163 Local Immune Response in Burn Patients levels of IL-8 and MCP1, especially early after injury [7]. Other studies have also shown that burn tissue contains large numbers of neutrophils in both human [31] and animals [13,32]. The vast majority of neutrophils that infiltrated the wound area were mature, whereas, in peripheral blood from severely burned patients high numbers of immature neutrophils were detected [7]. This release of immature neutrophils may well be a compensatory response by the bone marrow [33]. Nucleus flexibility and chemotactic activity increases with neutrophil age and could explain the presence of mainly mature neutrophils in burn tissue [34]. If only mature neutrophils are able to enter the wound site, immature neutrophils would be trapped in the circulation until they reach maturity. As immature neutrophils are proposedly more active and less predictable in reacting to danger signals [35], they are likely to enhance systemic inflammation, thereby delaying recovery. In burn tissue, we found only a small number of immature neutrophils and only at PBW 1, which could have been released from the blood circulation by capillary leakage caused by the burn injury. Expression of CD11b and CD66b was increased on neutrophils isolated from burn tissue. This highlights the inflammatory state of the infiltrating neutrophils as CD11b and CD66b are important for neutrophil activation, adhesion and migration to inflamed tissue [36,37]. The surges of active neutrophils in the wound could lead to an overproduction of products such as elastase, MPO and ROS which can (further) damage surrounding tissues and organs [38,39]. Blood monocytes are progenitors of both pro-inflammatory macrophages and wound healing macrophages. Although there is little evidence in this respect, it has been suggested that classical monocytes could be predisposed progenitors to proinflammatory macrophages [40], while intermediate and non-classical monocytes are biased progenitors to wound healing macrophages [41,42]. The initial monocyte population in burn tissue consisted mainly of classical monocytes. The relative decrease in classical monocytes in PBW 3 could indicate a relevant shift towards more wound healing macrophages, which is assumed to happen during wound healing [8]. In burn tissue, the number of macrophages was increased this population showed a different composition of M1 and M2 markers. CD163+ macrophages with low to moderate expression of CD40, CD80 and CD206 were more abundant in burn tissue. M1 macrophage differentiation factor GM-CSF was increased in burn tissue from PBW 1-3 and mediators that are known to be actively produced by M1 macrophages such as TNF-α, IFN-γ, IL-1β, IL-6, IL-8 and MCP-1 [8,43], were all increased in these burn tissues. While typical M2 macrophage factors like IL-4, IL-10, IL-13 were unaffected, the levels of TGF-β1 and VEGF-α, which are also described as M2 mediators [42], were increased in burn tissue. Altogether, the monocyte/macrophage composition and cytokine environment possibly supports the generation of macrophages with a pro-inflammatory phenotype. Timely transition towards more suppressive, regenerative macrophages is however essential for 5
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