Our laboratory is interested in a family of granule-secreted enzymes (granzymes) in health and disease. There are 5 human granzymes: Granzyme A (GrA), Granzyme B (GrB), Granzyme H (GrH), Granzyme K (GrK) and Granzyme M (GrM). Granzymes are serine proteases that differ in their functions and substrate specificities. To date we have focused primarily on GrB, although recent studies from our lab have identified novel roles for GrK in inflammation. GrB has been viewed traditionally as a mediator of immune-cell mediated apoptosis, through a mechanism that involves the membrane perforating molecule perforin facilitating GrB entry into the target cell. GrB, which was originally thought to be expressed exclusively by cytotoxic T cells and NK cells, is the most widely studied member of the granzyme family.

Later discoveries revealed that other immune cells including, neutrophils, dendritic cells, macrophages, basophils and mast cells may also express and release GrB in the absence of perforin. These findings highlight the potential role of GrB in inflammation that is independent of target cell recognition and/or entry, and involves non-specific GrB release. Indeed, GrB is constitutively released from stimulated NK cells and CTLs in the absence of target cell engagement. In addition, GrB accumulates in the extra cellular matrix (ECM) of inflamed tissues and is present in several bodily fluids in disease including rheumatic arthritis, atherosclerosis, chronic obstructive lung disease (COPD), aortic abdominal aneurysm, skin disease and cancer. Further, under pro-inflammatory conditions GrB is expressed by non-immune cells that are incapable of forming an immunological synapse including chondrocytes, keratinocytes, type II pneumocytes and syncytial trophoblasts. Collectively, these finding indicates the potential extracellular role of GrB in inflammation, and thus serves as the driving force of our current research aiming to explore the role of extracellular GrB in disease. Work from our group and other have identified a large number of ECM substrates that can be cleaved by GrB. These findings gave rise to a number of hypothesises implicating on a number of ways extracellular GrB might contribute to disease progression during chronic inflammatory disorders. More recently, we have discovered a novel role for extracellular GrK in inducing pro-inflammatory cytokine release by specifically activating protease activated receptors (PARs) on target cells. These findings collectively signify the potential, yet undiscovered, roles for granyzmes in disease progression. Thus the goal of our laboratory is to expand our current knowledge in granzyme biology and their role in pathogenesis and to translate this knowledge to develop novel therapeutic approaches for management of chronic inflammatory disorders in which granzymes are involved in disease progression.