Macrophage Differentiation
Dr Joseph Boyle - Head of Group
Dr Joseph Boyle in the laboratory
Cardiovascular disease is still a major cause of disease and death in developed nations; and is increasingly important in developing nations. The commonest cause of cardiovascular disease by far is progressive narrowing of arteries, including the coronary arteries that supply the heart. These narrowings are driven by high blood pressure, high cholesterol, diabetes, smoking, age, gender and other genetic factors. The narrowings that really matter the most are highly inflamed. In these fatty deposits including cholesterol have simulated infection triggered numerous specialised defence cells called macrophages. In fatal narrowings, these activated macrophages degrade the artery wall causing it break apart and trigger a clot.
The aim of this group is to understand better the workings of macrophages in arteries with vascular disease, with the long term goal of switching them from damaging arteries to helping repair.
Current research projects include:
Molecular cardiovascular pathology
Successes in understanding many of the mechanisms of cardiovascular diseases have led to real improvement in treatment and prevention (eg aspirin, statins, antihypertensives, thrombolysis). However, since people are living longer, cardiovascular disease is still responsible for most deaths in Western societies. Continued progress requires a deeper and more sophisticated understanding of its molecular pathology.
Most so-called heart attacks are due to plaque rupture, cracking of narrowed coronary arteries at points weakened by inflammation. These are associated with other destabilising events including plaque hemorrhage. This inflammation is part of the underlying process of hardening and narrowing, called atherosclerosis. Atherosclerosis is now widely accepted to be an inflammatory disease principally involving macrophages.
Transcriptional mechanisms switching macrophages to atheroprotection
Unstable plaques, including culprit lesions, are characterised by intraplaque haemorrhages as well as the more obvious thrombosis. In Professor Dorian Haskard's department, I have recently shown that human atherosclerotic plaques contain Hemorrhage-associated macrophages (HA-mac / M-hem) (Am.J.Pathol. 2009). These surround intraplaque haemorrhages and appear to defend the arterial wall from the atherogenic consequences of intraplaque hemorrhage. In this work, we also identified that lysosomal degradation of phagocytosed hemoglobin is key in driving differentiation to the HA-mac phenotype.
We now study the transcriptional regulatory mechanisms that determine commitment to this anti-oxidant macrophage subset. We are currently examining the signalling and transcriptional mechanisms determining commitment to this subset. Based on transcriptional biochemistry, microarray analysis, computational biology and transfection of primary macrophages, we have identified a novel transcriptional network. This has, at its core, a 'master regulator' transcription factor. We are currently dissecting the molecular mechanism of the transcription factor operating the hub of the network.
Since oxidation, especially of LDL, is a key contributor to atherosclerosis, understanding macrophage antioxidant differentiation has potential to contribute to the pathological understanding of vascular disease. In the longer term, we are actively assessing whether this phenotype could be exploited for therapy or imaging.
People:
Joseph Boyle, Emma Piper, Heather Harrington (Mathematics), Laurence Game (MRC CSC), Dominik Schaer (Zurich), Justin Mason, Dorian Haskard
Experimental modulation of atherosclerosis in vivo
I also supervise the pathological characterisation of atherosclerosis in in vivo genetically engineered models. This work has defined the protective role of complement components C1q, DAF and CD59, published in Am.J.Pathol. and ATVB.
People:
Dorian Haskard (PI), Joseph Boyle, Marina Botto, Justin Mason, Paul Evans
Subspecialist clinical work - cardiovascular pathology
I establish tissue diagnosis of surgically removed cardiovascular tissues and of vasculitis, primarily in temporal artery biopsies. This is in close conjunction with Justin Mason, Professor of Rheumatology. Any primary diagnosis of vasculitis is normally done within 24 hours. Referral work, principally vasculitis, is welcome.
Selected publications
- Leung,V.W., S.Yun, M.Botto, J.C.Mason, T.H.Malik, W.Song, D.Paixao-Cavalcante, M.C.Pickering, J.J.Boyle, and D.O.Haskard. 2009. Decay-accelerating factor suppresses complement C3 activation and retards atherosclerosis in low-density lipoprotein receptor-deficient mice. Am. J. Pathol. 175:1757-1767.
- Lewis,M.J., T.H.Malik, M.R.Ehrenstein, J.J.Boyle, M.Botto, and D.O.Haskard. 2009. Immunoglobulin M is required for protection against atherosclerosis in low-density lipoprotein receptor-deficient mice. Circulation 120:417-426.
- Boyle,J.J., H.A.Harrington, E.Piper, K.Elderfield, J.Stark, R.C.Landis, and D.O.Haskard. 2009. Coronary intraplaque hemorrhage evokes a novel atheroprotective macrophage phenotype. Am. J. Pathol. 174:1097-1108.
- Aitman,T.J., R.Dong, T.J.Vyse, P.J.Norsworthy, M.D.Johnson, J.Smith, J.Mangion, C.Roberton-Lowe, A.J.Marshall, E.Petretto, M.D.Hodges, G.Bhangal, S.G.Patel, K.Sheehan-Rooney, M.Duda, P.R.Cook, D.J.Evans, J.Domin, J.Flint, J.J.Boyle, C.D.Pusey, and H.T.Cook. 2006. Copy number polymorphism in Fcgr3 predisposes to glomerulonephritis in rats and humans. Nature 439:851-855.
- Boyle,J.J., D.E.Bowyer, P.L.Weissberg, and M.R.Bennett. 2001. Human blood-derived macrophages induce apoptosis in human plaque-derived vascular smooth muscle cells by Fas-ligand/Fas interactions. Arterioscler. Thromb. Vasc. Biol. 21:1402-1407.
- Boyle,J.J. 1997. Association of coronary plaque rupture and atherosclerotic inflammation. J. Pathol. 181:93-99.
