Haematopoesis and Leukocyte Biology Group
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Head of Laboratory
Associate Professor Andrew Murphy+61 3 8532 1292
Research Overview
Our group studies the fundamental biological process contributing to the retention and liberation of haematopoietic stem cells (HSCs) within specific bone marrow (BM) niches and how these HSCs and the BM niche become altered in disease. We are interested in how these HSCs traffic to the spleen and initiate extramedullary haematopoiesis. In particular we have a focus on how inflammatory diseases associated with increased cardiovascular risk influence these pathways, including diabetes, obesity and autoimmune diseases such as rheumatoid arthritis. We also explore how these diseases influence the function of circulating cells, namely monocytes, neutrophils and platelets. We also have a strong interest in the role of plaque macrophages and pathways contributing to foam cell formation.
We are also exploring the two main outcomes of vascular disease, myocardial infarction and stroke and how these diseases influence the haematopoietic system to promote enhanced myelopoiesis, which is associated with a worse outcome.
We are also focused on exploring the utility or current treatments and developing novel therapies to target the pathways we have identified in our preclinical models that are also detect in patients with these diseases.
Research focus:
- Fundamental process regulating haematopoiesis.
- Exploring how the lipidomes of immune cells regulates their function.
- Understand multi-organ communication to stimulate haematopoiesis.
- Determining how the body responds to hyperglycaemic spikes.
- Exploring if and how inflammatory diseases that are associated with increased cardiovascular risk, and how this might result in impaired regression of atherosclerotic lesions.
- Understanding how enhanced reticulated platelets influence accelerated atherosclerosis in diabetes.
- Exploring the role of human monocyte subsets in cardiovascular disease.
- Investigating pathways contributing to foam cell formation in the atherosclerotic lesion.
Staff
Dr Graeme Lancaster
Dr Man Kit "Sam" Lee
Dr Dragana Dragoljevic
Dr Andrew Fleetwood
Collaborators
Dr Prabhakara Nagareddy, Ohio State University, Colombus, USA
Dr Laurent Yvan-Charvet, INSREM, Nice, France
Drs Edward Fisher and Ira Goldber, New York University, NY, USA
Drs Edwin Hawkins, Marco Herold and Seth Masters, WEHI, Melbourne
Funding
NHMRC investigator grant
NHMRC project grant
CSL Centenery Award
Research Outcomes
1. Anti-inflammatory effects of High-Density Lipoproteins: Over the past decade I have made a number of seminal discoveries on how cholesterol efflux can dampen inflammation. In 2008 we published a paper in ATVB describing the anti-inflammatory effect of HDL on monocytes and followed this up with another article in ATVB examining the effects on neutrophils.
These studies using ex vivo and pre-clinical models were also validated in clinical studies using infusion of reconstituted (r)HDL in people. During my post-doctoral training I continued to study the effect of cholesterol metabolism on inflammation and made the novel discovery that apolipoprotein E was highly expressed in haematopoietic stem cells (HSCs) and regulated the production of myeloid cells – published in JCI. My research program then went on to show that increased production of myeloid cells accelerated atherogenesis, largely independent of monocyte activation. We then linked defects in cholesterol efflux to enhanced HSC mobilization, published in Cell Stem Cell.
Finally, we also made the discovery that the cholesterol transporter ABCG4 regulated platelet production by altering cell cholesterol levels and modulating growth factor receptor turnover. We also showed that rHDL infusion could lower platelet levels in people with peripheral vascular disease – published in Nature Medicine. I also contributed to, and led, studies where we developed and tested novel formulations of rHDL and HDL mimetics that dramatically increased the plasma half-life of rHDL while retaining all of its anti-inflammatory effects.
a. Murphy AJ, et al. High-density lipoprotein reduces the human monocyte inflammatory response. Arterioscler Thromb Vasc Biol. 2008;28:2071-7.
b. Murphy AJ, et al. Neutrophil activation is attenuated by high-density lipoprotein and apolipoprotein A-I in in vitro and in vivo models of inflammation. Arterioscler Thromb Vasc Biol. 2011;31:1333-41.
c. Shaw JA, Bobik A, Murphy A, et al. Infusion of reconstituted high-density lipoprotein leads to acute changes in human atherosclerotic plaque. Circ Res. 2008;103:1084-91
d. Murphy AJ, et al. ApoE regulates hematopoietic stem cell proliferation, monocytosis, and monocyte accumulation in atherosclerotic lesions in mice. J Clin Invest. 2011;121:4138-49.
e. Westerterp M*, Gourion-Arsiquaud S*, Murphy AJ*, et al. Regulation of hematopoietic stem and progenitor cell mobilization by cholesterol efflux pathways. Cell Stem Cell. 2012;11:195-206.
f. Murphy AJ, et al. Cholesterol efflux in megakaryocyte progenitors suppresses platelet production and thrombocytosis. Nat Med. 2013;19:586-94.
g. Murphy AJ, et al. Pegylation of high-density lipoprotein decreases plasma clearance and enhances antiatherogenic activity. Circ Res. 2013;113:e1-9.
h. Murphy AJ, et al. Anti-inflammatory functions of apolipoprotein A-I and high-density lipoprotein are preserved in trimeric apolipoprotein A-I. J Pharmacol Exp Ther. 2013;344:41-9.
