Prof Jim Middleton

Title: Honorary Visiting Professor
Reader in Cellular Immunology

Phone: +44 (0)117 342 4146 or +44 (0)1691 404149
Email:
Location: Leopold Muller Arthritis Research Centre, School of Medicine, Keele University
RJAH Orthopaedic Hospital, Oswestry, Shropshire SY10 7AG United Kingdom
Role: ISTM Research theme: 1. Infection, Inflamation & Immunity
2. Bioengineering & Therapeutics
Contacting me: By e-mail please.
Dr Jim Middleton

My interests are in inflammatory diseases, mainly rheumatoid arthritis:

  • What is the function of chemokine presenting and transporting molecules in the endothelium, leading to leukocyte migration into the inflamed tissue?
  • What are the chemokine receptors on leukocytes that mediate their migration?
  • Can stem cells be used as anti-inflammatory therapy?
  • Can stem cells be targeted to inflamed tissues by using chemokine receptors?

My group is based in laboratories at the Robert Jones & Agnes Hunt Orthopaedic Hopital at Oswestry. It uses a variety of techniques: cell culture, flow cytometry, chemotaxis assays, immunohistochemistry, confocal microscopy, RT-PCR, western blots.

In 2010 I moved to Bristol University and retain a visiting honorary role at Keele University from 1 October 2010 to 30 September 2013.

For further details please see: Prof Middleton's page at the University of Bristol

 

ISTM Research theme: 1. Infection, Inflamation & Immunity
                                    2. Bioengineering & Therapeutics

Expression of the Duffy antigen/receptor for chemokines by blood vessels in the synovium Left: Non-rheumatoid synovium Right: Rheumatoid synovium  

       Non-rheumatoid synovium                   Rheumatoid synovium
Expression of the Duffy antigen/receptor for chemokines by blood vessels in the synovium

We are interested in the mechanism of leukocyte emigration from the blood and into tissues at sites of inflammation, with focus on rheumatoid arthritis. The involvement of chemokines and their receptors/binding sites are being examined.

We are currently studying the expression of chemokine binding sites on the endothelium that may be involved in transcytosing chemokines and presenting them to blood leukocytes. These sites include glycosaminoglycans and the Duffy receptor and their functional contribution is beginning to be addressed.

Another project is studying the expression of chemokine receptors on leukocytes in rheumatoid arthritis with the aim of revealing therapeutic targets in the disease. This has been by using a functional genomic and protein expression approach. Selective expression of chemokine receptors on leukocytes in the rheumatoid synovium has been found, which may cause the recruitment of specific leukocyte subsets into the diseased tissue.

Funding for our work is from the Arthritis Research Campaign, Smith’s Charity, Wellcome Trust, BBSRC and Astrazeneca.

Chemokine and chemokine receptor mRNA expression in rheumatoid (A) and non-rheumatoid (B) synovia using microarrays  

Chemokine and chemokine receptor mRNA expression in rheumatoid (A) and non-rheumatoid (B) synovia using microarrays.

 

 

Selection 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.

Patterson, A.M., Siddall, H., Chamberlain, G., Gardner, L. and Middleton, J. (2002). Expression of the duffy antigen/receptor for chemokines (DARC) by the inflamed synovial endothelium. Journal of Pathology 197(1): 108-116.

Patterson, A.M., Schmutz, C., Davis, S., Gardner, L., Ashton, B.A. and Middleton, J. (2002). Differential binding of chemokines to macrophages and neutrophils in the human inflamed synovium. Arthritis Research 4(3): 209-214.

Middleton, J., Patterson, A.M., Gardner, L., Schmutz, C. and Ashton, B.A. (2002). Leukocyte extravasation: chemokine transport and presentation by the endothelium. Blood 100(12): 3853-3860.

