Granzyme B in skin inflammation and disease

Turner, Cathy; Lim, Darielle J.; Granville, David J.

doi:10.1016/j.matbio.2017.12.005

Cited by 91 publications

(87 citation statements)

References 136 publications

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“…Several cytotoxic [natural killer (NK), CD8+, T], non-cytotoxic immune (mast, macrophages, basophils), and non-immune cells (spermatozoa, keratinocytes) express GzmB. In addition to its well-established intracellular role, GzmB also has important extracellular functions in immune regulation and the degradation of extracellular matrix (ECM) proteins (8)(9)(10)(11)(12). Experimental The five layers of BM and major ECM proteins are shown in blue text.…”

Section: Introductionmentioning

confidence: 99%

Retinal Distribution and Extracellular Activity of Granzyme B: A Serine Protease That Degrades Retinal Pigment Epithelial Tight Junctions and Extracellular Matrix Proteins

et al. 2020

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Granzymes are a family of serine proteases first shown to be intracellular initiators of immune-mediated cell death in target pathogenic cells. In addition to its intracellular role, Granzyme B (GzmB) has important extracellular functions in immune regulation and extracellular matrix (ECM) degradation. Verified substrates of extracellular GzmB activity include tight junctional and ECM proteins. Interestingly, little is known about the activity of GzmB in the outer human retina, a tissue in which the degradation of the tight junctional contacts of retinal pigment epithelial (RPE) cells and within the external limiting membrane, as well as remodeling of the ECM in Bruch's membrane, cause the breakdown of the blood-retinal barrier and slowing of metabolite transport between neuroretina and choroidal blood supply. Such pathological changes in outer retina signal early events in the development of age-related macular degeneration (AMD), a multifactorial, chronic inflammatory eye disease. This study is the first to focus on the distribution of GzmB in the outer retina of the healthy and diseased post-mortem human eye. Our results revealed that GzmB is present in RPE and choroidal mast cells. More immunoreactive cells are present in older (>65 years) compared to younger (<55 years) donor eyes, and choroidal immunoreactive cells are more numerous in eyes with choroidal neovascularization (CNV), while RPE immunoreactive cells are more numerous in eyes with soft drusen, an early AMD event. In vitro studies demonstrated that RPE-derived tight junctional and ECM proteins are cleaved by exogenous GzmB stimulation. These results suggest that the increased presence of GzmB immunoreactive cells in outer retina of older (healthy) eyes as well as in diseased eyes with CNV (from AMD) and eyes with soft drusen exacerbate ECM remodeling in the Bruch's membrane and degradation of the blood-retinal barrier. Currently there are no treatments that prevent remodeling of the Bruch's membrane and/or the loss of function of the outer blood-retinal barrier, Matsubara et al. Granzyme B in Outer Retina known to promote early AMD changes, such as drusen deposition, RPE dysfunction and pro-inflammation. Specific inhibitors of GzmB, already in preclinical studies for non-ocular diseases, may provide new strategies to stop these early events associated with the development of AMD.

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Section: Introductionmentioning

confidence: 99%

Retinal Distribution and Extracellular Activity of Granzyme B: A Serine Protease That Degrades Retinal Pigment Epithelial Tight Junctions and Extracellular Matrix Proteins

et al. 2020

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“…As advanced by Turner and collaborators, GrB is a serine protease emerging as an important mediator of skin injury, inflammation and repair. Found at low levels in healthy skin, GrB is dramatically elevated in chronic disease and inflammatory skin disorders, including diabetic ulcers, hypertrophic scarring, autoimmune skin disorders, cutaneous leishmaniasis and aging skin . Human cytotoxic granules contain also Grly, an antimicrobial peptide which selectively destroys cholesterol poor microbial membranes .…”

Section: Discussionmentioning

confidence: 99%

“…The arrows indicate the double-stained cells skin disorders, cutaneous leishmaniasis and aging skin. 37 Human cytotoxic granules contain also Grly, an antimicrobial peptide which selectively destroys cholesterol poor microbial membranes. [38][39][40][41] Together, Grly, perforine (PFN) and GrB are able to kill rapidly intracellular bacteria.…”

