Inflammation and Immunology
BSc in Applied Biology from Bath University and PhD in cartilage biochemistry and ultrastructure from Lancaster University. Postdoctoral positions were at Strangeways Research Laboratory Cambridge and Bath University. Senior Scientist in immunopharmacology at Novartis Research Institute, Vienna. Senior Lecturer, Reader, then Professor and Head of Arthritis Research at the RJAH Orthopaedic Hospital, Oswestry which is part of the Medical School, Keele University. Visiting professor at Endocube, a biotech company in Toulouse, France. Consultant for GlaxoSmithKline. Joined Bristol University in Sept 2010 and became Professor and Reader in Cellular Immunology and Head of Inflammation and Immunology group, School of Oral and Dental Sciences, Faculty of Medicine and Dentistry.
Inflammation and Immunology
The mechanism of leukocyte and stem migration into sites of inflammation is fundamental to all inflammatory diseases such as periodontitis of the gums and rheumatoid arthritis. Chemokines are cytokines that function by stimulating leukocytes to migrate across endothelial cells and into inflamed tissues. By understanding these mechanisms the aim is to identify which molecules to target therapeutically.
Endothelial cells and leukocytes
In order for leukocytes to leave the blood they need to adhere to the luminal surface of endothelial cells, migrate across these cells, and enter tissues. Chemokines are involved in both of these mechanisms, and exert their migratory effects on leukocytes by interacting with cell-surface chemokine receptors. Work is focused on the mechanism by which endothelial cells transport chemokines to their luminal surfaces where they are presented to blood leukocytes on the tips of finger-like protrusions (microvilli). Molecules such as syndecans, the Duffy antigen/receptor for chemokines (DARC) and chemokines are involved. The role of several receptors such as CCR9 and GPR15/Bob on monocytes and macrophages, and their effects on cell migration and differentiation, is also being studied.
Mesenchymal stem cells
Mesenchymal stem cells (MSCs) have anti-inflammatory properties that make them potentially interesting cells in inflammatory diseases. MSCs have the ability to migrate into tissues where they can reduce inflammation and enhance tissue repair. Particular receptors such as CCR3, CCR5, CXCR4, CXCR5 and CXCR6 occur on human MSCs. These receptors are functional in MSC migration and could be used to enhance the entry and accumulation of MSCs in inflamed tissues.
Examples of publications
Middleton, J., Neil,S., Wintle, J., Clark-Lewis, I., Moore, H., Lam, C., Auer, M., Hub, E. and Rot, A. (1997). Transcytosis and surface presentation of IL-8 by venular endothelial cells. Cell 91(3), 385-395.
Wolff, B., Burns, A., Middleton, J. and Rot, A. (1998). Endothelial cell memory of inflammatory stimulation: human venular endothelial cells store interleukin-8 in Weibel-Palade bodies. Journal of Experimental Medicine 188, 1757-1762.
Patterson, A.M., Chamberlain, G., Siddall, H. Gardner, L. and Middleton, J. (2002a). Expression of the Duffy antigen/receptor for chemokines (DARC) by the inflamed synovial endothelium. Journal of Pathology 197, 108-116.
Middleton, J., Patterson, A., Gardner, L., Schmutz, C. and Ashton, B. (2002). Leukocyte extravasation: chemokine transport and presentation by the endothelium. Blood 100 (12), 3853-3860.
Gardner, L., Patterson, A.M., Ashton, B.A., Stone, M.A. and Middleton, J. (2004). The human Duffy antigen binds selected inflammatory but not homeostatic chemokines. Biochemical Biophysical Research Communications 321, 306-312.
Schmutz, C., Hulme, A., Burman, A., Salmon, M., Ashton, B., Buckley, C. and Middleton, J. (2005). Chemokine receptors in the rheumatoid synovium: up-regulation of CXCR5. Arthritis Research and Therapy 7, 217-229.
Patterson, A.M., Gardner, L., Shaw, J., David,G., Loreau, E., Aguilar,L., Ashton, B.A. and Middleton, J. (2005). Induction of a CXCL8 binding site on endothelial syndecan-3 in the rheumatoid synovium. Arthritis and Rheumatism 52, (8) 2331-2342.
Gardner L, Wilso n C, Patterson AM,Bresnihan B,Stone MA, Ashton BA, Middleton J. (2006) Temporal expression pattern of Duffy antigen in early rheumatoid arthritis: up-regulation in early disease. Arthritis and Rheumatism 54, (6) 2022-2026.
Chamberlain G, Fox J, Ashton B, Middleton J. (2007). Mesenchymal Stem Cells: their Phenotype, Differentiation Capacity, Immunological Features and Potential for Homing. Stem Cells. 25(11):2739-49.
Patterson AM, Cartwright A, DavidG, Fitzgerald O, Bresnihan B, Ashton BA, Middleton J. (2008). Differential expression of syndecans and glypicans in chronically inflamed synovium. Annals of Rheumatic Diseases 67 (5) 592-601.
Chamberlain G, Wright K, Rot A, Ashton B, Middleton J (2008). Murine mesenchymal stem cells exhibit a restricted repertoire of functional chemokine receptors: comparison with human. PLoS ONE 3, (8) 1-6 (e2934)
Pruenster M, Mudde L, Bombosi P, Dimitrova S, Zsak M, Middleton J, Richmond A, Graham G, Segerer S, Nibbs R, Rot A. (2009) Duffy antigen receptor for chemokines transports chemokines and supports their pro-migratory activity. Nature Immunology 10(1):101-8.
Schmutz C, Cartwright A, Williams H, Haworth O, Williams J, Filer A, Mike Salmon M, Christopher D Buckley CD, Middleton J. (2010) Monocytes/macrophages express CCR9 in rheumatoid arthritis and CCL25stimulates their differentiation. Arthritis Research & Therapy 12:R161 (pages 1-12)
Chamberlain G, Smith H, Rainger G. Ed, Middleton J. (2011). Mesenchymal stem cells exhibit firm adhesion, crawling, spreading and transmigration across aortic endothelial cells: effects of chemokines and shear. PloS ONE 6(9):e25663. 1-9
Smith H, Whittall C, Weksler B, Middleton J. (2012). Chemokines stimulate bi-directional migration of human mesenchymal stem cells across bone marrow endothelial cells. Stem Cells and Development Feb 10;21(3):476-86.
Keywords: chemokines, chemokine receptors, inflammatory and autoimmune diseases, leukocytes, stem cells and endothelial cells
Leukocyte trafficking, inflammation
Andrew Eustace, Sophie King
Immunofluoresence microscopy, electron microscopy, flow cytometry, cell culture, in vivo models
Simi Ali, Newcastle, UK Chris Buckley, Birmingham, UK Guido Davide, Leuven, Belgium Ofer Reizes, Cincinnatti, USA Antal Rot, Birmingham, UK
I am interested in the mechanism of leukocyte recruitment in inflammatory diseases, such as rheumatoid arthritis and periodontal disease. The focus is on chemokines and their receptors. Research is in three main areas: 1) how chemokines are transported and presented by endothelial cells leading to leukocyte migration from the blood and into the tissue; 2)the chemokine receptors on leukocytes; 3) how stem cells migrate into inflamed tissues.
Full publications list in the University of Bristol publications system
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