Potential implications of granzyme B in keloids and hypertrophic scars through extracellular matrix remodeling and latent TGF-β activation
Keloid scars (KS) and hypertrophic scars (HS) are fibroproliferative wound healing defects characterized by excessive accumulation of extracellular matrix (ECM) in the dermis of affected individuals. Although transforming growth factor (TGF)-β is known to be involved in the formation of KS and HS, t...
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Frontiers Media S.A.
2025-01-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2024.1484462/full |
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| author | Alexandre Aubert Alexandre Aubert Alexandre Aubert Jenna Goeres Jenna Goeres Jenna Goeres Amy Liu Amy Liu Amy Liu Martin Kao Martin Kao Martin Kao Katlyn C. Richardson Katlyn C. Richardson Katlyn C. Richardson Karen Jung Karen Jung Karen Jung Boris Hinz Boris Hinz Richard I. Crawford Richard I. Crawford David J. Granville David J. Granville David J. Granville |
| author_facet | Alexandre Aubert Alexandre Aubert Alexandre Aubert Jenna Goeres Jenna Goeres Jenna Goeres Amy Liu Amy Liu Amy Liu Martin Kao Martin Kao Martin Kao Katlyn C. Richardson Katlyn C. Richardson Katlyn C. Richardson Karen Jung Karen Jung Karen Jung Boris Hinz Boris Hinz Richard I. Crawford Richard I. Crawford David J. Granville David J. Granville David J. Granville |
| author_sort | Alexandre Aubert |
| collection | DOAJ |
| description | Keloid scars (KS) and hypertrophic scars (HS) are fibroproliferative wound healing defects characterized by excessive accumulation of extracellular matrix (ECM) in the dermis of affected individuals. Although transforming growth factor (TGF)-β is known to be involved in the formation of KS and HS, the molecular mechanisms responsible for its activation remain unclear. In this study we investigated Granzyme B (GzmB), a serine protease with established roles in fibrosis and scarring through the cleavage of ECM proteins, as a potential new mediator of TGF-β activation in KS and HS. Increased GzmB-positive mast cells were identified in the dermis of KS and HS but not healthy skin controls. Elevated levels of substance P, a neuropeptide involved in mast cell degranulation, suggest that GzmB is released extracellularly, as confirmed by the significant reduction of the established extracellular GzmB substrate decorin in KS and HS. Similarly, presence of latent TGF-β binding protein 1 (LTBP1), a protein involved in the extracellular tethering of latent TGF-β, was disrupted proximal to the dermal-epidermal junction (DEJ) of GzmBhigh KS and HS lesions. Using LTBP1-enriched medium as well as purified LTBP1, its cleavage by GzmB was confirmed in vitro. Increased TGF-β/Smad signaling pathway was observed in keratinocytes treated with GzmB-digested LTBP1 and was abolished by the addition of a pan-TGF-β inhibitor, suggesting that GzmB cleavage of LTBP1 contributes to TGF-β activation. In dermal fibroblasts, GzmB also cleaved cell-derived LTBP1 and induced TGF-β activation through the cleavage of one or more unidentified fibroblast-secreted proteins. Altogether, the present results suggest that GzmB contributes to KS and HS through ECM remodeling and TGF-β activation. |
| format | Article |
| id | doaj-art-d7ebe38f8dd945999dc0ad902e59ec57 |
| institution | Kabale University |
| issn | 1664-3224 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Immunology |
| spelling | doaj-art-d7ebe38f8dd945999dc0ad902e59ec572025-01-16T05:10:18ZengFrontiers Media S.A.Frontiers in Immunology1664-32242025-01-011510.3389/fimmu.2024.14844621484462Potential implications of granzyme B in keloids and hypertrophic scars through extracellular matrix remodeling and latent TGF-β activationAlexandre Aubert0Alexandre Aubert1Alexandre Aubert2Jenna Goeres3Jenna Goeres4Jenna Goeres5Amy Liu6Amy Liu7Amy Liu8Martin Kao9Martin Kao10Martin Kao11Katlyn C. Richardson12Katlyn C. Richardson13Katlyn C. Richardson14Karen Jung15Karen Jung16Karen Jung17Boris Hinz18Boris Hinz19Richard I. Crawford20Richard I. Crawford21David J. Granville22David J. Granville23David J. Granville24International Collaboration on Repair Discoveries (ICORD) Centre, Vancouver Coastal Health Research Institute (VCHRI), University of British Columbia (UBC), Vancouver, BC, CanadaDepartment of Pathology and Laboratory Medicine, University of British Columbia (UBC), Vancouver, BC, CanadaBritish Columbia Professional Firefighters’ Burn and Wound Healing Group, Vancouver Coastal Health Research Institute (VCHRI), Vancouver, BC, CanadaInternational Collaboration on Repair Discoveries (ICORD) Centre, Vancouver Coastal Health Research Institute (VCHRI), University of British Columbia (UBC), Vancouver, BC, CanadaDepartment of Pathology and Laboratory Medicine, University of British Columbia (UBC), Vancouver, BC, CanadaBritish Columbia Professional Firefighters’ Burn and Wound Healing Group, Vancouver Coastal Health Research Institute (VCHRI), Vancouver, BC, CanadaInternational Collaboration on Repair Discoveries (ICORD) Centre, Vancouver Coastal Health Research Institute (VCHRI), University of British Columbia (UBC), Vancouver, BC, CanadaDepartment of Pathology and Laboratory Medicine, University of British Columbia (UBC), Vancouver, BC, CanadaBritish Columbia Professional Firefighters’ Burn and Wound Healing Group, Vancouver Coastal Health Research Institute (VCHRI), Vancouver, BC, CanadaInternational Collaboration on Repair Discoveries (ICORD) Centre, Vancouver Coastal Health Research Institute (VCHRI), University of British Columbia (UBC), Vancouver, BC, CanadaDepartment of Pathology and Laboratory Medicine, University of