Pivotal Role for α1-Antichymotrypsin in Skin Repair

α1-Antichymotrypsin (α1-ACT) is a specific inhibitor of leukocyte-derived chymotrypsin-like proteases with largely unknown functions in tissue repair. By examining human and murine skin wounds, we showed that following mechanical injury the physiological repair response is associated with an acute p...

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Bibliographic Details
Published in:The Journal of biological chemistry 2011-08, Vol.286 (33), p.28889-28901
Main Authors: Hoffmann, Daniel C., Textoris, Christine, Oehme, Felix, Klaassen, Tobias, Goppelt, Andreas, Römer, Axel, Fugmann, Burkhard, Davidson, Jeffrey M., Werner, Sabine, Krieg, Thomas, Eming, Sabine A.
Format: Article
Language:English
Subjects:
Cell Biology
Inflammation
Leukocyte
Serine Protease
Serpin
Skin
Tissue Injury
Wound Healing
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Summary:α1-Antichymotrypsin (α1-ACT) is a specific inhibitor of leukocyte-derived chymotrypsin-like proteases with largely unknown functions in tissue repair. By examining human and murine skin wounds, we showed that following mechanical injury the physiological repair response is associated with an acute phase response of α1-ACT and the mouse homologue Spi-2, respectively. In both species, attenuated α1-ACT/Spi-2 activity and gene expression at the local wound site was associated with severe wound healing defects. Topical application of recombinant α1-ACT to wounds of diabetic mice rescued the impaired healing phenotype. LC-MS analysis of α1-ACT cleavage fragments identified a novel cleavage site within the reactive center loop and showed that neutrophil elastase was the predominant protease involved in unusual α1-ACT cleavage and inactivation in nonhealing human wounds. These results reveal critical functions for locally acting α1-ACT in the acute phase response following skin injury, provide mechanistic insight into its function during the repair response, and raise novel perspectives for its potential therapeutic value in inflammation-mediated tissue damage.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M111.249979