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    • The altered frequency of CD

    2023-02-06

    The altered frequency of CD4+ T different experience in 5-LO−/− mice led us to hypothesize that these leukocytes could be exerting a primary control of the inflammatory response. In fact, the lack of 5-LO resulted in the accumulation of CD4+CD25+ cells expressing Treg markers. It is plausible to speculate that 5-LO products like LTB4 and cysLT may participate in the inhibition of regulatory mechanisms, like those mediated by Tregs [65,66], which could dampen immune response in the skin inflammation. One of such immunosuppressive mechanisms used by Tregs is related to its typical regulatory molecules including but not exclusively related to forkhead box P3 (FoxP3), glucocorticoid-induced tumor necrosis factor receptor-related protein (GITR) and programmed cell death protein (PD-1) [67], which are able to inhibit inflammatory responses as those in wound healing. In fact, FoxP3, which is involved in the differentiation and function of Tregs is one of the regulatory markers most associated to the activity of these cells. The absence or reduction of FoxP3 may lead to the development of severe inflammatory disorders [68], thus reinforcing the importance of this transcription factor for the suppressor activity of Tregs. Furthermore, mutations in FoxP3 gene might impair differentiation or function of CD25+ Treg cells [69]. GITR is a co-stimulatory receptor belonging to the tumor necrosis factor receptor superfamily (TNFRSF), and is one of the most important regulatory markers. Regarding GITR function, one of the leading mechanisms is related to its ability to induce Tregs proliferation besides enhancing the suppressive activity of this cell population [70]. PD-1 inhibitory activity depends on the strength of the TCR signaling, with greater inhibition delivered at low levels of TCR stimulation. The activity of this molecule can be either observed on cytokine production, with significant reduction in IFN-γ, TNF-α and IL-2 secretion [71,72] or on cell death by inhibiting surviving factors such as Bcl-xL [73]. Then, the persistent inflammation in WT mice may be a result of a non-sustained expression of regulatory cell markers or activity after surgery. On the other hand, the up regulation of regulatory mechanisms at different time points may have contributed to a less severe development of inflammation, thus favoring faster wound healing in 5-LO−/− mice. The production and deposition of fibronectin and collagen, which are structural molecules of the extracellular matrix, contributes to the formation of granulation tissue, production of growth factors and efficient wound repair [16,74]. In our experiments we observed increased collagen deposition in 5-LO−/− wounds, which may have been influenced by the local inflammation. Besides the connective tissue fibroblasts, the leukocyte mediators released in the wounds might modulate tissue remodeling by interfering with the local expression of MMPs and TIMPs [75,76] which are critical for proper repair [76]. Here, the increased inflammation and augmented expression of MMP2 in WT lesions together with a higher TIMP1 only later in the healing process (compared to 5-LO−/− mice) may have facilitated the degradation of the extracellular matrix and a consequent delayed wound closure. In accordance, under physiological conditions, the dermis of WT mice expressed a consistent low level of MMP-2 and TIMP1 [77]. Moreover, in agreement with our results that showed elevated TGF-β mRNA expression in WT wounds, Gomes and colleagues demonstrated that this cytokine up regulated MMP2 production as a common regulator of MMPs and TIMPs, then playing a crucial role in breast cancer progression by modulating key elements of extracellular matrix homeostasis [78]. The role of TGF-β in inducing the production of MMP9, MMP12, TIMP1 and TIMP2 was further explored in a study with vein samples harvested from subjects who underwent coronary bypass graft surgery [79]. For this purpose, vein samples were treated in vitro with TGF-β. On the other hand, decreased vascular TGF-β levels and MMP-2 activity were detected in hypertensive rats treated with a combination of atorvastatin and sildenafil, which resulted in the amelioration of vascular remodeling [80], thus reinforcing a relationship between TGF-β as regulator of MMPs. However, it is of note that TGF-β is a multifunctional cytokine [81] that acts under physiological or pathological conditions and its effects may vary depending on the target or the context of cell stimulation [82]. Then, it is possible that a complex interplay among inflammatory infiltrate, growth factors, cytokines, lipid mediators, proteases and their inhibitors must occur in the skin lesions in order to determine the outcome of the healing wound.