British Columbia (UBC), Vancouver, BC, CanadaBritish Columbia Professional Firefighters’ Burn and Wound Healing Group, Vancouver Coastal Health Research Institute (VCHRI), Vancouver, BC, CanadaInternational Collaboration on Repair Discoveries (ICORD) Centre, Vancouver Coastal Health Research Institute (VCHRI), University of British Columbia (UBC), Vancouver, BC, CanadaDepartment of Pathology and Laboratory Medicine, University of British Columbia (UBC), Vancouver, BC, CanadaBritish Columbia Professional Firefighters’ Burn and Wound Healing Group, Vancouver Coastal Health Research Institute (VCHRI), Vancouver, BC, CanadaInternational Collaboration on Repair Discoveries (ICORD) Centre, Vancouver Coastal Health Research Institute (VCHRI), University of British Columbia (UBC), Vancouver, BC, CanadaDepartment of Pathology and Laboratory Medicine, University of British Columbia (UBC), Vancouver, BC, CanadaBritish Columbia Professional Firefighters’ Burn and Wound Healing Group, Vancouver Coastal Health Research Institute (VCHRI), Vancouver, BC, CanadaLaboratory of Tissue Repair and Regeneration, Keenan Research Institute for Biomedical Science of the St. Michael’s Hospital, Toronto, ON, CanadaFaculty of Dentistry, University of Toronto, Toronto, ON, CanadaDepartment of Pathology and Laboratory Medicine, University of British Columbia (UBC), Vancouver, BC, CanadaDepartment of Dermatology and Skin Science, University of British Columbia (UBC), Vancouver, BC, CanadaInternational Collaboration on Repair Discoveries (ICORD) Centre, Vancouver Coastal Health Research Institute (VCHRI), University of British Columbia (UBC), Vancouver, BC, CanadaDepartment of Pathology and Laboratory Medicine, University of British Columbia (UBC), Vancouver, BC, CanadaBritish Columbia Professional Firefighters’ Burn and Wound Healing Group, Vancouver Coastal Health Research Institute (VCHRI), Vancouver, BC, CanadaKeloid scars (KS) and hypertrophic scars (HS) are fibroproliferative wound healing defects characterized by excessive accumulation of extracellular matrix (ECM) in the dermis of affected individuals. Although transforming growth factor (TGF)-β is known to be involved in the formation of KS and HS, the molecular mechanisms responsible for its activation remain unclear. In this study we investigated Granzyme B (GzmB), a serine protease with established roles in fibrosis and scarring through the cleavage of ECM proteins, as a potential new mediator of TGF-β activation in KS and HS. Increased GzmB-positive mast cells were identified in the dermis of KS and HS but not healthy skin controls. Elevated levels of substance P, a neuropeptide involved in mast cell degranulation, suggest that GzmB is released extracellularly, as confirmed by the significant reduction of the established extracellular GzmB substrate decorin in KS and HS. Similarly, presence of latent TGF-β binding protein 1 (LTBP1), a protein involved in the extracellular tethering of latent TGF-β, was disrupted proximal to the dermal-epidermal junction (DEJ) of GzmBhigh KS and HS lesions. Using LTBP1-enriched medium as well as purified LTBP1, its cleavage by GzmB was confirmed in vitro. Increased TGF-β/Smad signaling pathway was observed in keratinocytes treated with GzmB-digested LTBP1 and was abolished by the addition of a pan-TGF-β inhibitor, suggesting that GzmB cleavage of LTBP1 contributes to TGF-β activation. In dermal fibroblasts, GzmB also cleaved cell-derived LTBP1 and induced TGF-β activation through the cleavage of one or more unidentified fibroblast-secreted proteins. Altogether, the present results suggest that GzmB contributes to KS and HS through ECM remodeling and TGF-β activation.https://www.frontiersin.org/articles/10.3389/fimmu.2024.1484462/fullkeloidshypertrophic scarsgranzymesinflammationextracellular matrix remodelingTGF-β activation |
| spellingShingle | Alexandre Aubert Alexandre Aubert Alexandre Aubert Jenna Goeres Jenna Goeres Jenna Goeres Amy Liu Amy Liu Amy Liu Martin Kao Martin Kao Martin Kao Katlyn C. Richardson Katlyn C. Richardson Katlyn C. Richardson Karen Jung Karen Jung Karen Jung Boris Hinz Boris Hinz Richard I. Crawford Richard I. Crawford David J. Granville David J. Granville David J. Granville Potential implications of granzyme B in keloids and hypertrophic scars through extracellular matrix remodeling and latent TGF-β activation Frontiers in Immunology keloids hypertrophic scars granzymes inflammation extracellular matrix remodeling TGF-β activation |
| title | Potential implications of granzyme B in keloids and hypertrophic scars through extracellular matrix remodeling and latent TGF-β activation |
| title_full | Potential implications of granzyme B in keloids and hypertrophic scars through extracellular matrix remodeling and latent TGF-β activation |
| title_fullStr | Potential implications of granzyme B in keloids and hypertrophic scars through extracellular matrix remodeling and latent TGF-β activation |
| title_full_unstemmed | Potential implications of granzyme B in keloids and hypertrophic scars through extracellular matrix remodeling and latent TGF-β activation |
| title_short | Potential implications of granzyme B in keloids and hypertrophic scars through extracellular matrix remodeling and latent TGF-β activation |
| title_sort | potential implications of granzyme b in keloids and hypertrophic scars through extracellular matrix remodeling and latent tgf β activation |
| topic | keloids hypertrophic scars granzymes inflammation extracellular matrix remodeling TGF-β activation |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2024.1484462/full |
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