Granzyme B degrades extracellular matrix and contributes to delayed wound closure in apolipoprotein E knockout mice.

TitleGranzyme B degrades extracellular matrix and contributes to delayed wound closure in apolipoprotein E knockout mice.
Publication TypeJournal Article
Year of Publication2013
AuthorsHiebert, PR, Wu, D, Granville, DJ
JournalCell Death Differ
Volume20
Issue10
Pagination1404-14
Date Published2013 Oct
ISSN1476-5403
KeywordsAnimals, Apolipoproteins, Apolipoproteins E, Extracellular Matrix, Granzymes, Inflammation, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Wound Healing
Abstract

Chronic inflammation and excessive protease activity have a major role in the persistence of non-healing wounds. Granzyme B (GzmB) is a serine protease expressed during chronic inflammation that, in conjunction with perforin, has a well-established role in initiating apoptotic cell death. GzmB is also capable of acting extracellularly, independent of perforin and can degrade several extracellular matrix (ECM) proteins that are critical during wound healing. We used apolipoprotein E (ApoE) knockout (AKO) mice as a novel model of chronic inflammation and impaired wound healing to investigate the role of GzmB in chronic wounds. Wild-type and AKO mice were grown to 7 weeks (young) or 37 weeks (old) of age on a regular chow or high-fat diet (HFD), given a 1-cm diameter full thickness wound on their mid dorsum and allowed to heal for 16 days. Old AKO mice fed a HFD exhibited reduced wound closure, delayed contraction, chronic inflammation and altered ECM remodeling. Conversely, GzmB/ApoE double knockout mice displayed improved wound closure and contraction rates. In addition, murine GzmB was found to degrade both fibronectin and vitronectin derived from healthy mouse granulation tissue. In addition, GzmB-mediated degradation of fibronectin generated a fragment similar in size to that observed in non-healing mouse wounds. These results provide the first direct evidence that GzmB contributes to chronic wound healing in part through degradation of ECM.

DOI10.1038/cdd.2013.96
Alternate JournalCell Death Differ.
PubMed ID23912712
PubMed Central IDPMC3770318
Grant List / / Canadian Institutes of Health Research / Canada