Granzyme B as a therapeutic target: an update in 2022

ABSTRACTIntroduction Granzyme B is a serine protease extensively studied for its implication in cytotoxic lymphocyte-mediated apoptosis. In recent years, the paradigm that the role of granzyme B is restricted to immune cell-mediated killing has been challenged as extracellular roles for the protease have emerged. While mostly absent from healthy tissues, granzyme B levels are elevated in several autoimmune and/or chronic inflammatory conditions. In the skin, its accumulation significantly impairs proper wound healing.Areas covered After an overview of the current knowledge on granzyme B, a description of newly identified functions will be presented, focussing on granzyme B ability to promote cell–cell and dermal-epidermal junction disruption, extracellular matrix degradation, vascular permeabilization, and epithelial barrier dysfunction. Progress in granzyme B inhibition, as well as the use of granzyme B inhibitors for the treatment of tissue damage, will be discussed.Expert opinion The absence of endogenous extracellular inhibitors renders extracellular granzyme B accumulation deleterious for the proper healing of chronic wounds due to sustained proteolytic activity. Consequently, specific granzyme B inhibitors have been developed as new therapeutic approaches. Beyond applications in wound healing, other autoimmune and/or chronic inflammatory conditions related to exacerbated granzyme B activity may also benefit from the development of these inhibitors.KEYWORDS: Granzyme Bwound healinginflammationsmall molecule inhibitortissue remodelingskin integrity Article highlights Granzyme B is a pro-apoptotic serine protease with diverse emerging extracellular functions in disease.Granzyme B levels are minimal to absent in healthy individuals but are increased in the extracellular space and biological fluids of patients suffering from autoimmune disorders, chronic inflammatory conditions, or chronic wounds.Within the extracellular space, granzyme B cleaves numerous substrates involved in cell–cell junction, basement membrane integrity, and extracellular matrix organization.Due to the absence of endogenous inhibitor in human, proteolytic activity of extracellular granzyme B is believed to be dysregulated.Genetic deletion of granzyme B in mice reduces contact dermatitis and pemphigoid disorders severity, and improves thermal-, diabetic- and age-dependent impaired wound healing.Topical application of VTI-1002, a specific granzyme B inhibitor, showed high potential to treat inflammatory dermatological conditions and wound healing in mice.EOTT – List of abbreviationAAD = allergic airway diseaseACT = α-1-antichymotrypsinAD = atopic dermatitisAMD = age-related macular degenerationApoE = apolipoprotein EBM = basement membraneBP = bullous pemphigoidCC3 = cleaved Caspase-3CD = Crohn’s diseaseCTL = cytotoxic T lymphocyteDEJ = dermal-epidermal junctionDEP = diesel exhaust particlesDH = dermatitis herpetiformisEBA = epidermolysis bullosa acquisitaECM = extracellular matrixFGFR1 = fibroblast growth factor receptor 1GzmA = granzyme AGzmB = granzyme BHFD = high-fat dietHMD = house dust miteIBD = inflammatory bowel diseases(s)ICAM = (soluble) intracellular adhesion molecule-1IEL = intraepithelial lymphocytesIL = interleukinJAM-A = junctional adhesion molecule-ALPS = lipopolysaccharideLTBP = latent TGF-β binding proteinMIP-2 = macrophage inflammatory protein-2MMP = matrix metalloproteinaseNE = neutrophil elastaseNK = natural killerOVA = ovalbuminOXA = oxazolonePAR2 = protease-activator receptor 2PD = pemphigoid diseasesPI = pressure injuriesRPE = retinal pigment epitheliumSerpina3N = serine peptidase inhibitor, clade 3, member 3NSJS = Stevens-Johnson syndromeTEN = toxic epidermal necrolysisTGF-β1 = transforming growth factor-β1TIMP = tissue inhibitor of metalloproteinaseTJ = tight junctionTNF = tumor necrosis factorTREM-1 = triggering receptor expressed by myeloid cells-1UV = ultravioletVEGF = vascular endothelial growth factorVEGFR = vascular endothelial growth factor receptorWT = wild typeZO-1 = zonula occludens protein-1Declaration of interestDavid J. Granville is the Co-Founder and Chief Scientific Officer of viDA Therapeutics, which owns proprietary granzyme B inhibitor VTI-1002. The other authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.Reviewer disclosuresPeer reviewers on this manuscript have no relevant financial or other relationships to disclose.Supplementary materialSupplemental data for this article can be accessed online at https://doi.org/10.1080/14728222.2022.2161890Additional informationFundingThis manuscript was funded by the Canadian Institutes for Health Research, Michael Smith Foundation for Health Research, National Sciences and Engineering Research Council (NSERC) of Canada, Leo Foundation, Cancer Research Society, Eczema Society of Canada, Mitacs Canada, and the Rick Hansen Institute to DJ Granville.