 

 

 

Selected Publications

  • Pruenster M, Dimitrova S, Middleton J, Richmond A, Graham GJ, Segerer S, Nibbs RJB, Rot A. 2009. Duffy antigen/receptor for chemokines transports chemokines and supports their pro-migratory activity 'in vitro' and 'in vivo'. EUROPEAN JOURNAL OF CLINICAL INVESTIGATION, vol. 39, 23-24. link>
  • Wright HL, McCarthy HS, Middleton J, Marshall MJ. 2009. RANK, RANKL and osteoprotegerin in bone biology and disease. Curr Rev Musculoskelet Med, vol. 2(1), 56-64. link> doi>
  • Pruenster M, Mudde L, Bombosi P, Dimitrova S, Zsak M, Middleton J, Richmond A, Graham GJ, Segerer S, Nibbs RJB, Rot A. 2009. The Duffy antigen receptor for chemokines transports chemokines and supports their promigratory activity (vol 10, pg 101, 2008). NATURE IMMUNOLOGY, vol. 10(2), 223. link> doi>
  • MIDDLETON JFS, Smith E, McGettrick HM, Stone MA, Shaw JS, Nash GB, Buckley CD, Rainger GE. 2008. Duffy antigen receptor for chemokines and CXCL5 are essential for the recruitment of neutrophils in a multicellular model of rheumatoid arthritis synovium. Arthritis and Rheumatism, vol. 58(7), 1968-1973. doi>
  • Patterson AM, Cartwright A, David G, Fitzgerald O, Bresnihan B, Ashton BA, Middleton J. 2008. Differential expression of syndecans and glypicans in chronically inflamed synovium. link> doi>

