Neovascularization upon IMQ treatment was

Neovascularization upon IMQ treatment was observed to different degrees in WT and GAL3-KO mice, whereas the increase in vascular endothelial growth factor mRNA levels was genotype independent. Because we observed lower levels of the cytokines IL-17A, IL-22, IL-23, and TNF-α in IMQ-treated skin of GAL3-KO mice, we addressed the question of whether the lower cytokine levels could be linked to IL-17– and IL-22–expressing mast cells or neutrophils (Mashiko et al., 2015, Taylor et al., 2014). Because mast cells in the skin originate from progenitors but neutrophils are recruited from blood into the skin, altered neovascularization occurring during the course of disease could contribute to variations in neutrophil number between WT and GAL3-KO mice. Indeed, we observed lower numbers of neutrophils but not mast cells in GAL3-KO compared with WT mice, which is in line with the reduced MPO activity. Furthermore, this supports our hypothesis that the expression of GAL3-R on blood vessels is important for disease progression. Accordingly, we detected GAL3-R mRNA in human and murine dermal vessels. Recent advances in the GAL field led to the development of specific peptidergic agonists and antagonists with higher specificity and increased stability (Lang et al., 2015). Despite the major effort of several research groups to generate non-peptidergic ligands (Bulaj et al., 2008, Reyes-Alcaraz et al., 2016), the only available non-peptidergic GAL3-R ligands are SNAP 37889 and SNAP 398299, a less soluble derivative of SNAP 37889 (Swanson et al., 2005). In the skin it was shown that SNAP 37889 blocks plasma extravasation induced by substance P and gdc-0980 gene-related peptide injection (Schmidhuber et al., 2009). Further research with this antagonist showed unspecific toxic effects on immune cells when used in high concentrations (Koller et al., 2016). Therefore, local administration, especially on the skin, could potentially be toxic to immune cells, and thereby mimic an anti-inflammatory effect. However, intraperitoneal administration of SNAP 37889 has been reported to have anti-inflammatory effects in a model of murine pancreatitis and to suppress alcohol drinking and morphine self-administration in mice (Barreto et al., 2011, Scheller et al., 2017). In these studies no adverse effects were reported, possibly because of the intraperitoneal route of administration. Thus, further studies should investigate if a dermal application of SNAP 37889 is feasible and could be used to treat psoriasis.
Materials and Methods
Conflict of Interest
Acknowledgments The authors greatly acknowledge support by the EC FP7 Capacities Specific Program-funded EMMA service project, which provided B6;129S5-Galr3tm1Lex/Orl mice. We thank Marina Picciotto for providing GAL2-KO mice. The study was supported by the Austrian Research Promotion Agency (FFG, 822782/THERAPEP) and the Paracelsus Medical University Salzburg (PMU-FFF E-13/17/087-LAN).
Introduction The expression and secretion of neuropeptides by tumors has gained increasing interest since these peptides were shown to influence tumor proliferation and correlate with the appearance of characteristic clinical symptoms. Neuroendocrine tumors arising from neuroendocrine cells synthesize a variety of neuroendocrine factors, and have been shown to produce and secrete neuropeptides and express corresponding receptors (for review see Barakat et al., 2004, Reubi, 2003). Chromogranins, pancreatic polypeptide, chorionic gonadotropin subunits and somatostatin are the most consistently expressed peptides in neuroendocrine tumors (Wood et al., 1983). The secretion of these peptides can result in elevated plasma levels as it can be observed for chromogranin A in patients with endocrine pancreatic tumors, pheochromocytomas, neuroblastomas and ganglioneuromas (Boomsma et al., 1995, Hsiao et al., 1991, Kogner, 1995, Kogner et al., 1995, Pagani et al., 1992). Peptide levels can correlate with tumor stage and prognosis (Kogner, 1995). High density expression of neuropeptide receptors has been reported for somatostatin, vasoactive intestinal peptide, cholecystokinin, gastrin releasing peptide and neurotensin in a wide variety of neuroendocrine tumors (for review see Reubi, 2003). Also non-endocrine tumors such as meningiomas, gliomas and several peripheral cancers have been shown to express peptides and peptide receptors (for review see Reubi, 2003). The clinical implications of the presence of peptide receptors in human cancers are: (1) tumor diagnosis with radioactive analogues, (2) tumor therapy with radioactive or cytotoxic analogues and (3) systemic long-term therapy with analogues.