The role of skin macrophages under conditions of stress and injury: ultraviolet irradiation and wound healing

Abstract

Macrophages are immune cells known to have a diverse array of functions dependant on the local tissue environment. This thesis aimed to investigate the role of macrophages in the skin. The first aim was to study if targeting inflammatory cytokines and cellular pathways was able to improve the rate of wound closure in acute and/or chronic wounds. These inflammato r y pathways included the IL-17/IL-23 axis, the IL-33/ST2 pathway and the NLRP3 inflammasome. The next aim was to identify the role of macrophages in UV irradiatio n, specifically neonatal UV and the long-term effects in the skin and on local immune suppression. Finally, we aimed to identify the long-term effects of inflammation in the skin on the resident macrophage populations, studying the kinetics of their self-renewal.Macrophages play a vital role in wound healing, with either excessive or insufficie nt infiltration both able to induce impaired healing responses. Current therapies for chronic wounds have poor prognosis and outcomes, and as such the development of alternative treatments are required. We found IL-17 and IL-23 inhibition improved wound closure in obese, diabetic mice by switching the macrophage phenotype from pro-inflammatory to prohealing. IL-17 secreted from gamma delta T-cells significantly impaired wound closure, and the inhibition of IL-17 and its upstream regulator IL-23 by blocking antibodies was able to significantly improve chronic wound healing by increasing the percentage of alternative ly activated, pro-healing macrophages.IL-33 is a molecule that can function as an alarmin through its receptor, ST2. We used ST2-/-mice to assess the action of IL-33 during wound healing. We found ST2-/-mice had impaired wound closure, reduced angiogenesis and altered collagen deposition/remodelling compared to BALB/C controls. There was increased neutrophilic infiltrate and altered macrophage polarisation in ST2-/-mice wounds. These results indicate that ST2 signalling is important for macrophage differentiation, which may improve wound closure, increase angiogenesis and delay or prevent scarring.The NLRP3 inflammasome has been implicated in a variety of inflammatory diseases .We used MCC950, a water-soluble small molecule inhibitor of NLRP3 in a chronic wound healing mouse model in an attempt to improve wound healing. We failed to identify any significant differences in the rate of wound healing, or angiogenesis in MCC950-treated mice compared to controls. Our results indicated that the NLRP3 inflammasome is not significantly involved in chronic wound healing.iii UVR has been repeatedly reported to induce immune suppression, one of the driving factors for tumour formation. Delayed-type contact hypersensitivity (CHS) is the leading mechanism for testing UVR-mediated immune suppression. Previous studies in the Khosrotehrani lab identified that clodronate depletion was able to inhibit neonatal development of melanoma in transgenic mice. I therefore aimed to investigate the changes in the immune environment which were causing the inhibition of m...