Skip to main content

ORIGINAL RESEARCH article

Front. Immunol.
Sec. Molecular Innate Immunity
Volume 15 - 2024 | doi: 10.3389/fimmu.2024.1484462
This article is part of the Research Topic Roles of Granzymes in Inflammation, Aging, and Autoimmunity View all articles

Potential implications of Granzyme B in Keloids and Hypertrophic Scars through extracellular matrix remodeling and latent TGF-Beta activation

Provisionally accepted
Alexandre Aubert Alexandre Aubert 1Jenna Goeres Jenna Goeres 1Amy Liu Amy Liu 1Martin Kao Martin Kao 1Karen Jung Karen Jung 1Boris Hinz Boris Hinz 2Richard I Crawford Richard I Crawford 1David J Granville David J Granville 1*
  • 1 University of British Columbia, Vancouver, Canada
  • 2 Keenan Research Centre for Biomedical Science, St Michael's Hospital, Toronto, Ontario, Canada

The final, formatted version of the article will be published soon.

    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)-Beta 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-Beta 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-Beta binding protein 1 (LTBP1), a protein involved in the extracellular tethering of latent TGF-Beta, 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-Beta/Smad signaling pathway was observed in keratinocytes treated with GzmB-digested LTBP1 and was abolished by the addition of a pan-TGF-Beta inhibitor, suggesting that GzmB cleavage of LTBP1 contributes to TGF-Beta activation. In dermal fibroblasts, GzmB also cleaved cell-derived LTBP1 and induced TGF-Beta 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-Beta activation.

    Keywords: Keloids, Hypertrophic scars, Granzymes, Inflammation, extracellular matrix remodeling, TGF-b activation

    Received: 21 Aug 2024; Accepted: 20 Dec 2024.

    Copyright: © 2024 Aubert, Goeres, Liu, Kao, Jung, Hinz, Crawford and Granville. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence: David J Granville, University of British Columbia, Vancouver, Canada

    Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.