Cutaneous manipulation of vascular growth factors leads to alterations in immunocytes, blood vessels and nerves: Evidence for a cutaneous neurovascular unit

Abstract

Background Skin cells produce soluble factors which influence keratinocyte proliferation, angiogenesis, nerve innervation and immunocyte response. Objective To test the hypothesis that epidermal-dermal interactions influence neural outgrowth, vascular survival, immunocyte recruitment and keratinocyte proliferation. Methods We genetically manipulated the epidermis to express excess vascular endothelial growth factor (VEGF) and/or angiopoietin-1 (Ang1) and then examined the epidermal and dermal phenotypes. We compared these findings with those occurring following overexpression of the Ang1 receptor Tie2 in endothelial cells or keratinocytes. Results Keratinocyte-overexpression of Ang1 resulted in increased epidermal thickness compared to control littermates. Keratinocyte-specific overexpression of Ang1 or VEGF increased dermal angiogenesis compared to control animals and combined Ang1-VEGF lead to further increases. Cutaneous leukocyte examination revealed increases in CD4+ T cell infiltration in mice with keratinocyte-specific overexpression of Ang1, VEGF and Ang1-VEGF combined; in contrast only keratinocyte-specific Ang1 overexpression increased cutaneous F4/80+ macrophage numbers. Interestingly, combined keratinocyte-derived Ang1-VEGF overexpression reduced significantly the number of F4/80+ and Cd11c+ cells compared to mice overexpressing epidermal Ang1 alone. Endothelial cell-specific Tie2 overexpression increased dermal angiogenesis but failed to influence the epidermal and immune cell phenotypes. Keratinocyte-specific Tie2 expressing mice had the highest levels of CD4+, CD8+ and CD11c+ cell numbers and acanthosis compared to all animals. Finally, increases in the number of cutaneous nerves were found in all transgenic mice compared to littermate controls. Conclusion These findings demonstrate that change to one system (vascular or epidermal) results in change to other cutaneous systems and suggest that individual molecules can exert effects on multiple systems.

Induction of Alternative Proinflammatory Cytokines Accounts for Sustained Psoriasiform Skin Inflammation in IL-17C+IL-6KO Mice

“…Taking advantage of the KC-Tie2 psoriasis mouse which has elevated cutaneous IL-17C and TNFα (Ward N. L. et al, 2011, Wolfram et al, 2009)(Figure S2a), and when backcrossed with IL-6KO mice has a sustained skin phenotype (Golden, 2015), we validated the findings observed in IL-17C+KO mice and determined that intradermal injections of IL-6 or TNFα into the skin of KC-Tie2-IL-6KO mice also lead to an exacerbation of skin inflammation (Figure S2b), demonstrating in a second psoriasiform model (one where IL-17C is not genetically manipulated) that similar synergy between IL-17C, IL-6 and TNFα may contribute to skin phenotype. Further evidence of this was seen in primary keratinocytes stimulated with combinations of IL-17C, IL-6 and TNFα where increases in expression of proinflammatory transcripts, including S100A8/A9, IL-36γ and TNFα were observed (Figures S3–4).…”

“…Epidermal thickness (acanthosis) measurements and immune cell quantification of skin was done as previously described (Ward Nicole L. et al, 2011, Wolfram et al, 2009). …”

SIV-induced impairment of neurovascular repair: a potential role for VEGF

“…Studies indicate proliferating keratinocytes are a major source of nerve growth factors, and growth factors secreted by vessels and nerves in turn influence the growth of epidermal keratinocytes. (Albers and Davis 2007; Brown et al 1992; Park et al 2003; Pincelli et al 1996; Ward et al 2011). The strong association between epidermal regrowth and neurovascular growth in control animals clearly indicates co-dependent interactions between the vessels and nerves at the cutaneous level during regenerative phases of repair post-axotomy.…”

645 Imiquimod has strain-dependent effects in mice and does not uniquely model human psoriasis

“…Spleens from each mouse were removed and weighed immediately following sacrifice. Formalin-fixed paraffin-embedded skin was sectioned and stained with H&E. Epidermal thickness measurements were completed blind to treatment, background strain, and sex as described previously [27,28]. For each strain, CTL and IMQ groups were compared with respect to body weight change (post-treatment versus pre-treatment), epidermal thickness, and spleen weight using linear models with simultaneous evaluation of contrasts (IMQ versus CTL) based upon the exact multivariate t-distribution (R package, multcomp; function, glht; Fig.…”