Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)

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Shirasawa, S. et al.

Shirasawa, Sugiyama, Baba, Inokuchi, Sekine, Ogino, Kawamura, Dohi, Fujimoto, Sasazuki,

Dermatitis due to epiregulin deficiency and a critical role of epiregulin in immune-related responses of keratinocyte and macrophage.

Epidermal growth factor (EGF) family members, including epiregulin (EP), play a fundamental role in epithelial tissues; however, their roles in immune responses and the physiological role of EP remain to be elucidated. The skin has a versatile system of immune surveillance. Biologically active IL-1alpha is released to extracellular space upon damage from keratinocytes and is a major player in skin inflammation. Here, we show that EP is expressed not only in keratinocytes but also in tissue-resident macrophages, and that EP-deficient (EP(-/-)) mice develop chronic dermatitis. Wound healing in the skin in EP(-/-) mice was not impaired in vivo, nor was the growth rate of keratinocytes from EP(-/-) mice different from that of WT mice in vitro. Of interest is that in WT keratinocytes, both IL-1alpha and the secreted form of EP induced down-regulation of IL-18 mRNA expression, which overexpression in the epidermis was reported to induce skin inflammation in mice, whereas the down-regulation of IL-18 induced by IL-1alpha was impaired in EP(-/-) keratinocytes. Although bone marrow transfer experiments indicated that EP deficiency in non-bone-marrow-derived cells is essential for the development of dermatitis, production of proinflammatory cytokines by EP(-/-) macrophages in response to Toll-like receptor agonists was much lower, compared with WT macrophages, whose dysfunction in EP(-/-) macrophages was not compensated by the addition of the secreted form of EP. These findings, taken together, suggested that EP plays a critical role in immune/inflammatory-related responses of keratinocytes and macrophages at the barrier from the outside milieu and that the secreted and membrane-bound forms of EP have distinct functions.[1]

References

Dermatitis due to epiregulin deficiency and a critical role of epiregulin in immune-related responses of keratinocyte and macrophage. Shirasawa, S., Sugiyama, S., Baba, I., Inokuchi, J., Sekine, S., Ogino, K., Kawamura, Y., Dohi, T., Fujimoto, M., Sasazuki, T. Proc. Natl. Acad. Sci. U.S.A. (2004) [Pubmed]

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