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    • Nevertheless though the LO pathway

    2023-11-27

    Nevertheless, though the 5-LO pathway dictates the production of lipid mediators with opposite roles in the immune reactions, like LTs and LXA4 [32], our results seemed to corroborate others that pointed to LTB4 as an outstanding mediator involved in persistent and chronic inflammatory skin diseases [8–10,33]. Then, we demonstrated that besides cysLT, the presence of LTB4 could also be associated to the exacerbated local reaction and a delayed repair in WT mice when compared to 5-LO−/− ones. In agreement, the use of ONO-4057, a LTB4 receptor antagonist, was shown to be effective in the inhibition of spontaneous itch-related behavior in a murine model of atopic dermatitis [10]. Moreover, the suppression of LTB4 production by a treatment using a mixture of docosahexaenoic Cholesterol and eicosapentaenoic acid together with the immunosuppressant FK506, ameliorated atopic dermatitis-like skin disease in mice [34]. In this context, a previous work, using an experimental model of skin wounds induction similar to that used in our study, showed that the absence of 5-LO led to improved wound healing by an antioxidant mechanism based on heme‑oxygenase-1 induction [11]. Neutrophils and eosinophils are important source of inflammatory mediators, LT and proteases in cutaneous wounds [35,36]. Then, their continuous accumulation may lead to prolonged injury and delayed healing [37–39], as observed in the WT lesions of the present work. Our data also pointed to increased accumulation of mast cells in these wounds, suggesting that the release of cytokines, histamine, proteases and LT by these leukocytes may have contributed to the skin inflammation [40,41]. Indeed, mast cells are one of the most relevant TNF-α producers [42], a cytokine that was highly expressed in WT mice after injury. This cytokine might be related to the increased expression of eotaxin [43], which is capable of inducing the recruitment of eosinophils, mast cells, basophils and Th2 cells, through interaction with the chemokine receptor CCR3, selectively expressed by these leukocytes [44]. Eotaxin may also lead to eosinophil degranulation and contribute to amplify tissue damage and inflammation [45,46] as observed in our studies in the presence of 5-LO. Furthermore, we believe that the decreased cellularity in the inflamed skin of 5-LO−/− mice might have accounted for the diminished TNF-α and eotaxin, since the sources of these mediators in this inflamed tissue may be local resident cells [47], dermal fibroblasts [48], endothelial cells [49], macrophages [50], gamma delta T cells [51], monocytes, keratinocytes [52] or mast cells [53,54]. Lymphocytes are effector cells capable of producing growth factors and cytokines that modulate the local immune response in human skin during tissue remodeling [55,56]. Then, the reduced frequency of CD8+ and CD3+CD49b+ cells (possibly NKT) in the skin of 5-LO−/− mice pointed to a participation of this enzyme in inducing inflammation post injury. It is known that NKT cells participate in the early cutaneous inflammation and their absence accelerate wound closure [57]. Moreover, LTB4 production by mast cells, which are reduced in the skin samples of 5-LO−/− mice, may be responsible for the chemotaxis of CD8+ cells to the inflamed tissues, since these lymphocytes but not NK cells express the LTB4 receptor BLT1 [58]. However, the immune modulation mediated by 5-LO in the local lesion and in the draining lymphoid organs seemed to be different and other chemotaxis mechanisms might underlie the leukocyte accumulation as well as their traffic to the inflamed skin. In fact, the absence of 5-LO interfered in the expression of other important chemokine and chemokine receptors in the wounds, besides CCL11 (eotaxin). The low detection of CXCL9, CCL2, CCL7, CXCR2 and CCR1 also probably accounted for the diminished infiltrate in the lesions of 5-LO−/− mice, with consequent accelerated repair. Indeed, CXCL9 is a chemokine induced by IFN-γ involved in T cell migration and cutaneous inflammation [59]. CCL2 attracts macrophages to skin wounds and impairs the resolution of the inflammatory phase during tissue repair [60]. The chemokine CCL7, that binds to CCR1, CCR2, CCR3 or CCR5 receptors, can contribute to the migration of macrophages, eosinophils, T cells or other leukocytes to cutaneous lesions. This chemokine, besides being involved in the chemotaxis of multiple cells, are related to TNF-α-dependent inflammation in psoriatic skin, in agreement with our data that showed reduced TNF-α and CCL7 in the 5-LO−/− wounds [61,62]. Regarding CCR1, it may be expressed by monocytes, T cells, dendritic cells or neutrophils [63], which migrate in response to many ligands including CCL7. Furthermore, CXCR2 and the LTB4 receptor, BLT1, act together to induce neutrophil accumulation in a model of skin inflammation [64]. Altogether, these results corroborate our findings that showed reduced infiltrate and better inflammation control in the skin of mice that did not present the 5-LO enzyme.