Immune responses to altered skin microenvironments

Abstract

The immune system responds to perturbation of the skin microenvironment through an exquisitely complex network of cellular and molecular processes. In response to wounding, immune cells must co-operate in a tightly organised manner to replace damaged tissue and restore the barrier function of skin in a timely manner. Diabetes dysregulates repair processes in the skin, which often leads to chronic wounds that have serious effects on morbidity and mortality. New therapies for the prevention and management of chronic wounds are urgently required. We therefore investigated the effects of two immunomodulatory therapies on wound healing in animal models of diabetes: narrowband ultraviolet B (NBUVB) radiation. and RP23 – a novel immunomodulatory drug derived from a naturally occurring human peptide. Our investigation of the effects NBUVB pre-treatment in a mouse model of excisional wound healing revealed surprising new insights into the pathways through which NBUVB modulates the immune system at the site of irradiation and in distant, non-skin tissues. We also designed and optimised an imaging mass cytometry (IMC) panel of 40 markers focused on immune cells and structural components of inflamed human skin for implementation in a study of chronic diabetic wound tissue. The data presented in this thesis build on our understanding of how the immune system responds to altered skin microenvironments. Our exploration of the effects of NBUVB on local and systemic immune responses will help inform future studies aiming to harness the beneficial effects of sunlight to promote human health. This thesis also highlights the complexity of impaired wound healing in diabetes and the need for mouse models that more closely recapitulate human wounds. The implementation of our human IMC panel will inform the design of new animal models of diabetic wound healing and help identify therapeutic targets for chronic wounds and other conditions involving skin inflammation