Inflammatory Murine Skin Responses to UV-B Light Are Partially Dependent on Endothelin-1 and Mast Cells

Abstract

Endothelin (ET-1) has been shown to crucially contribute to UV-induced skin responses such as tanning.To test whether ET-1 is also involved in early cutaneous reactions to UV, we assessed ET-1 skin levels in UV-irradiated mice. In correlation with the levels of UV-induced skin inflammation, ET-1 concentrations increased substantially and continually. Moreover, blocking of ET-1 receptors (ET A ) resulted in significantly decreased cutaneous inflammation following UV irradiation. When we assessed skin responses to ET-1 injections, we observed prominent mast cell degranulation and mast cell-dependent inflammation. Since mast cells also critically contributed to UV-induced inflammation, we determined the ET-1-dependent inflammatory response to UV in the absence and presence of these cells. Interestingly, ET A blockade did not decrease UV-induced inflammation in mast cell-deficient mice, unless these mice had been adoptively transferred with mast cells before irradiation. This indicates that skin inflammation due to UV irradiation is caused in part by ET-1 acting on skin mast cells. Immediate skin responses following exposure to sunlight are largely mediated by UV-B light (UVB): low to moderate doses of UVB result in tanning, whereas intense UVB irradiation also gives rise to considerable inflammation, ie, solar dermatitis. UVB-induced tanning is widely regarded to result from the up-regulation of pigment production in epidermal melanocytes, which is induced by melanogens released from activated keratinocytes. In contrast, the cellular and molecular mechanisms involved in the induction of inflammatory skin responses to UVB are largely unknown.Recently, the vasoconstrictor peptide endothelin-1 (ET-1), one of the melanogens that contributes to UVBinduced tanning, 1,2 was found to promote inflammation in various pathological processes. For example, we and others have recently shown that ET-1 levels are up-regulated in murine septic peritonitis and that elevated ET-1 levels contribute to morbidity and mortality in this setting.3,4 Increased ET-1 production and mRNA expression have been demonstrated in lung tissue and bronchoalveolar lavage fluid in different models of airway inflammation. [5][6][7] In addition, elevated ET-1 concentrations are also present in patients with systemic lupus erythematosus, Takayasu arteritis, or Raynaud's phenomenon, where, in the latter case, the increase was shown clearly to contribute to disease severity. 8 These observations indicate that ET-1, in addition to having stimulatory effects on melanocytes, may orchestrate the induction of inflammatory responses after UVB irradiation. Two recent reports support this notion. First, the expression of ET-1 and its receptors ET A and ET B in murine skin was found to be markedly and rapidly upregulated after UVB irradiation, both in the dermis and epidermis.9 Second, intracutaneous injections of ET-1 reportedly trigger inflammatory reactions, including a pronounced flare response associated with sensations of a burning itch, a classic symptom of a ...

Mast cell functions in the innate skin immune system

“…In the response to sunburn, MC activation has been demonstrated to be accompanied by a rapid degranulation of cutaneous MCs (Gilchrest et al, 1981;Walsh, 1995). More recently, we have shown that this MC activation after UVB irradiation does contribute, at least in mice, significantly to the inflammation following a severe sunburn (Metz et al, 2006a). Although the activation of MCs in this setting initially contributes to the pathology of excessive UV light exposure, i.e.…”

“…Skin MCs from mice and humans on the other hand share many characteristic features (Table 1), e.g. they are both preferentially localized in close proximity to hair follicles and blood vessels (Weber et al, 2003;Paus et al, 2006b), their numbers increase similarly in chronic skin inflammation and they are known to respond to the same physical and biochemical stimuli (Metz et al, 2006a;Theoharides and Kalogeromitros, 2006). Because of these similarities it can be hypothesized that the essential role of murine skin MCs in certain innate immune responses described above may be of similar importance in the human system.…”

Langerhans cells are not required for graft-versus-host disease

“…44,45 Indeed, the effects of both donor T cells and UV irradiation are pleiotropic. UV irradiation causes acute cell death and local inflammation, [49][50][51][52] and alloreactive T cells induce systemic cytokines and local inflammation in skin and can directly target nonhematopoietic and hematopoietic cells in addition to LCs. Our finding that donor LCs engrafted in Langerin-DTA recipients, which have a very specific loss of only LCs, 23 without the need for allogeneic T cells or UV irradiation indicates that skin inflammation per se is not required for donor LC engraftment.…”

Control of Pseudomonas aeruginosa Skin Infections in Mice Is Mast Cell-Dependent

“…Moreover, the subsequent skin inflammation requires the activation by ET-1, which is increased to amounts comparable with those seen after PA infection. 33 ET-1 is only one of many candidate signalswhich also include other neuropeptides and complement mice (n ϭ 9 -32), and Kit W /Kit W-v mice (n ϭ 9 -27) injected subcutaneously with PA. Skin was harvested 24 hours after subcutaneous infection with PA. Histological sections were processed for H&E staining and imaged at ϫ50 (D-F) and ϫ400 (G-I) magnification.…”