Abstract
Granzymes (granule-secreted enzymes) are a family of serine proteases that have been viewed as redundant cytotoxic enzymes since their discovery more than 30 years ago. Predominantly produced by cytotoxic lymphocytes and natural killer cells, granzymes are delivered into the cytoplasm of target cells through immunological synapses in cooperation with the pore-forming protein perforin. After internalization, granzymes can initiate cell death through the cleavage of intracellular substrates. However, evidence now also demonstrates the existence of non-cytotoxic, pro-inflammatory, intracellular and extracellular functions that are granzyme specific. Under pathological conditions, granzymes can be produced and secreted extracellularly by immune cells as well as by non-immune cells. Depending on the granzyme, accumulation in the extracellular milieu might contribute to inflammation, tissue injury, impaired wound healing, barrier dysfunction, osteoclastogenesis and/or autoantigen generation.
Key points
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Granzymes are serine proteases with both cytotoxic and non-cytotoxic functions; phenotypic and mechanistic characterization of granzymes in rheumatic diseases is needed to delineate their specific roles.
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The five human granzymes have unique substrate specificities and functional roles, as determined by granzyme-specific cleavage preferences, location of accumulation (intracellular or extracellular) and exposure to substrates in tissues.
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Extracellular granzyme activity can contribute to tissue injury, inflammation, autoimmunity, epithelial and endothelial barrier dysfunction, bullae formation, impaired wound healing, and degenerative or pathological aging.
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In addition to cytoplasmic proteins involved in apoptosis, granzyme B substrates include extracellular matrix proteins, hemidesmosomal or desmosomal proteins, pro-inflammatory cytokines, cell surface receptors and autoantigens.
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Granzyme A and granzyme B are elevated in synovial fluid, tissues and plasma of people with rheumatoid arthritis; in an arthritis model, Gzma−/− mice have lower disease severity than that of wild-type mice.
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CD8+ T cells expressing granzyme B and granzyme K are enriched in the peripheral blood and inflamed tissues of people with rheumatoid arthritis, systemic lupus erythematosus or Sjögren syndrome.
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Acknowledgements
D.J.G. is funded by grants-in-aid from the Canadian Institutes for Health Research (CIHR). A.A. is the recipient of the Arthritis Society Canada Training Postdoctoral Fellowship. J.P. is funded by CIBER (Centro de Investigación Biomédica en Red; CB21/13/00087), Instituto de Salud Carlos III, FEDER (Fondo Europeo de Desarrollo Regional), Gobierno de Aragón (Group B29_23R, and LMP139_21), Grant PID2020-113963RBI00 by MCIN/AEI/10.13039/501100011033, ASPANOA, and Carrera de la Mujer de Monzón.
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D.J.G. is a co-founder and chief scientific officer of viDA Therapeutics, which owns patents for and is developing inhibitors targeting granzymes as therapeutics. The remaining authors declare no competing interests.
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Aubert, A., Jung, K., Hiroyasu, S. et al. Granzyme serine proteases in inflammation and rheumatic diseases. Nat Rev Rheumatol 20, 361–376 (2024). https://doi.org/10.1038/s41584-024-01109-5
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DOI: https://doi.org/10.1038/s41584-024-01109-5