Mast cells as targets of corticotropin-releasing factor and related peptides

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Several inflammatory skin conditions, including atopic dermatitis (AD) and psoriasis, are exacerbated by stress. Recent evidence suggests that crosstalk between mast cells, neurons and keratinocytes might be involved in such exacerbation. Mast cells are distributed widely in the skin, are present in increased numbers in AD and are located in close proximity to substance P- or neurotensin-containing neurons. Corticotropin-releasing factor (CRF), its structurally related peptide urocortin (Ucn) and their receptors are also present in the skin and their levels are increased following stress. Human mast cells synthesize and secrete both CRF and Ucn in response to immunoglobulin E receptor (FcεRI) crosslinking. Mast cells also express CRF receptors, activation of which leads to the selective release of cytokines and other pro-inflammatory mediators. Thus, we propose that CRF receptor antagonists could be used together with natural molecules, such as retinol and flavonoids, to inhibit mast cell activation and provide new therapeutic options for chronic inflammatory conditions exacerbated by stress.

Section snippets

A skin ‘brain’ and mast cells

It has often humorously been argued that the brain is an appendix of the skin! Recent evidence shows that many genes known to be expressed in the CNS are also expressed in vast epidermal domains of a hemichordate organism, suggesting the presence of a ‘skin brain’ [17]. Extensive neuroendocrinological associations in the skin have also been described [18]. Indeed, there are anatomical and functional interactions between peripheral nerves and mast cells in the skin [19]; studies suggest that

CRF and mast cell-dependent actions in the skin

There are fundamental differences between CRF signaling systems in human and rodent skin. Thus, although human skin expresses both CRF and Ucn mRNA, mouse skin cells produce only Ucn peptides; the most prevalent cutaneous stressor, UV radiation, can also stimulate CRF protein production by human skin cells 32, 33, 34. The gene encoding CRF is not expressed in mouse skin but the peptide is delivered to the skin by nerve endings [35]. Furthermore, human epidermis expresses predominantly CRF1

Mast cells, keratinocytes and infections

Typically, chronic stress attenuates immune processes whereas acute stress appears to stimulate these processes. This latter effect appears to involve mast cell activation [29] and re-distribution of leukocytes from the blood to the skin, leading to enhanced delayed hypersensitivity reactions [1]. Recent findings indicate that mast cells might be crucial for defense against bacterial infections. For example, adherent Escherichia coli activates mouse mast cells in vitro, whereas W/Wv mast

Conclusions and future directions

Mast cells have emerged recently as versatile effector cells in the regulation of numerous processes, including the regulation of immunity [2], inflammation, the blood–brain barrier [1] and cancer growth [16] (Figure 1). Skin and hypothalamic mast cells appear to have important physiological functions as sensors of stressful events with bidirectional regulation of the HPA axis; a local increase of the levels of CRF or Ucn in extracranial tissues under stress could adversely affect different

Acknowledgements

Aspects of this work were supported in part by grant No. AR47652 from the US NIH, to T.C.T. Thanks to Jessica Christian for her word processing skills. The possible therapeutic use of CRF receptor antagonists alone, or in combination with mast cell secretion inhibitors, in stress-induced dermatoses is covered by US Patents No. 6,020 305 and 6,689 748 awarded to T.C.T.

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