Epidermal Reactions to Injury with Implications for Innate Immunity
Sammanfattning: Abstract The epidermis is one of our primary interfaces towards the external milieu. Following injury, the physical barrier function of the skin is destroyed and the epidermis is left vulnerable to microbial invasion. Inducible innate immune response mechanisms exist to keep the wound site free from infection, thus allowing the wound to heal and the epidermis to re-establish its barrier function. The main focus of the present thesis has been to investigate the regulatory mechanisms of some of these responses. In paper I we present an injury-induced mechanism for increasing the production of antimicrobial peptides (AMPs) in the skin mediated by the epidermal growth factor receptor (EGFR) transactivation process. In paper II we further highlight the importance of this mechanism by demonstrating that it is responsible for the bulk of the expression of the AMPs known to be induced in epidermis during the proliferative phase of wound healing. In addition we show that the EGFR-mediated increase in interleukin-8 (IL-8) production represents the primary source of chemotactic activity towards neutrophils generated in injured human epidermis. Thus a novel molecular link between cutaneous injury and neutrophil accumulation is provided. In paper III we disclose a possible role of the prion protein as an AMP in host defense, based on its antimicrobial properties and EGFR-dependent induction in response to injury. In paper IV we furthermore report an increased expression of several protease inhibitors during wound healing and a change in gene expression in the epidermal tissue representing a shift in the apoptotic balance. The shift indicates a reduced sensitivity to the extrinsic pathway of apoptosis and concomitantly, an apparently increased sensitivity to the intrinsic pathway of apoptosis. Taken together we hypothesize that this represents an epidermal response to cope with the external detrimental effects of inflammation while safeguarding itself against the increased risk of malignant transformation accompanying the increased proliferation. Finally we identify a highly significant overrepresentation of transcription factor binding sites for forkhead box O1 (FOXO1), FOXO4 and STAT5A, in the most differentially expressed genes in injured skin. This indicates, for the first time, that these transcription factors might play a major role in the wound healing process.
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