76 Chapter 3 of monocytes to (M1) macrophages and degranulation responses of myeloid cells [33]. This is in line with increased macrophage activity after burn injury that we reported previously [8]. IFN-γ and TNF-α were also increased after burn injury and are known to stimulate macrophage M1 polarization as well (Figure 4 and Figure 5). As a result of M1 polarization, the expression of IL-1α, IL-1β, IL-6 and TNF-α will increase [34,35], which was also the case for wound tissue levels shown here (Figure 4). M2 polarization on the other hand is induced by IL-4, IL-10, and IL-13, and is characterized by increased secretion of IL-10 and TGF-β1 [36,37]. After burn injury the levels of IL-4 and IL-13 were indifferent from healthy control animals, but the levels of TGF-β1 and IL-10 mRNA were increased, suggesting that there is M2 macrophage activity to some degree, but it might be limited. As M2 macrophage activity is essential during the proliferation and remodeling phase of healing [38], therapy directed to enhance this activity in burn patients could be beneficial for wound healing. T cells and B cells have a protective role and can resolve inflammation, generate tailored pathogen defense responses and support wound healing together with M2 macrophages [39]. Information on lymphocyte responses and related mediators after burn injury is, however, limited. While the numbers of neutrophils and monocytes were high, the number of lymphocytes was actually decreased after burn injury [3,8,40,41]. Reduced lymphocyte activity can cause immune paralysis leading to poor immune regulation and increased risk of nosocomial infections [42]. IL-10 and TGF-β1, factors that typify regulatory T cell (Treg) activity, have inhibitory effects on pro-inflammatory cytokine production and support tissue restoration [43–45]. Although IL-10 and TGF-β1 were increased upon burn injury, Treg function and levels of anti-inflammatory factors may be insufficient to effectively control aberrant inflammation. For example, other cytokines typically associated with anti-inflammatory and tissue repair responses such as IL-2, IL-4, IL-5 and IL-13, were not increased after burn injury (Figure 4). These cytokines are produced by Th2 cells to drive B cell proliferation and M2 macrophage polarization [46]. After burn injury, Treg and Th2 responses might be delayed or insufficient. To treat uncontrolled inflammation successfully, patients might benefit from interventions that stimulate lymphocyte activity [47–49], e.g., by enhancing Th2 or Treg responses. The levels of IL-6, blood IL-1β, IL-10 and TNF-α were higher in large burns as compared to moderate burns. Similarly, blood IL-6 were increased when animals were burned on both sides as compared to sole dorsal burns. This relation between the burn size and the intensity of the immune response has been demonstrated before in individual studies [50–52]. Scalds induced higher blood levels of IL-1β, IL-6 and IFN-γ than contact burns. Striking differences in the levels of IL-1β, IL-6, IL-10 and TNF-α were related to study model characteristics such as species (mouse or rat), sex and age. Circulatory levels of IL-1β,
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