A role for granzyme M in TLR4-driven inflammation and endotoxicosis
| Autor: | Phillip I. Bird, Shizou Akira, Sally V. Watt, Desiree A Anthony, Melvyn T. Chow, Joseph A. Trapani, Mark J. Smyth, Daniel M. Andrews, Colin M. House |
|---|---|
| Rok vydání: | 2010 |
| Předmět: |
Lipopolysaccharides
medicine.medical_treatment Immunology Inflammation Biology Ligands Granzymes Mice medicine Immunology and Allergy Cytotoxic T cell Animals Myeloid Cells Mice Knockout Shock Septic Immunity Innate Cell biology Killer Cells Natural Mice Inbred C57BL Toll-Like Receptor 4 Cytokine Granzyme Perforin TLR4 biology.protein Tumor necrosis factor alpha medicine.symptom Granzyme M Inflammation Mediators Signal Transduction |
| Zdroj: | Journal of immunology (Baltimore, Md. : 1950). 185(3) |
| ISSN: | 1550-6606 |
| Popis: | 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-1α, IL-1β, TNF, and IFN-γ 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. |
| Databáze: | OpenAIRE |
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