Introduction
Rheumatoid arthritis (RA) stands as a multifaceted autoimmune disorder marked by persistent inflammation impacting the synovial tissues of numerous joints. Granzymes (Gzms) are serine proteases that are unleashed into the immune synapse, the interface between cytotoxic lymphocytes and target cells.
With the aid of perforin, they infiltrate target cells, initiating programmed cell death in both inflammatory and tumor cells. The relationship between Gzms and RA is noteworthy.
Primarily, elevated levels of Gzms have been detected in the serum (specifically GzmB), plasma (comprising GzmA and GzmB), synovial fluid (comprising GzmB and GzmM), and synovial tissue (including GzmK) of RA patients.
Furthermore, Gzms may exacerbate inflammation by degrading the extracellular matrix and encouraging the release of cytokines.
This implicates their potential role in the pathogenesis of RA, suggesting their viability as biomarkers for RA diagnosis, even though their precise functions remain to be fully comprehended.
The objective of this review is to succinctly consolidate the existing knowledge concerning the potential involvement of the granzyme family in RA. This endeavor seeks to serve as a reference point for forthcoming research focused on unraveling the intricacies of RA mechanisms and the development of innovative therapeutic interventions.
GzmA-mediated proinflammatory cytokine-induced bone destruction in RA
GzmA, the most prevalent granzyme among killer cells, has a pivotal role in autoimmune diseases like rheumatoid arthritis (RA).
It is abundantly expressed in CD8 cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells and functions as a serine protease. GzmA’s actions extend to initiating cell death by targeting the SET complex within the endoplasmic reticulum-associated oxidative stress response, leading to single-stranded DNA damage.
Furthermore, GzmA is implicated in various proinflammatory mechanisms, including cytokine release and the cleavage of specific proteins, contributing to inflammation.
Its overexpression is associated with inflammatory reactions, and in RA, GzmA levels are elevated during active periods, promoting synovial inflammation and cartilage and bone injury.
Additionally, GzmA plays a role in pyroptosis through the cleavage of gasdermin B (GSDMB). Abnormal GzmA expression is linked to immune cells like T cells, NK cells, and NKT cells, while perforin, responsible for forming pores on target cell membranes, is associated with cytotoxic reactions in RA, further contributing to disease severity and joint damage.
InthecontextofRA,chemokineshavebeenshown to regulate GzmA release, with many of these chemokines being upregulated in the synovial tissue of RA patients. GzmA and GzmB also exhibit the ability to degrade extracellular matrix (ECM) proteins.
Moreover, GzmA’s association with inflammatory arthritis, particularly its impact on osteoclasts (OCs) involved in bone resorption, suggests its influence on bone destruction in RA. GzmA activates OC precursors to secrete tumor necrosis factor (TNF), exacerbating the proinflammatory cytokine-induced bone damage observed in RA.
This complex interaction may involve the direct promotion of OC differentiation or indirect contributions via other inflammatory responses. Overall, GzmA’s multifaceted functions and abnormal expression have significant implications in the pathogenesis of RA.
GzmB-mediated inflammation and ECM degradation in RA
GzmB, a prominent member of the granzyme family, possesses potent apoptotic capabilities, characterized by its caspase-like ability to cleave substrates at aspartic acid residues. It is a 32 kDa serine protease secreted by NK cells and CTLs.
GzmB enters target cells through perforin and induces apoptosis by cleaving various intracellular substrates, including those associated with DNA maintenance.
GzmB is produced by a range of immune and non-immune cells, contributing to extracellular functions such as ECM component degradation, cytokine processing, and cell receptor cleavage. Abnormal GzmB expression is observed in RA synovial tissues, with CD8 T cells expressing GzmB.
Elevated GzmB levels in blood and synovial fluid are linked to its release from inflamed joints. Additionally, GzmB can be stimulated by extracellular ATP, further exacerbating inflammation in RA.
GzmB plays a multifunctional role in RA, processing and activating proinflammatory mediators and contributing to inflammation, ECM remodeling, and tissue repair. It has also been associated with bone destruction and can serve as a biomarker for RA diagnosis.
While GzmB is generally considered proinflammatory in RA, some studies suggest reduced GzmB production in regulatory B cells (Bregs) in RA patients, possibly due to decreased IL-21 receptor expression.
The number of GzmB-producing Bregs is negatively correlated with disease activity, and their reduction may contribute to RA progression. However, further research is needed to determine any cell-specific functional differences in GzmB. Another granzyme, GzmH, exhibits distinct enzymatic activities compared to GzmB.
It induces rapid apoptosis in target cells and is primarily expressed in NK cells. Its specific role in RA remains to be explored, and IL-15 may play a role in regulating granzyme expression in RA.
GzmK- and GzmM-mediated cytokine-based inflammation in RA
GzmK is a granzyme family member expressed by various immune cells, and while its exact function is not well understood, it can induce non-apoptotic cell death and activate caspase-independent apoptosis, making it a potential player in inflammation and tissue damage in RA.
It can activate PAR-1 receptors and promote the release of inflammatory cytokines. Elevated GzmK levels in RA synovial tissues suggest its proinflammatory role, and it could be a biomarker for diagnosing a subtype of RA.
GzmM, another granzyme, is specific to NK cells and is found in various immune cell types. It shares similarities with GzmB in its ability to induce cell death, release cytokines, and damage cellular components. In RA, GzmM is expressed in synovial fluid cells and may contribute to inflammation by triggering the release of proinflammatory cytokines. However, further research is needed to fully understand GzmM’s specific role in RA.
Discussion
This review provides an overview of the role of five members of the granzyme (Gzm) family in rheumatoid arthritis (RA).
Granzymes are traditionally involved in inducing apoptotic cell death but also exhibit non-cytotoxic activities with diverse effects, including stimulating proinflammatory cytokines and extracellular matrix remodeling. These functions position Gzms as potential contributors to the pathogenesis of inflammatory diseases, including RA.
GzmA is significantly elevated in the plasma and synovial fluid of RA patients and can degrade extracellular matrix proteins, potentially contributing to bone destruction.
Elevated GzmB levels in serum are correlated with increased disease activity and cartilage destruction in RA. B cells expressing GzmB may help regulate proinflammatory responses in RA.
GzmM promotes inflammation by stimulating the release of proinflammatory cytokines and is elevated in RA. GzmK is associated with endothelial cells and fibroblasts, potentially playing a role in abnormal angiogenesis and synovial hyperplasia in RA.
The specific role of GzmH in RA requires further investigation.
While clinical inhibitors targeting Gzms are limited, there is evidence suggesting their potential value in the clinical treatment and management of RA.
Further research, combining molecular biology, cellular immunology, and other technologies, is needed to fully understand the significance of Gzms as proinflammatory mediators in RA.
Investigating the association between different cell death pathways and RA, as well as exploring Gzm-activated proinflammatory pathways, may offer promising directions for future studies in this context.
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