2. Role of neutrophil-drive sterile inflammation in metabolic and chronic disease: In collaboration with Dr. Nagareddy (Ohio State University) my research program has made significant progress in understanding how diabetes and obesity contribute to accelerated atherosclerosis and impaired atherosclerotic lesion regression by promoting myeloid cell production. We initially discovered that hyperglycaemia caused neutrophils to produce a complex of proteins S100A8/A9, that signalled the bone marrow progenitor cells to make more myeloid cells. This could be reversed by administering at that time a novel glucose-lowering agent, which is now used to treat people with diabetes (sodium-glucose co-transporter 2 inhibitor) – published in Cell Metabolism. We have describing the clinical relevance of this pathway in a model of transient intermittent hyperglycaemia experienced by people with pre-diabetes and diabetes following a meal. We then followed this finding up by examining models of obesity and showed that local S100A8/A9 production in the obese adipose tissue promoted IL-1β production and monocytosis. We found that treatment with the IL-1 receptor antagonist, Anakinra could inhibit this pathway – published in Cell Metabolism. We are now extending our program to develop monoclonal antibodies against S100A8/A9 and to test small molecule inhibitors of this protein (i.e. ABR-215757). Furthermore, I am also extending the program on this molecule to explore its role in diabetes associated reticulated thrombocytosis – published in the JCI in 2018. We have also explored the role of other inflammasomes, namely NLRP1 in the context of IL-18 production and obesity, published in Cell Metabolism. Extending our findings on neutrophil activation, S100A8/A9 and IL-1β with the involvement of inflammatory diseases to produce macrophages we recently published in Circulation showing an important role in the post myocardial infarction inflammatory response.
a. Nagareddy PR*, Murphy AJ*, et al. Hyperglycemia promotes myelopoiesis and impairs the resolution of atherosclerosis. Cell Metab. 2013;17:695-708. *Co-first authors
b. Nagareddy PR, …..Murphy AJ. Adipose tissue macrophages promote myelopoiesis and monocytosis in obesity. Cell Metab. 2014;19:821-35
c. Murphy AJ, et al. IL-18 Production from the NLRP1 Inflammasome Prevents Obesity and Metabolic Syndrome. Cell Metab. 2016;23:155-64.
d. Kraakman MJ*, Lee M.K.S*,… Nagareddy PR^ & Murphy AJ^. Neutrophil-derived S100A8/S100A9 promotes reticulated thrombocytosis and atherogenesis in diabetes. J Clin Invest. 2017. 127(6):2133-2147. ^Co-senior authors
e. Sreejit G, …. Murphy AJ^ & Nagareddy PR^. Neutrophil-derived S100A8/A9 amplify granulopoiesis following myocardial infarction. Circulation. 2020, (13):1080-1094. PMID: 31941367141. ^Co-senior authors
f. Flynn MC*, Kraakman MJ*, …., Nagareddy PR^, Thomas MC^, Murphy AJ^. Transient intermittent hyperglycemia accelerates atherosclerosis by promoting myelopoiesis. Circ Res, 2020 (In Press). ^Co-senior authors
Research Publications
1. Murphy AJ, Akhtari M, Tolani S, Pagler T, Bijl N, Kuo CL, Wang M, Sanson M, Abramowicz S, Welch C, Bochem AE, Kuivenhoven JA, Yvan-Charvet L and Tall AR. ApoE regulates hematopoietic stem cell proliferation, monocytosis, and monocyte accumulation in atherosclerotic lesions in mice. J Clin Invest. 2011;121:4138-49
2.Murphy AJ, Bijl N, Yvan-Charvet L, Welch CB, Bhagwat N, Reheman A, Wang Y, Shaw JA, Levine RL, Ni H, Tall AR and Wang N. Cholesterol efflux in megakaryocyte progenitors suppresses platelet production and thrombocytosis. Nature Medicine. 2013;19:586-94.