Full Publications List show

Journal Articles

  • Pruenster M, Dimitrova S, Middleton J, Richmond A, Graham GJ, Segerer S, Nibbs RJB, Rot A. 2009. Duffy antigen/receptor for chemokines transports chemokines and supports their pro-migratory activity 'in vitro' and 'in vivo'. EUROPEAN JOURNAL OF CLINICAL INVESTIGATION, vol. 39, 23-24. link>
  • Wright HL, McCarthy HS, Middleton J, Marshall MJ. 2009. RANK, RANKL and osteoprotegerin in bone biology and disease. Curr Rev Musculoskelet Med, vol. 2(1), 56-64. link> doi>
  • Pruenster M, Mudde L, Bombosi P, Dimitrova S, Zsak M, Middleton J, Richmond A, Graham GJ, Segerer S, Nibbs RJB, Rot A. 2009. The Duffy antigen receptor for chemokines transports chemokines and supports their promigratory activity (vol 10, pg 101, 2008). NATURE IMMUNOLOGY, vol. 10(2), 223. link> doi>
  • MIDDLETON JFS, Smith E, McGettrick HM, Stone MA, Shaw JS, Nash GB, Buckley CD, Rainger GE. 2008. Duffy antigen receptor for chemokines and CXCL5 are essential for the recruitment of neutrophils in a multicellular model of rheumatoid arthritis synovium. Arthritis and Rheumatism, vol. 58(7), 1968-1973. doi>
  • 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, vol. 3(8), e2934. link> doi>
  • Chamberlain G, Fox J, Ashton B, Middleton J. 2007. Concise review: mesenchymal stem cells: their phenotype, differentiation capacity, immunological features, and potential for homing. Stem Cells, vol. 25(11), 2739-2749. link> doi>
  • Fox JM, Chamberlain G, Ashton BA, Middleton J. 2007. Recent advances into the understanding of mesenchymal stem cell trafficking. Br J Haematol, vol. 137(6), 491-502. link> doi>
  • MIDDLETON JFS, Hughes SF, Hendricks BD, Edwards DR, Bastawrous SS, Roberts GE. 2007. Mild episodes of tourniquet-induced forearm ischaemia-reperfusion injury results in leukocyte activation and changes in inflammatory and coagulation markers. Journal of Inflammation, vol. 4(12), 1-8. doi>
  • Barksby HE, Milner JM, Patterson AM, Peake NJ, Hui W, Robson T, Lakey R, Middleton J, Cawston TE, Richards CD, Rowan AD. 2006. Matrix metalloproteinase 10 promotion of collagenolysis via procollagenase activation: implications for cartilage degradation in arthritis. Arthritis Rheum, vol. 54(10), 3244-3253. link> doi>
  • Gardner L, Wilson C, Patterson AM, Bresnihan B, FitzGerald O, Stone MA, Ashton BA, Middleton J. 2006. Temporal expression pattern of Duffy antigen in rheumatoid arthritis: up-regulation in early disease. Arthritis Rheum, vol. 54(6), 2022-2026. link> doi>
  • Milner JM, Kevorkian L, Young DA, Jones D, Wait R, Donell ST, Barksby E, Patterson AM, Middleton J, Cravatt BF, Clark IM, Rowan AD, Cawston TE. 2006. Fibroblast activation protein alpha is expressed by chondrocytes following a pro-inflammatory stimulus and is elevated in osteoarthritis. Arthritis Res Ther, vol. 8(1), R23. link> doi>
  • MIDDLETON JFS, Ashton BA, Gardner L, Patterson AM. 2005. Induction of a CXCL8 binding site on endothelial syndecan-3 in rheumatoid synovium. Arthritis and Rheumatism, vol. 52(8), 2331-2342. doi>
  • Middleton J, Americh L, Gayon R, Julien D, Mansat M, Mansat P, Anract P, Cantagrel A, Cattan P, Reimund JM, Aguilar L, Amalric F, Girard JP. 2005. A comparative study of endothelial cell markers expressed in chronically inflamed human tissues: MECA-79, Duffy antigen receptor for chemokines, von Willebrand factor, CD31, CD34, CD105 and CD146. J Pathol, vol. 206(3), 260-268. link> doi>
  • Schmutz C, Hulme A, Burman A, Salmon M, Ashton B, Buckley C, Middleton J. 2005. Chemokine receptors in the rheumatoid synovium: upregulation of CXCR5. Arthritis Res Ther, vol. 7(2), R217-R229. link> doi>
  • GARDNER L, PATTERSON AM, ASHTON BA, STONE MA, MIDDLETON J. 2004. The human Duffy antigen binds selected inflammatory but not homeostatic chemokines. Biochemical Biophysical Research Communications. doi>
  • SCHMUTZ C, HULME A, BURMAN A, SALMON M, ASHTON B, BUCKLEY C, MIDDLETON J. 2004. Differential expression of the chemokine receptor CXCR5 in the rheumatoid synovium. Arthritis and Rheumatism, vol. 50(9), 87.
  • MIDDLETON J, AMERICH L, GAYON R, JULIEN D, AGUILAR L, AMALRICH F, GIRARD JP. 2004. Endothelial cell phenotypes in the rheumatoid synovium: activated, angiogenic, apoptotic and leaky. Arthritis Research and Therapy. doi>
  • PATTERSON AM, GARDNER L, SHAW J, LOREAU E, AGUILAR L, MIDDLETON J. 2004. Syndecan-3 binds CXCL8 on the synovial endothelium in rheumatoid arthritis. Rheumatology.
  • MIDDLETON JFS, Gardener L, Patterson A, Schmutz C. 2002. Leukocyte extravasation: chemokine transport and presentation by the endothelium. Blood, vol. 100(12), 3853-3860. doi>
  • Patterson AM, Siddall H, Chamberlain G, Gardner L, Middleton J. 2002. Expression of the duffy antigen/receptor for chemokines (DARC) by the inflamed synovial endothelium. J Pathol, vol. 197(1), 108-116. link> doi>
  • Patterson AM, Schmutz C, Davis S, Gardner L, Ashton BA, Middleton J. 2002. Differential binding of chemokines to macrophages and neutrophils in the human inflamed synovium. ARTHRITIS RESEARCH, vol. 4(3), 209-U13. link> doi>
  • Patterson AM, Schmutz C, Davis S, Gardner L, Ashton BA, Middleton J. 2002. Differential binding of chemokines to macrophages and neutrophils in the human inflamed synovium. Arthritis Res, vol. 4(3), 209-214. link>
  • MIDDLETON JFS, Patterson A, Chamberlain G, Siddall H. 2001. Chemokine binding sites of the endothelium of rheumatoid synovium: expression of potential chemokine presenters and transporters. Rheumatology, vol. 40, Supplement 1, 186.

Other

  • Patterson AM, Cartwright A, David G, Fitzgerald O, Bresnihan B, Ashton BA, Middleton J. 2008. Differential expression of syndecans and glypicans in chronically inflamed synovium. link> doi>
  • Chamberlain G, Rot A, Ashton B, Middleton J. 2008. Chemokine receptors on human and murine mesenchymal stem cells. RHEUMATOLOGY (vol. 47, pp. II61-II62). link>