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  • Psoriasis is an inflammatory skin disease characterized by e

    2022-06-22

    Psoriasis is an inflammatory skin disease characterized by epidermal hyperplasia; micro-abscesses; neo-angiogenesis; a proinflammatory cytokine environment involving alterations of IL-17A, IL-23, and TNF-α; and activation of and infiltration by macrophages, mast cells, neutrophils, CD11c+ dendritic cells, and T Loxapine (Elder et al., 2010, Ha et al., 2014). Topical application of imiquimod (IMQ), an innate toll like receptor 7/8 ligand, induces a dermatitis closely resembling human psoriasis. Similar to psoriasis observed in the clinic, inflamed, scaly, and plaque skin lesions; epidermal hyperproliferation; abnormal differentiation; and neo-vascularization occur upon IMQ treatment. This is caused by the infiltration of neutrophils and macrophages and the activation of mast cells, followed by recruitment of specific dendritic cells and T cells (Brembilla et al., 2017, Cai et al., 2011, Pantelyushin et al., 2012, Schon and Schon, 2007, van der Fits et al., 2009). There is clinical evidence that absence of neural input resulting from denervation injury leads to improvement of psoriasis, which suggests a role of the nervous system in the pathophysiology of this skin disease (Zhu et al., 2016). For example, α-melanocyte–stimulating hormone ameliorates inflammation in an IMQ-induced psoriasiform-inflammation model (Auriemma et al., 2012). Recently, a topical formulation of α-melanocyte–stimulating hormone was developed that reduced IMQ-induced psoriasiform inflammation in mice (Shah et al., 2016). The aim of this study was to determine GAL receptor expression in human psoriatic skin and to elucidate progression of inflammation in murine models of psoriasis in GAL2-KO and GAL3-KO animals.
    Results
    Discussion In this study, we showed that endothelial cells of the dermal vasculature of healthy individuals express GAL3-R and that nestin-positive neovessels in psoriatic skin co-express GAL3-R. Nestin, a type VI intermediate filament protein, is a selective marker for bone marrow-derived mesenchymal stem cells and is expressed on perivascular and endothelial cells during angiogenesis in different tissues (Suzuki et al., 2010, Xie et al., 2015). GAL2-R and GAL3-R mRNA is expressed in mouse embryonic cells, and GAL expression was observed during embryonic development (Jones et al., 2009, Tarasov et al., 2002). These data indicate a potential role of GAL3-R in stem cell function and suggest that it may have a neo-angiogenic effect. A recent study reported the distribution of GAL receptors in the human eye, which is a model organ for studying vascularization: all three GAL receptor types were found to be expressed on choroidal blood vessels, GAL1-R and GAL3-R on iris vessels, and GAL3-R alone on ciliary vessels, indicating localization and tissue-specific expression patterns of GAL receptors (Schrodl et al., 2015). The abundance of GAL receptors in the eye could indicate a role in vascularization-related events. In psoriasis development, a small population of mast cells and macrophages residing in the skin can act as sentinel cells that initiate neutrophil recruitment by increasing the permeability of local blood vessels and the release of chemokines (Ajuebor et al., 1999, Vieira et al., 2009). The first wave of infiltrating immune cells after IMQ treatment consists of neutrophils. On days 2 to 4 a second wave of neutrophils is accompanied by macrophages (Flutter and Nestle, 2013). We observed an increase in macrophages and neutrophils after 4 days of IMQ treatment and a reduction of both cells types by day 7. Molecular analysis of the skin showed no abnormalities in M1- and M2-related genes between WT and GAL3-KO animals. In skin sections of GAL3-KO animals, a trend toward a lower amount of Fpr2 expression was observed on day 4. Because Fpr2 is also present on neutrophils (Hartt et al., 1999) and plays a role in homing of endothelial progenitor cells (Heo et al., 2014), which show stemness characteristics and are crucially involved in the formation of vascular networks, we hypothesize that the lower Fpr2 levels in GAL3-KO animals may contribute to the vascular phenotype in vivo.