Abstract
Granzymes are generally recognized for their capacity to induce various pathways of perforin-dependent target cell death. Within this serine protease family, Granzyme M (GrzM) is unique owing to its preferential expression in innate effectors such as natural killer (NK) cells. During Listeria monocytogenes infection, we observed markedly reduced secretion of macrophage inflammatory protein-1 alpha (MIP-1α) in livers of GrzM-deficient mice, which resulted in significantly impaired NK cell recruitment. Direct stimulation with IL-12 and IL-15 demonstrated that GrzM was required for maximal secretion of active MIP-1α. This effect was not due to reduced protein induction but resulted from heightened intracellular accumulation of MIP-1α, with reduced release. These results demonstrate that GrzM is a critical mediator of innate immunity that can regulate chemotactic networks and has an important role in the initiation of immune responses and pathogen control.
Highlights
GrzA and K have trypsin-like activity; GrzB and H (Human) and B-G exhibit chymotryptic activity, whereas Granzyme M (GrzM) processes its substrates at the carboxy side of long, hydrophobic side chain amino acids such as Met and Leu.[7]
We show that GrzM intrinsically regulates the release of Mip-1a from Natural killer (NK) cells and that this is dependent upon IL-12/IL-15 signaling
Our data provide a molecular target for GrzM of biological relevance to inflammation. These studies demonstrate that GrzM is required for the optimal release of macrophage inflammatory protein-1alpha (MIP-1a) from NK cells
Summary
GrzA and K have trypsin-like activity; GrzB and H (Human) and B-G (rodent) exhibit chymotryptic activity, whereas GrzM processes its substrates at the carboxy side of long, hydrophobic side chain amino acids such as Met and Leu.[7]. Recent studies have suggested that GrzM delivered by CD8 T cells can regulate Human Cytomegalovirus replication by targeting heterogeneous ribonucleotide particles.[13] GrzM is able to induce Pfp-dependent target cell death in vitro, with some studies suggesting that this occurs independently of caspse,[14,15,16] whereas others show a requirement of caspase activity.[17,18,19] Interestingly, GrzM À / À mice have no defect of NK cell-mediated cytotoxicity, so the physiological relevance of these cell death pathways and GrzM’s major biological role are still to be elucidated. GrzM during Listeria monocytogenes infection where the pathophysiology of the inflammatory process is well characterized. Mouse models of Listeria infection have demonstrated a clear role for NK cells and APCs in the control of disease[21,22] where chemokine signaling networks are key components during the crosstalk that leads to effective immunity
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