Control of inflammation by re-instructing macrophages
Joseph Boyle is a Clinical Reader in Molecular Vascular Pathology in the National Heart and Lung Institute.
Dr Boyle’s research focus is in understanding the gene regulation of macrophages in order to re-instruct them from being por-inflammatory to pro-resolution. This is particularly in atherosclerosis.
Dr Boyle's first degree is in Pharmacology (Class I Hons, 1988, plus Prize) from the University of Glasgow. At the University of Glasgow, this comes with a very solid grounding in organic and physical chemistry, laboratory practicals, and integration with world-leading investigators in cell signalling and vascular biology.
Dr Boyle then completed training in Medicine, scoring in the top few in the year (MBChB with Hons, 1991). Work as a junior doctor witnessing fatal cardiovascular disease inspired a career in its pathogenesis. He specialised in Histopathology and then subspecialised in renal and cardiovascular histopathology.
Concurrently, Dr Boyle moved to the University of Cambridge and did a PhD on macrophage biology in atherosclerosis with Professors Peter Weissberg and Martin Bennett and Dr David Bowyer.
In London, Dr Boyle became a BHF Intermediate Clinical Research Fellow with Professor Dorian Haskard. In this work, he defined a novel macrophage pro-resolution phenotype related to intraplaque hemorrhage (Figure) and defined its driving transcription factor, which is Activating Transcription Factor 1 (ATF1) (Figure). ATF1 in turn was activated by Adenosine Monophosphate Activated Kinase (AMPK).
Dr Boyle then became a BHF Senior Clinical Research Fellow to develop mechanistic and translational studies of the AMPK-ATF1-HMOX1-Mhem pathway.
Major insights we revealed include:
- there is a distinct type of pro-resolving macrophage in human atherosclerotic plaques (2008) - this was highly novel at the time and has been very highly cited.
- the common antidiabetic drug metformin suppresses atherosclerosis in vivo via anti-inflammatory effects of macrophage AMPK, rather than via reduced blood glucose.
- normal resolution of tissue hemorrhage in vivo requires AMPK and ATF1; Their deficiency results in inflammation and oxidative stress. This has major implications for intraplaque hemorrhage, which causes heart attacks and strokes, 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) (https://www.biorxiv.org/content/10.1101/2023.05.01.538808v1)
- In close collaboration with Prof Nick Long and group in Chemistry (Molecular Sciences Research Hub), we designed, synthesised and validated a novel fluorescence turn-on break-apart probe specifically for Heme Oxygenase activity. Whilst similar probes have been used with oligonucleotides and oligopeptides, this seems to be a first for a metabolite. This shows promise as a research reagent, and an in vitro diagnostic. It is aimed at development into a clinical diagnostic with certain types of fluorescence imaging. It is starting to show promise as a point of care approach to hemolysis.
Current work is focussed on 3 aspects of pro-resolution macrophages:
- clinical translation of HO-1 probes
- chromatin modifications, and the role of atherosclerotic genetic risk loci on chromatin modifications;
- gene regulation by by homeostatic mediators such as prostacyclin and specialised pro-resolving mediators.
Dr Boyle is fully clinically trained in histopathology, mainly at Cambridge, and specialised in cardiovascular and renal pathology. The research interests come from real-world clinical insights.
British Atherosclerosis Society John French Lecture
University of Glasgow Tenovus Lecture
Multiple international invited seminars.
et al., 2021, A coumarin-porphyrin FRET break-apart probe for heme oxygenase-1, Journal of the American Chemical Society, Vol:143, ISSN:0002-7863, Pages:6460-6469
et al., 2021, Metformin directly suppresses atherosclerosis in normoglycemic mice via haematopoietic Adenosine Monophosphate-Activated Protein Kinase (AMPK), Cardiovascular Research, Vol:117, ISSN:0008-6363, Pages:1295-1308
et al., 2020, Cells of the adult human heart, Nature, Vol:588, ISSN:0028-0836, Pages:466-472
et al., 2020, Hematoma resolution in vivo is directed by Activating Transcription Factor 1, Circulation Research, Vol:127, ISSN:0009-7330, Pages:928-944
et al., 2019, Cartilage oligomeric matrix protein associates with a vulnerable plaque phenotype in human atherosclerotic plaques, Stroke, Vol:50, ISSN:0039-2499
et al., 2019, The transcription factor ERG regulates super-enhancers associated with an endothelial-specific gene expression program, Circulation Research, Vol:124, ISSN:0009-7330, Pages:1337-1349
et al., 2015, Developmental origin of age-related coronary artery disease, Cardiovascular Research, Vol:107, ISSN:0008-6363, Pages:287-294
et al., 2014, Requirement of JNK1 for endothelial cell injury in atherogenesis, Atherosclerosis, Vol:235, ISSN:1879-1484, Pages:613-618
et al., 2013, 5′-AMP-Activated Protein Kinase-Activating Transcription Factor 1 Cascade Modulates Human Monocyte-Derived Macrophages to Atheroprotective Functions in Response to Heme or Metformin, Arteriosclerosis Thrombosis and Vascular Biology, Vol:33, ISSN:1079-5642, Pages:2470-2480
Boyle JJ, 2012, Heme and haemoglobin direct macrophage Mhem phenotype and counter foam cell formation in areas of intraplaque haemorrhage, Current Opinion in Lipidology, Vol:23, ISSN:0957-9672, Pages:453-461
et al., 2011, Activating Transcription Factor 1 Directs Mhem Atheroprotective Macrophages Through Coordinated Iron Handling and Foam Cell Protection., Circulation Research
et al., 2011, Heme Induces Heme Oxygenase 1 via Nrf2 Role in the Homeostatic Macrophage Response to Intraplaque Hemorrhage, Arteriosclerosis Thrombosis and Vascular Biology, Vol:31, ISSN:1079-5642, Pages:2685-U826
et al., 2009, Coronary Intraplaque Hemorrhage Evokes a Novel Atheroprotective Macrophage Phenotype, American Journal of Pathology, Vol:174, ISSN:0002-9440, Pages:1097-1108
et al., 2019, SMARCA4 REDIRECTS BINDING OF MACROPHAGE ACTIVATING TRANSCRIPTION FACTOR 1 (ATF1) FROM GENES FOR INFLAMMATION RESOLUTION TO GENES FOR ERYTHROCYTE RESOLUTION, 87th Congress of the European-Atherosclerosis-Society (EAS), ELSEVIER IRELAND LTD, Pages:E78-E78, ISSN:0021-9150
et al., 2020, COMPOUNDS FOR THE DETECTION OF HEME OXYGENASE 1 (HO-1), AND METHODS AND USES INVOLVING THE SAME, UK, 2017871.1