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Cross-Linking of Elafin/SKALP to Elastic Fibers in Photodamaged Skin: Too Much of a Good Thing?

2007; Elsevier BV; Volume: 127; Issue: 6 Linguagem: Inglês

10.1038/sj.jid.5700691

1523-1747

Joost Schalkwijk,

Dermatological and Skeletal Disorders

Muto et al. report that UVA light induces the expression of elafin, a potent elastase inhibitor, in skin fibroblasts. Elafin binds to elastic fibers by transglutaminase-mediated cross-linking and protects against proteolytic breakdown. Decreased degradation could contribute to accumulation of elastotic material in photodamaged skin. Elastase and its locally produced inhibitors play a role in actinic elastosis. Muto et al. report that UVA light induces the expression of elafin, a potent elastase inhibitor, in skin fibroblasts. Elafin binds to elastic fibers by transglutaminase-mediated cross-linking and protects against proteolytic breakdown. Decreased degradation could contribute to accumulation of elastotic material in photodamaged skin. Elastase and its locally produced inhibitors play a role in actinic elastosis. The fibrillary basophilic material present in the upper dermis of photodamaged skin is largely composed of elastic material. It is unclear to what extent this accumulation is caused by increased synthesis of elastin or by breakdown of existing and nascent elastic fibers, or by a relative decrease of collagen (Lewis et al., 2004Lewis K.G. Bercovitch L. Dill S.W. Robinson-Bostom L. Acquired disorders of elastic tissue. I. Increased elastic tissue and solar elastotic syndromes.J Am Acad Dermatol. 2004; 51: 1-21Google Scholar; Sellheyer, 2003Sellheyer K. Pathogenesis of solar elastosis: synthesis or degradation.J Cutan Pathol. 2003; 30: 123-127Google Scholar). The paper by Muto et al. (Muto et al., 2007Muto J. Kuroda K. Wachi H. Hirose S. Tajima S. Accumulation of elafin in actinic elastosis of sun-damaged skin: elafin binds to elastin and prevents elastolytic degradation.J Invest Dermatol. 2007; 127: 1358-1366Google Scholar, this issue) contains two interesting new findings. First, it shows that the serine protease inhibitor elafin (Wiedow et al., 1990Wiedow O. Schröder J. Gregory H. Young J.A. Christophers E. Elafin: an elastase specific inhibitor of human skin. Purification, characterization, and complete amino acid sequence.J Biol Chem. 1990; 265: 14791-14795Google Scholar), otherwise known as skin-derived antileukoproteinase (SKALP) (Molhuizen et al., 1993Molhuizen H.O. Alkemade H.A. Zeeuwen P.L. de Jongh G.J. Wieringa B. Schalkwijk J. SKALP/elafin: an elastase inhibitor from cultured human keratinocytes. Purification, cDNA sequence, and evidence for transglutaminase cross-linking.J Biol Chem. 1993; 268: 12028-12032Google Scholar), can be expressed by mesenchymal cells. This is a surprising finding, as it was assumed that elafin expression was strictly limited to epithelial cells (Pfundt et al., 1996Pfundt R. van Ruissen F. van Vlijmen I.M.J.J. Alkemade J.A.C. Zeeuwen P.L.J.M. Jap P.K. et al.Constitutive and inducible expression of SKALP/elafin provides anti-elastase defense in human epithelia.J Clin Invest. 1996; 98: 1389-1399Google Scholar). The authors confirm previous findings that resting skin fibroblasts in vivo and in vitro are negative for elafin, but they show that UVA irradiation (and not UVB) induces elafin expression in these cells. Second, it is shown that elafin binds to elastic fibers in vivo and in vitro, thereby protecting against elastase-mediated breakdown. Elafin is a member of the trappin gene family (Schalkwijk et al., 1999Schalkwijk J. Wiedow O. Hirose S. The trappin gene family: proteins defined by an N-terminal transglutaminase substrate domain and a C-terminal four-disulphide core.Biochem J. 1999; 340: 569-577Google Scholar). The proteins encoded by the trappin family are characterized by a proteinase-inhibiting whey acidic protein (WAP) domain and a domain that contains the consensus GQDPVK hexapeptide motifs that are excellent substrates for transglutaminases (Molhuizen et al., 1993Molhuizen H.O. Alkemade H.A. Zeeuwen P.L. de Jongh G.J. Wieringa B. Schalkwijk J. SKALP/elafin: an elastase inhibitor from cultured human keratinocytes. Purification, cDNA sequence, and evidence for transglutaminase cross-linking.J Biol Chem. 1993; 268: 12028-12032Google Scholar). Muto et al. (Muto et al., 2007Muto J. Kuroda K. Wachi H. Hirose S. Tajima S. Accumulation of elafin in actinic elastosis of sun-damaged skin: elafin binds to elastin and prevents elastolytic degradation.J Invest Dermatol. 2007; 127: 1358-1366Google Scholar) show that, in vitro, elafin can be cross-linked to elastic fibers, while retaining its proteinase-inhibiting activity. Immunohistochemical analysis of skin biopsies from photodamaged skin showed strong elafin staining associated with the elastotic material. The accumulation of elastase inhibitors on elastic fibers is not unprecedented, as the association of another WAP domain protein, secretory leukocyte protease inhibitor (SLPI), has been documented in connective tissue of the lung (Kramps et al., 1989Kramps J.A. te Boekhorst A.H.T. Fransen J.A.M. Ginsel L.A. Dijkman J.H. Antileukoprotease is associated with elastin fibers in the extracellular matrix of the human lung. An immunoelectron microscopic study.Am Rev Respir Dis. 1989; 140: 471-476Google Scholar) and skin (Wingens et al., 1998Wingens M. Van Bergen B.H. Hiemstra P.S. Meis J.F. Vlijmen-Willems I.M. Zeeuwen P.L. et al.Induction of SLPI (ALP/HUSI-I) in epidermal keratinocytes.J Invest Dermatol. 