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Detection of Inflammasome Activation and Pyroptotic Cell Death in Murine Bone Marrow-derived Macrophages
Published on: May 21, 2018
Serum amyloid A protects murine macrophages from lethal toxin-mediated death
Kira Rose1, Paul Long, Malini Shankar
1Immunobiology and Cancer Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA.
Abstract:
Lethal toxin, a key virulence factor produced by Bacillus anthracis, induces cell death, in part by disrupting numerous signaling pathways, in mouse macrophages. However, exposure to sublethal doses of lethal toxin allows some cells to survive. Because these pro-survival signaling events occur within a few hours after exposure to sublethal doses, we hypothesized that acute phase proteins might influence macrophage survival. Our data show that serum amyloid A (SAA) is produced in response to lethal toxin treatment. Moreover, pre-treatment of macrophages with exogenous SAA protected macrophages from lethal toxin-mediated death. Exogenous SAA activated the p38 mitogen activated protein kinase (MAP) kinase pathway, while lethal toxin mutants incapable of p38 activation were incapable of causing cell death. Chemical inhibition of the p38 activation pathway abrogated the protective effects of SAA. These data show that SAA affords protection against lethal toxin in mouse macrophages and link this response to the p38 pathway.
Insights
Serum amyloid A (SAA) protects mouse macrophages from Bacillus anthracis lethal toxin-induced death. This protection is linked to the activation of the p38 mitogen-activated protein kinase (MAP) kinase pathway.
Area of Science:
- Immunology
- Microbiology
- Cell Biology
Background:
- Bacillus anthracis lethal toxin (LT) is a key virulence factor that induces macrophage cell death by disrupting signaling pathways.
- Sublethal LT exposure can trigger pro-survival signaling events in macrophages, suggesting a role for acute phase proteins in cellular defense.
Purpose of the Study:
- To investigate the role of acute phase proteins, specifically serum amyloid A (SAA), in mediating macrophage survival following sublethal lethal toxin exposure.
- To elucidate the signaling pathways involved in SAA-mediated protection against lethal toxin.
Main Methods:
- Macrophages were treated with lethal toxin and/or exogenous SAA.
- Serum amyloid A (SAA) production was assessed in response to lethal toxin.
- The activation of the p38 mitogen-activated protein kinase (MAP) kinase pathway was analyzed.
- Macrophage survival was evaluated following SAA pre-treatment and/or p38 pathway inhibition.
Main Results:
- Serum amyloid A (SAA) production was induced by lethal toxin treatment in mouse macrophages.
- Pre-treatment with exogenous SAA significantly protected macrophages from lethal toxin-mediated cell death.
- Exogenous SAA activated the p38 MAP kinase pathway.
- Inhibition of the p38 MAP kinase pathway abolished the protective effect of SAA.
Conclusions:
- Serum amyloid A (SAA) acts as a protective factor against Bacillus anthracis lethal toxin-induced macrophage death.
- The protective mechanism of SAA involves the activation of the p38 MAP kinase pathway.
- These findings highlight a novel host defense mechanism against anthrax toxin.
