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  • br Introduction The mammalian skin forms the largest organ o

    2021-10-19


    Introduction The mammalian skin forms the largest organ of the body and includes a network of cutaneous nerves, cells of the immune system, and mediators of the neuro-endocrine axis (Theoharides et al., 2016). Analogous to the hypothalamic-pituitary-adrenal axis, neuropeptides and their receptors are present in the skin, including galanin (GAL) (Lang et al., 2015, Theoharides et al., 2016). GAL is a neuropeptide with a length of 30 Bindarit receptor (29 in rodents) that is distributed in the central and peripheral nervous systems and in non-neuronal organs such as the skin (Lang et al., 2015). GAL is localized in afferent sensory neurons and specialized cutaneous sensory structures such as Merkel cells and Meissner corpuscles and in non-neuronal structures like eccrine sweat glands, in follicular and epidermal keratinocytes, and in smooth muscle cells of dermal blood vessels (Fantini and Johansson, 1995, Johansson et al., 1999, Johansson et al., 1988, Kofler et al., 2004, Pincelli et al., 1990, Xu et al., 1991). In addition, in a murine model of allergic contact dermatitis, a significant elevation of GAL-positive nerve fibers was observed compared with healthy skin. However, the concentration of the peptide, as measured by radioimmune assay of skin extracts, was markedly reduced (El-Nour et al., 2004). Carrageenan-induced inflammation in the rat hind paw led to elevated GAL-like immunoreactivity and GAL mRNA in the epidermis, as well as GAL-like immunoreactivity in ED-1–positive immunocytes in the dermis (Ji et al., 1995). GAL exerts its functions via three G protein-coupled receptors (GAL1-R, GAL2-R, and GAL3-R) (Fathi et al., 1997, Habert-Ortoli et al., 1994, Howard et al., 1997). The first evidence for GAL receptor expression in human skin was provided by receptor autoradiography, which detected GAL binding around dermal blood vessels and sweat gland cells (Kofler et al., 2004). Analysis of human skin showed GAL2-R–like immunoreactivity in the basal layer of the epidermis, around dermal blood vessels, and in sweat gland cells (Bovell et al., 2012, Dallos et al., 2006). GAL3-R–like immunoreactivity was detected in sweat gland cells, and GAL3-R mRNA was shown to be expressed by outer root sheath keratinocytes and hair follicles (Bovell et al., 2012, Holub et al., 2012). In addition, GAL2-R and GAL3-R are expressed on immune cells such as neutrophils, macrophages, and monocytes, which are, inter alia, important in maintaining skin immunity (Chiu et al., 2013, Locker et al., 2015). In contrast, there is no evidence so far for GAL1-R expression in human skin (Bovell et al., 2012, Dallos et al., 2006). It is well known that GAL receptors are expressed in rodent skin as well; however, the lack of specific GAL receptor antibodies for this species explains the deficit of data regarding the cellular distribution of GAL receptors on mouse and rat skin (Lu et al., 2005). As a vasoactive peptide, GAL is able to block plasma extravasation induced by different stimuli such as histamine, substance P, or antidromic C fiber stimulation in rodent and pigeon skin (Jancso et al., 2000, Xu et al., 1991). Furthermore, after cutaneous treatment with tumor necrosis factor-α (TNF-α), heat, or a combination of substance P and calcitonin gene-related peptide, GAL-knockout (KO) mice lack neutrophil accumulation in the skin (Schmidhuber et al., 2008). In the K/B×N serum transfer model of autoimmune arthritis, an increase in clinical severity and vascular hyperpermeability in GAL3-R–knockout (GAL3-KO) animals compared with wild-type (WT) littermates was observed (Botz et al., 2016b), suggesting an anti-inflammatory role of GAL3-R. However, GAL3-KO mice showed no change in the progression of oxazolone-induced contact dermatitis compared with WT mice (Botz et al., 2016a). The absence of an obvious phenotype of GAL3-KO mice in the dermatitis model and the discrepancy between the arthritis and oxazolone models highlight the complexity of the role of GAL3-R in inflammation, which seems to depend on the type of inflammatory disease and the tissue affected.