Granzyme B as a therapeutic target: an update in 2022

ABSTRACT

Introduction

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 B
• wound healing
• inflammation
• small molecule inhibitor
• tissue remodeling
• skin 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 abbreviation

AAD = allergic airway disease

ACT = α-1-antichymotrypsin

AD = atopic dermatitis

AMD = age-related macular degeneration

ApoE = apolipoprotein E

BM = basement membrane

BP = bullous pemphigoid

CC3 = cleaved Caspase-3

CD = Crohn’s disease

CTL = cytotoxic T lymphocyte

DEJ = dermal-epidermal junction

DEP = diesel exhaust particles

DH = dermatitis herpetiformis

EBA = epidermolysis bullosa acquisita

ECM = extracellular matrix

FGFR1 = fibroblast growth factor receptor 1

GzmA = granzyme A

GzmB = granzyme B

HFD = high-fat diet

HMD = house dust mite

IBD = inflammatory bowel diseases

(s)ICAM = (soluble) intracellular adhesion molecule-1

IEL = intraepithelial lymphocytes

IL = interleukin

JAM-A = junctional adhesion molecule-A

LPS = lipopolysaccharide

LTBP = latent TGF-β binding protein

MIP-2 = macrophage inflammatory protein-2

MMP = matrix metalloproteinase

NE = neutrophil elastase

NK = natural killer

OVA = ovalbumin

OXA = oxazolone

PAR2 = protease-activator receptor 2

PD = pemphigoid diseases

PI = pressure injuries

RPE = retinal pigment epithelium

Serpina3N = serine peptidase inhibitor, clade 3, member 3N

SJS = Stevens-Johnson syndrome

TEN = toxic epidermal necrolysis

TGF-β1 = transforming growth factor-β1

TIMP = tissue inhibitor of metalloproteinase

TJ = tight junction

TNF = tumor necrosis factor

TREM-1 = triggering receptor expressed by myeloid cells-1

UV = ultraviolet

VEGF = vascular endothelial growth factor

VEGFR = vascular endothelial growth factor receptor

WT = wild type

ZO-1 = zonula occludens protein-1

Declaration of interest

David 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 disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/14728222.2022.2161890

Additional information

Funding

This 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.