Immune-suppressive pathways in wound healing

Abstract

Immune cells play a key role in the successful healing of skin wounds, aiding the progression through the stages of inflammation, proliferation and tissue remodelling. However, inappropriate immune cell activity has been linked with chronic wound pathology, where chronic inflammation and insufficient pro-healing immune cell activities have been observed. Chronic wounds are particularly associated with the elderly and those with diabetes, and both of these groups display chronic low-grade inflammation, indicating that loss of control of immune cell activities could also have a role in impaired healing. Equally, scarring is an undesirable outcome of skin healing with loss of tissue function and flexibility, and is also associated with uncontrolled immune cell activity. Therefore, it was hypothesised that immune-suppressive pathways are important in controlling wound immune cell activity, and therefore could be important for healing outcomes. The roles of two candidate negative immune regulatory receptors, CD200R1 and PD-1 were examined in murine wound healing models. These analyses demonstrated an increase in expression of CD200R1 and PD-1 by ILC2 and Tregs in wound healing and cells expressing these negative regulators displayed functional differences such as increased expression of amphiregulin. Expression of ligands for these pathways was also altered with reductions in CD200+ epithelial cells in early healing and loss of PD-L1/2+ DCs during a similar timeframe with cells expressing either ligand likely to localise to hair follicle structures. However, modulation of CD200R1, PD-1 or both in young adult mice did not alter healing. During middle-age however, CD200R1-deficient mice displayed delayed healing with increased ILC2 and TH2 cells which may have contributed to the reduced wound contraction and increased collagen deposition in these wounds. A persistent scab was also seen on CD200R1KO wounds which may be linked to increases in neutrophils and reduced macrophage. Therefore, CD200R1 plays an age-dependent role in murine skin healing and may be needed to allow the transition to less fibrotic and more regenerative healing by suppressing type-2 responses as well as by limiting overall wound inflammation such as by limiting neutrophil recruitment. This increases our understanding of CD200R1’s role in response to tissue damage, could inform future work in chronic wound models and has potential relevance to the current trials therapeutically targeting CD200R1 for other conditions.

Date of Award	1 Aug 2024
Original language	English
Awarding Institution	The University of Manchester
Supervisor	Sheena Cruickshank (Supervisor), Kimberly Mace (Supervisor) & Amy Saunders (Supervisor)