A role for granzyme M in TLR4-driven inflammation and endotoxicosis.
Lymphocyte perforin and serine protease granzymes are well-recognized extrinsic mediators of apoptosis. We now demonstrate that cytotoxic lymphocyte granule components profoundly augment the myeloid cell inflammatory cytokine cascade in response to TLR4 ligation. Whereas caspase-1-deficient mice were completely resistant to LPS, reduced serum cytokine production and resistance to lethal endotoxicosis were also obtained with perforin-deficient mice, indicating a role for granzymes. Consistently, a lack of granzyme M (GrzM) resulted in reduced serum IL-1alpha, IL-1beta, TNF, and IFN-gamma levels and significantly reduced susceptibility to lethal endotoxicosis. These altered responses were also observed in granzyme A-deficient but not granzyme B-deficient mice. A role for APC-NK cell cross-talk in the inflammatory cascade was highlighted, as GrzM was exclusively expressed by NK cells and resistance to LPS was also observed on a RAG-1/GrzM-double deficient background. Collectively, the data suggest that NK cell GrzM augments the inflammatory cascade downstream of LPS-TLR4 signaling, which ultimately results in lethal endotoxicosis. Most importantly, these data demonstrate that granzymes should no longer be considered solely as mediators of apoptosis, but additionally as potential key regulators of inflammation.
Anthony
Desiree A
DA
Cancer Immunology Program, Sir Donald and Lady Trescowthick Laboratories, Peter MacCallum Cancer Centre, Locked Bag 1, A'Beckett Street, 8006, East Melbourne, Victoria, Australia.
Andrews
Daniel M
DM
Chow
Melvyn
M
Watt
Sally V
SV
House
Colin
C
Akira
Shizuo
S
Bird
Phillip I
PI
Trapani
Joseph A
JA
Smyth
Mark J
MJ
D000818:Animals; D053804:Granzymes / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D007113:Immunity, Innate / Q000276:immunology; D018836:Inflammation Mediators / Q000633:toxicity*; D007694:Killer Cells, Natural / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D008024:Ligands; D008070:Lipopolysaccharides / Q000633:toxicity; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D022423:Myeloid Cells / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D012772:Shock, Septic / Q000201:enzymology* / Q000401:mortality / Q000473:pathology*; D015398:Signal Transduction / Q000276:immunology; D051197:Toll-Like Receptor 4 / Q000172:deficiency / Q000378:metabolism / Q000502:physiology*
D018836:Inflammation Mediators; D008024:Ligands; D008070:Lipopolysaccharides; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D053804:Granzymes; C509219:Gzmm protein, mouse