund, Macrophage regulation in atherosclerosis, 2017 - 2027
Mat Daemen, AMC Amsterdam, Macrophages in atherosclerosis pathology, 2016 - 2027
Gillian Gray, University of Edinburgh, Macrophage regulation of myocardial ischemia-reperfusion damage, 2016 - 2027
James Leiper, University of Glasgow, Gene regulation by nitric oxide and cyclic-guanosine monophosphate, 2015 - 2020
Guido de Meyer, University of Antwerp, Macrophage regulation in atherosclerosis, 2014 - 2027
Nick Long, Imperial College London, Chemical biology of vascular inflammation, 2014 - 2027
Soren Moestrup, University of Aarhus, CD163, 2014 - 2027
Jorge Ferrer, Imperial College London, Genomics and gene regulation, 2014 - 2027
Mark Mercola, Pilar Luiz-Luzano, Stanford University, Cardiovascular pathology, 2012 - 2016
Prof Bart Staels, Institut Pasteur, University of Lille, INSERM 1011, Transcriptional regulation of macrophages in atherosclerosis, 2012
Ramzi Khamis, Imperial College London, Athersclerosis, 2011 - 2027
David Carling, Imperial college London, AMPK in macrophages, 2009 - 2027
Dominik Schaer, Zurich University Hospital / ETH Zurich, Macrophages, hemoglobin and anti-inflammatory approaches, 2008 - 2027
Prof Justin C Mason, Imperial College London, Heme oxygenase, anti-inflammatory mechanisms, vascular inflammation, vasculitis management and diagnosis, 2004 - 2027
James Scott, Imperial College London, Neuroinflammation
Claire Shovlin, Imperial college London, Iron and inflammation
Mhem macrophages in atherosclerosis: pathology to pharmacology and on to new cell biology. Nilsson Lab, University of Lund / Malmo, Sweden Feb 2017, University of Lund, Lund / Malmo, 2017
Mhem macrophages in atherosclerosis: pathology to pharmacology and epigenetic signalling. Novartis Institute of Biomedical Research, Basel, Oct 25, 2016, Novartis Institute of Biomedical Research, Basel, 2016
Hemorrhage and atherosclerosis: pathogenesis and imaging. Vulnerable Plaque Meeting. Reykjavik, June 25-30, 2016, Vulnerable Plaque Group, Reykjavik, 2016
Mhem macrophages in atherosclerosis: from cause to cure, University of Aberdeen, Aberdeen, 2015
Mhem macrophages in atherosclerosis: from pathogenesis to prevention. University of Sheffield, Sep 22-23, 2014, University of Sheffield,, Sheffield, 2014
Tenovus Medal Lecture for outstanding biomedical science, University of Glasgow, 2014, University of Glasgow, University of Glasgow, 2014
John French Lecture (given to younger scientist of exceptional promise), British Atherosclerosis Society 2014, British Atherosclerosis Society, Manchester Central, Manchester, 2014
An AMPK-ATF1 pathway drives Mhem atheroprotective macrophages, University of Edinburgh, Edinburgh, 2013
From intraplaque hemorrhage histology to metformin repurposing: the AMPK-ATF1-Mhem pathway of macrophage atheroprotection, Novartis NIBR, Basel, 2013
ATF1 drives atheroprotective macrophages., London Vascular Biology Forum, London, 2012
ATF1 coregulation of HO-1 and LXR defines an atheroprotective coregulatorypathway and corresponding Mhem plaque macrophage phenotype., Univ. of Lille/ Institut Pasteur / INSERM U1011 Aug 2012., Institut Pasteur, Lille, 2012
Atheroprotective macrophage subset defined by CD163., Session on macrophages inatherosclerosis. American Heart Association Scientific Sessions., Chicago, 2010
A novel atheroprotective macrophage phenotype., 5th European Vascular Biology andMedicine meeting (EVBM 2009) Organisation, Marseilles, 2009
Macrophage subsets in atherosclerosis, University of Reading, Reading, 2007
Macrophage smooth muscle cell interactions in atherosclerosis, The British Atherosclerosis Society, Oxford University, 2006
Macrophage-vascular smooth muscle cell interactions, Weill Medical School, Cornell University,, Manhattan, USA, 2001
Macrophages provoke killing of vascular smooth muscle cells, European Society for Cardiology, Stockholm, 2001
Apoptosis in Cardiovascular Disease, The Histochemical Society, 2000
CD163 defines a macrophage subset in coronary atherosclerosis,, Symposium on biology and medicine of CD163, Aarhus, Denmark, 2010