1998; 111: 996-1002Google Scholar). On the basis of their findings, Muto et al., 2007Muto J. Kuroda K. Wachi H. Hirose S. Tajima S. Accumulation of elafin in actinic elastosis of sun-damaged skin: elafin binds to elastin and prevents elastolytic degradation.J Invest Dermatol. 2007; 127: 1358-1366Google Scholar speculate that elafin binding to elastic fibers is a protective response against undesirable degradative action of elastolytic enzymes such as neutrophil elastase derived from the infiltrating cells after UV irradiation (Hawk et al., 1988Hawk J.L. Murphy G.M. Holden C.A. The presence of neutrophils in human cutaneous ultraviolet-B inflammation.Br J Dermatol. 1988; 118: 27-30Google Scholar). The authors argue that the accumulation of elastotic material in photodamaged skin is caused by decreased degradation of elastic fibers rather than by overproduction of elastic fibers. The findings in this paper are novel and exciting. I think, however, that the data are open to other interpretations than those offered by the authors. It is indeed very likely that elafin expression by fibroblasts after UVA exposure is a protective mechanism against unwanted breakdown of extracellular matrix molecules. I also agree with the authors that the accumulation of elastotic material in photodamaged skin could be the consequence of a protective mechanism gone awry. Normal turnover of collagens and elastin is limited, and regeneration of fully matured elastic fibers after skin injury happens very slowly, if at all. Teleologically speaking, our skin has ample reason to protect its elastic fibers, and secretion of an elastase inhibitor following an insult (excessive UV light) makes sense. Chronic exposure to UV light would cause sustained production of elafin, and the action of transglutaminases will result in an irreversible covalent binding with elastic fibers.Teleologically speaking, our skin has ample reason to protect its elastic fibers. Teleologically speaking, our skin has ample reason to protect its elastic fibers. Although this would position the protease inhibitor in exactly the right place to do its job, it also comes with a cost: modification of glutamines and lysines in the elastic fiber constituents. Accumulation of these modifications could in the end severely compromise the biochemical and cell-biological properties of these elastic fibers, including resistance to breakdown and normal turnover, propensity to aggregate, and activation of fibroblasts to increase tropoelastin synthesis. The assertion by Muto et al., 2007Muto J. Kuroda K. Wachi H. Hirose S. Tajima S. Accumulation of elafin in actinic elastosis of sun-damaged skin: elafin binds to elastin and prevents elastolytic degradation.J Invest Dermatol. 2007; 127: 1358-1366Google Scholar that fiber-associated elafin protects against breakdown does not, in itself, explain why there is a strong increase of elastic fiber material in photodamaged skin. There are, however, some lessons to be learned from a mouse model. Chronic UV irradiation of hairless mice is a model for actinic elastosis (Starcher and Conrad, 1995Starcher B. Conrad M. A role for neutrophil elastase in the progression of solar elastosis.Connect Tissue Res. 1995; 31: 133-140Google Scholar). It was shown, however, that mice that lack neutrophil elastase do not accumulate elastic fibers; this suggests a role for elastase not only in breakdown but also in increased production of elastic fibers. There is no mouse ortholog for the human elafin gene, but mice do have SLPI, which probably has the same function. Taken together, these observations suggest that elastase activity promotes elastin synthesis, possibly in an indirect way following the release of breakdown products of the elastic fibers. This process could be controlled to some extent by the local induction of elastase inhibitors such as elafin (Muto et al., 2007Muto J. Kuroda K. Wachi H. Hirose S. Tajima S. Accumulation of elafin in actinic elastosis of sun-damaged skin: elafin binds to elastin and prevents elastolytic degradation.J Invest Dermatol. 2007; 127: 1358-1366Google Scholar) and SLPI (Wingens et al., 1998Wingens M. Van Bergen B.H. Hiemstra P.S. Meis J.F. Vlijmen-Willems I.M. Zeeuwen P.L. et al.Induction of SLPI (ALP/HUSI-I) in epidermal keratinocytes.J Invest Dermatol. 1998; 111: 996-1002Google Scholar). When these safeguards fail, excess elastase activity cannot be controlled. Speculatively, elastic fibers altered by transglutaminase-mediated cross-linking and increased elastin production will in the end lead to the elastotic material seen in photodamaged skin. The author states no conflict of interest.