3. Nagareddy PR*, Murphy AJ*, Stirzaker RA, Hu Y, Yu S, Miller RG, Ramkhelawon B, Distel E, Westerterp M, Huang LS, Schmidt AM, Orchard TJ, Fisher EA, Tall AR and Goldberg IJ. Hyperglycemia promotes myelopoiesis and impairs the resolution of atherosclerosis. Cell Metab. 2013;17:695-708. * Equal fist author
4. Nagareddy PR, Kraakman M, Masters SL, Stirzaker RA, Gorman DJ, Grant RW, Dragoljevic D, Hong ES, Abdel-Latif A, Smyth SS, Choi SH, Korner J, Bornfeldt KE, Fisher EA, Dixit VD, Tall AR, Goldberg IJ and Murphy AJ. Adipose tissue macrophages promote myelopoiesis and monocytosis in obesity. Cell Metab. 2014;19:821-35.
5. Murphy AJ, Kraakman MJ, Kammoun HL, Dragoljevic D, Lee MK, Lawlor KE, Wentworth JM, Vasanthakumar A, Gerlic M, Whitehead LW, DiRago L, Cengia L, Lane RM, Metcalf D, Vince JE, Harrison LC, Kallies A, Kile BT, Croker BA, Febbraio MA and Masters SL. IL-18 Production from the NLRP1 Inflammasome Prevents Obesity and Metabolic Syndrome. Cell Metab. 2016;23:155-64.
6. M.J Kraakman, M.K.S Lee, A Al-Sharea, D Dragoljevic, T.J Barrett, E Montenont, D Basu, S Heywood, H.L Kammoun, M Flynn, A Whillas, N.M.J Hanssen, M.A Febbraio, E Westein, E.A Fisher, J Chin-Dusting, M.E Cooper, J.S Berger, I.J Goldberg, P.R Nagareddy, A.J Murphy. Neutrophil-derived S100A8/S100A9 promotes reticulated thrombocytosis and atherogenesis in diabetes. J Clin Invest. 2017. 127(6):2133-2147.
7. MJ Kraakman*, HL Kammoun*, D Dragoljevic, A Al-Sharea, MKS Lee, MC Flynn, CJ Stolz, AA Guirguis, GI Lancaster, J Chin-Dusting, DJ Curtis, AJ Murphy. Leptin-deficient obesity prolongs survival in a murine model of Myelodysplastic Syndrome. Haematologica. 2018.
8. D Dragoljevic, MJ Kraakman, PR Nagareddy, D Ngo, W Shihata, HL Kammoun, A Whillas, MKS Lee, A Al-Sharea, G Pernes, MC Flynn, GI Lancaster, MA Febbraio, J Chin-Dusting, BY Hanaoka, IP Wicks, AJ Murphy. Defective cholesterol metabolism in haematopoietic stem cells promotes monocyte-driven atherosclerosis in rheumatoid arthritis. European Heart Journal. 2018;39(23):2158-2167.
9. A Al-Sharea, MKS Lee, A Whillas, D Michell, W Shihata, AJ Nicholls, OD Cooney, MJ Kraakman, C Bertuzzo Veiga, A-M Jefferis, K Jackson, PR Nagareddy, G Lambert, CHY Wong, KL Andrews, GA Head, J Chin-Dusting, AJ Murphy. Chronic sympathetic driven hypertension promotes atherosclerosis by enhancing hematopoiesis. Haematologica. 2019;104(3):456-467.
10. G Sreejit, A Abdel-Latif, B Athmanathan, A Dhyani, SK Noothi, GA Quaife-Ryan, A Al-Sharea, G Pernes, D Dragoljevic, H Lal, Kate Schroder, BY Hanaoka, C Raman, MB Grant, JE Hudson, SS Smyth, ER Porrello, AJ Murphy*, PR Nagareddy*. Neutrophil-Derived S100A8/A9 Amplify Granulopoiesis After Myocardial Infarction. Circulation. 2020:141:1080-1094. *Joint senior authors.
11. MC Flynn, MJ Kraakman, C Tikellis, MKS Lee, NMJ Hanssen, HL Kammoun, RJ Pickering, D Dragoljevic, A Al-Sharea, TJ Barrrett, F Hortle, FL Byrne, E Olzomer, DA McCarthy, CG Schalkwijk, JM Forbes, K Hoehn, L Makowski, GI Lancaster, A El-Osta, EA Fisher, IJ Goldberg, ME Cooper, PR Nagareddy, MC Thimas, AJ Murphy. Transient intermittent hyperglycaemia accelerates atherosclerosis by promoting myelopoiesis. Circulation Research. 2020; doi:10.1161/CIRCRESAHA.120.316653. Online ahead of print.