Granzymes in age-related cardiovascular and pulmonary diseases

Hendel, Alon; Hiebert, Paul; Boivin, Wendy A.; Williams, Sarah; Granville, David J.

doi:10.1038/cdd.2010.5

Cited by 70 publications

(68 citation statements)

References 84 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…34,35 Interestingly, it is also known that GzmB-mediated cleavage of IL-1a can occur extracellularly by GzmB derived from NK cells, 35 further highlighting the potential importance of perforin-independent GzmB activity in health and disease. In fact, both cytotoxic and non-cytotoxic activities of GzmB are suggested to have a role in many inflammatory disorders such as diabetes, cancer, transplant rejection, autoimmunity, cardiovascular and pulmonary diseases (reviewed in refs [36][37][38][39][40] ). Although its role in wound healing has never been assessed, considerable evidence exists that would support a role for GzmB in chronic wounds.…”

Section: Discussionmentioning

confidence: 99%

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

Hiebert

Granville

2013

Cell Death Differ

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionmentioning

confidence: 99%

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

Hiebert

Granville

2013

Cell Death Differ

Self Cite

View full text Add to dashboard Cite

show abstract

“…More recently, novel extracellular and perforin-independent functions have been identified (24,25). It has been demonstrated that Gr-mediated extracellular matrix (ECM) degradation may contribute to inflammation (26)(27)(28)(29)(30). GrB degrades several ECM components, such as vitronectin, laminin, fibronectin, decorin, and the proteoglycans biglycan and betaglycan (31)(32)(33)(34)(35).…”

mentioning

confidence: 99%

Granzymes Regulate Proinflammatory Cytokine Responses

Wensink

Hack

Bovenschen

2015

The Journal of Immunology

120

153

View full text Add to dashboard Cite

Granzymes (Grs) are serine proteases mainly produced by cytotoxic lymphocytes and are traditionally considered to cause apoptosis in tumor cells and virally infected cells. However, the cytotoxicity of several Grs is currently being debated, and additional, predominantly extracellular, functions of Grs in inflammation are emerging. Extracellular soluble Grs are elevated in the circulation of patients with autoimmune diseases and infections. Additionally, Grs are expressed by several types of immune cells other than cytotoxic lymphocytes. Recent research has revealed novel immunomodulatory functions of Grs. In this review, we provide a comprehensive overview on the role of Grs in inflammation, highlighting their role in cytokine induction and processing.

show abstract

“…Although there are certainly more questions than answers at this time, many of these ideas are beginning to be addressed. As discussed in-depth in the review by Hendel et al, 13 emerging studies are beginning to demonstrate a potential perforin-independent, extracellular role for granzymes in disease.…”

mentioning

confidence: 99%