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Mast cell-derived TNF can exacerbate mortality during severe bacterial infections in C57BL/6-KitW-sh/W-sh mice
Adrian M Piliponsky1, Ching-Cheng Chen, Michele A Grimbaldeston
1Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305-5324, USA.
Abstract:
We used mast cell-engrafted genetically mast cell-deficient C57BL/6-Kit(W-sh/W-sh) mice to investigate the roles of mast cells and mast cell-derived tumor necrosis factor in two models of severe bacterial infection. In these mice, we confirmed findings derived from studies of mast cell-deficient WBB6F(1)-Kit(W/W-v) mice indicating that mast cells can promote survival in cecal ligation and puncture (CLP) of moderate severity. However, we found that the beneficial role of mast cells in this setting can occur independently of mast cell-derived tumor necrosis factor. By contrast, using mast cell-engrafted C57BL/6-Kit(W-sh/W-sh) mice, we found that mast cell-derived tumor necrosis factor can increase mortality during severe CLP and can also enhance bacterial growth and hasten death after intraperitoneal inoculation of Salmonella typhimurium. In WBB6F(1)-Kit(W-sh/W-sh) mice, mast cells enhanced survival during moderately severe CLP but did not significantly change the survival observed in severe CLP. Our findings in three types of genetically mast cell-deficient mice thus support the hypothesis that, depending on the circumstances (including mouse strain background, the nature of the mutation resulting in a mast cell deficiency, and type and severity of infection), mast cells can have either no detectable effect or opposite effects on survival during bacterial infections, eg, promoting survival during moderately severe CLP associated with low mortality but, in C57BL/6-Kit(W-sh/W-sh) mice, increasing mortality during severe CLP or infection with S. typhimurium.
Insights
Mast cells can improve survival in moderate bacterial infections but may worsen severe infections, depending on the context. Mast cell-derived tumor necrosis factor plays a role in severe Salmonella infections.
Area of Science:
- Immunology
- Microbiology
- Pathology
Background:
- Mast cells are key immune cells involved in host defense and inflammation.
- Their role in bacterial infections is complex and context-dependent.
- Mast cell-derived tumor necrosis factor (TNF) is a potent inflammatory mediator.
Purpose of the Study:
- To investigate the dual role of mast cells and mast cell-derived TNF in severe bacterial infections.
- To clarify the impact of mast cells on survival in different infection models and genetic backgrounds.
Main Methods:
- Utilized genetically mast cell-deficient mice (C57BL/6-Kit(W-sh/W-sh) and WBB6F(1)-Kit(W/W-v)) engrafted with mast cells.
- Employed two models of severe bacterial infection: cecal ligation and puncture (CLP) and intraperitoneal Salmonella typhimurium inoculation.
- Assessed survival rates, bacterial growth, and the influence of mast cell-derived TNF.
Main Results:
- Mast cells promoted survival in moderately severe CLP, independent of TNF.
- Mast cell-derived TNF increased mortality in severe CLP and Salmonella infection.
- In C57BL/6-Kit(W-sh/W-sh) mice, mast cells worsened outcomes in severe CLP and S. typhimurium infection.
- In WBB6F(1)-Kit(W/W-v) mice, mast cells improved survival in moderate CLP but had no significant effect in severe CLP.
Conclusions:
- Mast cell function in bacterial infections is highly variable, influenced by genetic background, deficiency type, and infection severity.
- Mast cells can be protective or detrimental, highlighting a complex immunomodulatory role.
- Mast cell-derived TNF can exacerbate severe bacterial infections, particularly in specific mouse models.
