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Review
. 2009 Nov;89(11):1195-220.
doi: 10.1038/labinvest.2009.91. Epub 2009 Sep 21.

Intracellular versus extracellular granzyme B in immunity and disease: challenging the dogma

Wendy Anne Boivin  1 , Dawn Michelle Cooper, Paul Ryan Hiebert, David James Granville
Affiliations
Review

Intracellular versus extracellular granzyme B in immunity and disease: challenging the dogma

Wendy Anne Boivin et al. Lab Invest. 2009 Nov.

Abstract

The cytotoxic granzyme B (GrB)/perforin pathway has been traditionally viewed as a primary mechanism that is used by cytotoxic lymphocytes to eliminate allogeneic, virally infected and/or transformed cells VSports手机版. Although originally proposed to have intracellular and extracellular functions, upon the discovery that perforin, in combination with GrB, could induce apoptosis, other potential functions for this protease were, for the most part, disregarded. As there are 5 granzymes in humans and 11 granzymes in mice, many studies used perforin knockout mice as an initial screen to evaluate the role of granzymes in disease. However, in recent years, emerging clinical and biochemical evidence has shown that the latter approach may have overlooked a critical perforin-independent, pathogenic role for these proteases in disease. This review focuses on GrB, the most characterized of the granzyme family, in disease. Long known to be a pro-apoptotic protease expressed by cytotoxic lymphocytes and natural killer cells, it is now accepted that GrB can be expressed in other cell types of immune and nonimmune origin. To the latter, an emerging immune-independent role for GrB has been forwarded due to recent discoveries that GrB may be expressed in nonimmune cells such as smooth muscle cells, keratinocytes, and chondrocytes in certain disease states. Given that GrB retains its activity in the blood, can cleave extracellular matrix, and its levels are often elevated in chronic inflammatory diseases, this protease may be an important contributor to certain pathologies. The implications of sustained elevations of intracellular and extracellular GrB in chronic vascular, dermatological, and neurological diseases, among others, are developing. This review examines, for the first time, the multiple roles of GrB in disease pathogenesis. .

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Figure 1
Figure 1
Classical granzyme B (GrB)/perforin-mediated apoptosis pathway. GrB internalization is facilitated by perforin. Upon internalization, GrB initiates apoptosis primarily through the cleavage of Bid into a truncated form (gtBid) that triggers mitochondrial cytochrome c release and apoptosome formation leading to caspase activation and manifestation of the apoptosis phenotype. GrB can also bypass the mitochondrial pathway and initiate caspase activation directly and/or cleave caspase substrates such as the inhibitor of caspase-activated deoxyribonuclease (ICAD), thereby allowing CAD to translocate to the nucleus to fragment DNA. GrB also cleaves the nuclear membrane protein lamin B, resulting in a loss of integrity of the nuclear membrane.
Figure 2
Figure 2
Putative extracellular (perforin-independent) roles for GrB in age-related chronic inflammatory disorders. During a number of chronic inflammatory conditions, GrB accumulates extracellularly in the tissues, blood stream, and other bodily fluids. GrB retains its activity in the blood, suggesting that, unlike MMPs and cathepsins, extracellular inhibitors of GrB activity may be limited. GrB can cleave proteins involved in structural integrity and wound healing such as fibronectin. GrB can also cleave proteins related to clotting (fibrinogen, vWF, plasminogen). GrB can induce detachment-mediated cell death (anoikis) through the cleavage of ECM. Although yet to be shown for granzymes, MMP-mediated fragments of fibronectin and elastin show chemotactic properties and may enhance the immune response in atherosclerosis. Fragments may also exhibit bioactive properties and may be able to release cytokines from the matrix. Granzymes may also have a role in the cleavage of cell surface receptors as seen with Notch1 and FGFR1.
Figure 3
Figure 3
Granzyme B in the pathogenesis of rheumatoid arthritis, skin disease, and atherosclerosis. (a) Infiltrating immune cells in RA (CTLs, macrophages, NK cells, and T-helper cells) express and release GrB in joints and induce apoptosis in resident cells (1). GrB may contribute to proteoglycan degradation as GrB-positive cells are found at the pannus–cartilage junction, an area of cartilage destruction (2). Extracelllular GrB levels are elevated in the synovial fluid of RA joints and are believed to further degrade matrix (3). Chondrocytes express GrB in RA and are capable of inducing apoptosis in neighboring cells and secreting GrB into the extracellular milieu, which causes further extracellular damage (4). (b) GrB may contribute to skin aging, alopecia, and disease through various intracellular and extracellular pathways. UVA light, which is believed to be responsible for visible aging that occurs in the skin, induces reactive oxygen species production, which leads to GrB expression in keratinocytes (1). GrB from keratinocytes cleaves the ECM protein fibronectin (2), inhibits cell migration, and can also induce apoptosis in neighboring cells (3). Mast cells from the skin are another cell type that express GrB (4). GrB from CTLs has been proposed to induce melanocyte apoptosis in vitiligo (5). Invading CTLs express GrB in alopecia areata and influence hair follicle regression (6). Substance P secreted by skin mast cells increases GrB-positive CTLs in the skin, further promoting AA (7). Whether substance P induces mast cell degranulation leading to the release of GrB is unknown. (c) At the early stages of atherosclerosis, after endothelial dysfunction and intimal lipid retention, CTLs, and monocytes infiltrate the vessel wall and migrate into the intima. SMCs and macrophages engulf oxidized lipoproteins and become lipid-laden foam cells, leading to GrB expression in these cells. The latter may promote foam cell apoptosis in developing plaques. GrB can also cleave various extracellular matrix proteins that maintain fibrotic cap stability. In addition to a loss in matrix integrity, ECM cleavage will also result in a loss of SMC–ECM interactions, which may promote apoptosis. SMC expression of PI-9 is decreased in unstable plaques, rendering SMCs susceptible to GrB-dependent apoptosis and further promoting plaque instability and rupture.
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