Immune suppressive pathways in wound healing

We aim to gain a better understanding of why chronic wounds such as diabetic foot ulcers (DFU) fail to heal and to gain a better understanding of immune cell roles in the healing process. These wounds have been observed to halt in the healing process during an inflammatory phase and fail to progress to re-epithelialisation, therefore we propose that mechanisms which suppress immune activity may be dysregulated. In this work we would aim to uncover whether these pathways are over-active in chronic wounds, creating an environment permissive to infection as chronic wounds are frequently infected. Alternatively such pathways could be under-active resulting in non-resolving inflammation causing tissue destruction and impairing healing. We initially propose to investigate a candidate immune suppressive pathway of CD200/CD200R due to expression of CD200 within the hair follicle, an important stem cell niche in the skin, and expression of the receptor by yo T-Cells and innate lymphoid cells in the skin which both have established roles in barrier immune responses. In addition we hope to identify potential interaction between wound infection status and immune suppressive pathways.

In order to investigate this we plan to study wound healing in murine models of chronic and acute wounding by diabetic wounding models including in CD200R deficient animals and to modify this process by addition of cells, blocking antibodies or CD200 ligand to such wounds. In parallel we are looking to investigate this in human DFU samples from which we also aim to correlate immune suppressive pathway activity with infection compostition. Additionally we will use RNAseq to identify other immune-suppressive pathway candidates in an unbiased way from human and mouse wound tissue.