Role of chemokine mediated inflammation during allograft rejection Professor Simi Ali (Newcastle University)
Organ transplantation is the treatment of choice for many patients with end-stage diseases. Despite its success transplantation is limited by the number of donor organs available. Furthermore, the biggest problem after organ transplantation is prevention of chronic deterioration of graft function. There is therefore an urgent need to prolong the life of a transplanted organ. The work I will present will be based on two major themes:
To develop and evaluate novel approaches that increases the availability of suitable donor organs for transplantation.
Following transplantation, the stress due to ischaemia reperfusion injury results in production of chemokines and reactive molecules such as peroxynitrite, which modify the chemokines by nitration. I will present our recent data that shows that the nitration of chemokines renders the chemokine non-functional. This phenomenon could be a natural form of chemokine regulation to prevent excessive inflammation, preventing its detection by conventional methods and therefore limiting the biological relevance of using unmodified chemokines as biomarkers.
Analysis of tissue re-modelling associated with allograft rejection.
Heparan Sulfate (HS) is involved in chronic inflammation and fibrosis development by binding proteins, enhancing their activity and creating chemokine gradients. Our data suggests that HS 3-O-sulfation is modified in fibrosis and highlights HS3ST1 as an attractive biomarker of fibrosis progression with a potential role in HB-EGF signaling. Additionally, recent evidence indicates that myofibroblasts, could be derived from other cell types including endothelial-to-mesenchymal transition (EndMT). Lineage tracing revealed expression of mesenchymal markers in endothelial derived cells, indicating the presence of EndMT in cardiac fibrosis. We have identified a microRNA signature of EndMT.
In summary our work has increased our understanding of the mechanisms involved in graft rejection and has suggested strategies to increase the survival of transplanted organs.
1) Barker CE, Thompson S, O'Boyle G, Lortat-Jacob H, Sheerin NS, Ali S, Kirby JA. CCL2 nitration is a negative regulator of chemokine-mediated inflammation. Scientific Reports, 2017, 7, 44384.
2) Alhasan AA, Spielhofer J, Kusche-Gullberg M, Kirby JA, Ali S. Role of 6-O-Sulfated Heparan Sulfate in Chronic Renal Fibrosis. Journal of Biological Chemistry, 2014, 289(29), 20295-20306.
3) Ladak, S. S., Ward, C. & Ali, S. The potential role of microRNAs in lung allograft rejection. The Journal of heart and lung transplantation 2016:35, 550-559.
4) Laura Ferreras, Anna Moles, Gerhard R. Situmorang, Rana el Masri, Imogen L. Wilson, Katie Cooke, Emily Thompson, Marion Kusche-Gullberg, Romain R. Vivès, Neil S. Sheerin, Simi Ali. Heparan sulfate in chronic kidney diseases: Exploring the role of 3-O-sulfation. Biochimica et Biophysica Acta - General Subjects, 2019 (May).