Research > Macrophage Biology (Wendy Jessup/Len Kritharides)
Macrophage Biology
Group Leaders: Professor Wendy Jessup and Professor Len Kritharides
Overview of Research
Our major research objective is to develop our knowledge of the biology of the macrophage, especially the macrophage foam cell in atherosclerosis. Foam cells are cholesterol and triglyceride-loaded macrophages, which form a large proportion of the developing atherosclerotic lesion and contribute much of the cholesterol deposited in the lesion core. Within this objective there are two major themes in the group. The first relates to investigating the mechanism, nature and impact of sterol accumulation in human disease, with particular emphasis on sterol accumulation in macrophages. The second relates to understanding the mechanisms regulating macrophage protein secretion, with a particular emphasis on apolipoprotein E (apoE).
We have ongoing research interests in the processes that mediate cellular lipid accumulation and by which cells export excess cholesterol. Understanding these processes and their application to lesion foam cell biology will provide new therapeutic targets for prevention and reversal of atherosclerosis. The knowledge also has wider application in many cell types whose biology is sensitive to lipid content.
ABC transporters and cell cholesterol export
Foam cell formation depends on a net excess of cholesterol import/synthesis over cholesterol export. Cholesterol export from macrophages is facilitated by ABCA1 and ABCG1, two members of the ATP Binding Cassette (ABC) Transporter family of proteins. Work from our group has shown that ABCA1 and ABCG1 work in synergy in this removal process, which may be impaired in foam cells. The mechanisms of action of these transporters as well as their post-translational regulation are poorly understood and these subjects are currently a major research focus. Besides vascular disease, ABC transporters are important in the development of a number of other conditions including cystic fibrosis, cancer (drug resistance) and general resistance to antibiotics. Learning more about the mode of action and regulation of these transporters can have benefits reaching far beyond heart disease.
ABC transporters in the plasma membrane export cell cholesterol to extracellular acceptors apolipoprotein AI and HDL (Jessup et al. (2006) Current Opin. Lipidol 17:247-257)Apolipoprotein E traffic and secretion
Secretion of apolipoprotein E (apoE) from foam cell macrophages is known to be anti-atherogenic, and the regulation of its secretion from other cell types may relate to the pathogenesis of other diseases such as Alzheimer’s disease. We have found that the secretion of apoE is closely regulated by constitutive protein kinase A activity and intracellular calcium levels, and can be stimulated by a range of molecules including apolipoprotein A-I (the main protein component of HDL). ApoE exits the Golgi within secretory vesicles that co-localise with the microtubular network (Figure). Future work will investigate in more detail how signalling pathways interact, how these regulate specific steps in intracellular transport, and their implications for the regulation of apoE secretion
in vivo.
ApoE-GFP vesicles align along the microtubules. Image courtesy of J Kay and J Stow, Institute of Molecular Biology, University of Queensland (Kockx et al. (2007) Circ. Res. 101:607-616).Group Members
| Wendy Jessup | Co-Leader |
| Len Kritharides | Co-Leader |
| Maaike Kockx | Senior Research Officer |
| Ingrid Gelissen | Senior Research Officer |
| Carmel Quinn | Senior Research Officer |
| Youra Lee | Postdoctoral Fellow |
| Mi-jurng Kim | Postdoctoral Fellow |
| Donna Dinnes | Postdoctoral Fellow |
| Denuja Karunakaran | Postdoctoral Fellow |
| Mathew Traini | Postdoctoral Fellow |
| Nicholas Proschogo | Postdoctoral Fellow |
| Cecilia Sandoval | Research Assistant |
| Heryanto Ng | Research Assistant |
| Sian Cartland | Postgraduate Student |
| Lily Guo | Postgraduate Student |
| Victar Hsieh | Postgraduate Student |
| Xianming Du | Postgraduate Student |
Key Publications
Out, R., W. W. Jessup. Le Goff, M. Hoekstra, I. C. Gelissen, Y. Zhao, L. Kritharides, G. Chimini, J. Kuiper, M. J. Chapman, T. Huby, T. J. Van Berkel, and M. Van Eck. (2008) Coexistence of foam cells and hypocholesterolemia in mice lacking the ABC transporters A1 and G1.
Circulation Research 102: 113-120.
Kockx M, Guo DL, Huby T, Lesnik P, Kay J, Sabaretnam T, Jary E, Hill M, Gaus K, Chapman J, Stow JL, Jessup W, Kritharides L. (2007) Secretion of apolipoprotein E from macrophages occurs via a protein kinase A and calcium-dependent pathway along the microtubule network.
Circulation Research101:607-616.
Gelissen, I. C., M. Harris, K. A. Rye, C. Quinn, A. J. Brown, M. Kockx, S. Cartland, M. Packianathan, L. Kritharides, and W. Jessup. (2006). ABCA1 and ABCG1 synergize to mediate cholesterol export to apoA-I.
Arterioscler Thromb Vasc Biol 26: 534-540.
Jessup W, Gelissen IC, Gaus K, Kritharides L. (2006) Roles of ATP binding cassette transporters A1 and G1, scavenger receptor BI and membrane lipid domains in cholesterol export from macrophages.
Curr Opin Lipidol. 17:247-257.
Kockx M, Rye KA, Gaus K, Quinn CM, Wright J, Sloane T, Sviridov D, Fu Y, Sullivan D, Burnett JR, Rust S, Assmann G, Anantharamaiah GM, Palgunachari MN, Lund-Katz S, Phillips MC, Dean RT, Jessup W, Kritharides L (2004). Apolipoprotein A-I-Stimulated Apolipoprotein E Secretion from Human Macrophages is Independent of Cholesterol Efflux.
J. Biol. Chem. 279: 25966-25977
Kockx M, Jessup W, Kritharides L (2008). Regulation of apoE secretion from macrophages. Review. Arterioscler.
Thromb. Vasc. Biol.In press
van Reyk DM, Brown AJ, Hult'en LM, Dean RT, Jessup W. (2006) Oxysterols in biological systems: sources, metabolism and pathophysiological relevance.
Redox Rep. 11:255-262.
Funding Sources