162 Chapter 5 signals [20]. Here, we aimed to provide detailed insight in the cellular and soluble immune response in burn injured skin during the first four weeks after injury. In this study, we showed that after burn injury, there is a fast, extensive and long-lasting increase in innate immune cells that is present even in burn tissue debrided 3 to 4 weeks after injury. Lymphocytes also rise in numbers, but mainly at PBW 2-4. In addition, the cytokine composition in these burn tissue samples is highly pro-inflammatory and likely continues the attraction and activation of immune cells. Excessive pro-inflammatory immune responses and a lack or delay of anti-inflammatory responses could complicate wound healing and patient recovery. Limitations of this study that should be addressed are minor differences in treatment between patients such as medication and timing of surgery that could have influenced the inflammatory response. In addition, the broad range in subject age, burn cause and TBSA could have increased variation in the responses. In tissue samples from PBW 1, the proportion of γδ T cells was increased, indicating that γδ T cells could play a role during the early phase of burn-induced response. γδ T cells possess a unique T cell receptor and can, unlike ab T cells, interact with antigens directly [21]. They execute immune surveilling functions and react to damaged cell structures by producing cytokines and chemokines to recruit immune cells [22]. Mouse studies have shown that γδ T cells regulate the infiltration of innate immune cells shortly after trauma [23,24]. Our data suggests that next to keratinocytes, fibroblasts, mast cells and platelets [25], γδ T cells could be important inducers of the inflammatory response in humans as well. Within the same timeframe (PBW 1), IL-1β, IL-6, IL-8 (CXCL8), MCP-1, and GROα (CXCL1) levels were highly augmented. Others have demonstrated that these cytokines are also elevated in burn wound exudate [26]. These factors are known enhancers of the inflammatory response and attract neutrophils and monocytes/macrophages to wound site [27]. On the contrary, levels of IL-1α, IL-18 and IL-33 in burn tissue were reduced, especially during at PBW 1. These IL-1 cytokine family members are constitutively produced by keratinocytes to maintain the immune surveillance aspect of the skin [28]. Reduction of these factors is presumably caused by extreme loss of keratinocytes due to destruction of the epidermal layer by thermal injury. In burn tissue from PBW 2-4, the levels of IL-1α, IL-18 and IL-33 were returning to the levels in healthy skin, which may be related to the presence of keratinocytes closing the defect. Levels of cytokines, as well as microRNAs [29], could be potential biomarkers to predict disease progression or recovery [30]. The rapid neutrophil response to burn injury is presumably caused by the persisting levels of neutrophil attractants, such as IL-8, MCP-1 and GROα. This can also be observed in the circulation of burn patients, where high levels of neutrophils were accompanied by high
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