Section: Discussionmentioning

confidence: 99%

Activated cytotoxic T cells within zoonotic cutaneous leishmaniasis lesions

Boussoffara

Boubaker

Ahmed

et al. 2019

Immunity Inflam & Disease

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Introduction Zoonotic cutaneous leishmaniasis (ZCL), due to infection by Leishmania (L). major, is characterized by polymorphic clinical manifestations which could be attributed to the host's immune response. In this study we investigated the involvement of cytotoxic cells on the outcome of the disease. Methods Expression of granzyme B (GrB), granulysine (Grly), and interferon (IFN)‐γ was evaluated within ZCL lesion specimens using the technique of real‐time quantitative polymerase chain reaction (RT‐qPCR). Immunohistochemical staining was performed using anti‐CD3, CD4, CD8, CD56, GrB, and IFN‐γ antibodies to identify the phenotype of GrB and IFN‐γ‐producing cells. Results GrB and Grly mRNA was detected within 75% and 80% of ZCL lesions, respectively. Statistical analysis demonstrated a significant correlation between levels of GrB and Grly. Interestingly, expression of these molecules correlates negatively with the lesion's age. The highest levels were measured in early lesions (E‐ZCL) (lesion age ≤1 month) comparing to late lesions (L‐ZCL) (lesion age >1 month). Otherwise, IFN‐γ mRNA was detected only within 56% and a positive correlation was found between levels of this cytokine and those of GrB. Immunohistochemical analysis showed that GrB is produced essentially by CD8+T cells whereas IFN‐γ is produced by both CD4+ and CD8+T cells. Conclusion Together our results demonstrate the presence of cytotoxic cells producing GrB and Grly within leishmaniasis cutaneous lesions.

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“…Many proteases, such as different members of the MMP family, cleave decorin and make it inactive (Järvinen and Prince, 2015). Protease-mediated cleavage of decorin has been implicated in the pathogenesis of different diseases (Järvinen and Prince, 2015;Turner et al, 2017). Whereas neonatal skin is completely devoid of catabolic fragments of decorin, inactive, cleaved decorin fragments accumulate in the skin during aging (Carrino et al, 2003).…”

Section: Decorin and Its Interactions With Signalling Moleculesmentioning

confidence: 99%

“…Cleavage of decorin by granzyme B in models of aortic aneurysms, in turn, leads to aneurysm ruptures and subsequent deaths of the animals (Ang et al, 2011). Interestingly, granzyme B also activates TGF-β (Turner et al, 2017).…”

Section: Decorin and Its Interactions With Signalling Moleculesmentioning

confidence: 99%

Generation of a multi‐functional, target organ‐specific, anti‐fibrotic molecule by molecular engineering of the extracellular matrix protein, decorin

Järvinen

Ruoslahti

2018

British J Pharmacology

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Extracellular matrix (ECM) molecules play important roles in regulating processes such as cell proliferation, migration, differentiation and survival. Decorin is a proteoglycan that binds to ('decorates') collagen fibrils in the ECM. Decorin also interacts with many growth factors and their receptors, the most notable of these interactions being its inhibitory activity on TGF-β, the growth factor responsible for fibrosis formation. We have generated a recombinant, multi-functional, fusion-protein consisting of decorin as a therapeutic domain and a vascular homing and cell-penetrating peptide as a targeting vehicle. This recombinant decorin (CAR-DCN) accumulates at the sites of the targeted disease at higher levels and, as a result, has substantially enhanced biological activity over native decorin. CAR-DCN is an example of how molecular engineering can give a compound the ability to seek out sites of disease and enhance its therapeutic potential. CAR-DCN will hopefully be used to treat severe human diseases. LINKED ARTICLES: This article is part of a themed section on Translating the Matrix. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.1/issuetoc.

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Granzyme B in skin inflammation and disease

Cited by 91 publications

References 136 publications

Retinal Distribution and Extracellular Activity of Granzyme B: A Serine Protease That Degrades Retinal Pigment Epithelial Tight Junctions and Extracellular Matrix Proteins

Retinal Distribution and Extracellular Activity of Granzyme B: A Serine Protease That Degrades Retinal Pigment Epithelial Tight Junctions and Extracellular Matrix Proteins

Activated cytotoxic T cells within zoonotic cutaneous leishmaniasis lesions

Generation of a multi‐functional, target organ‐specific, anti‐fibrotic molecule by molecular engineering of the extracellular matrix protein, decorin

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