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A Mouse Model to Assess Innate Immune Response to Staphylococcus aureus Infection
Published on: February 28, 2019
Increased inflammation, impaired bacterial clearance, and metabolic disruption after gram-negative sepsis in
W Joshua Frazier1, Xianxi Wang, Lyn M Wancket
1Center for Perinatal Research, The Research Institute at Nationwide Children's Hospital, Columbus, OH 43205, USA.
Abstract:
MAPKs are crucial for TNF-alpha and IL-6 production by innate immune cells in response to TLR ligands. MAPK phosphatase 1 (Mkp-1) deactivates p38 and JNK, abrogating the inflammatory response. We have previously demonstrated that Mkp-1(-/-) mice exhibit exacerbated inflammatory cytokine production and increased mortality in response to challenge with LPS and heat-killed Staphylococcus aureus. However, the function of Mkp-1 in host defense during live Gram-negative bacterial infection remains unclear. We challenged Mkp-1(+/+) and Mkp-1(-/-) mice with live Escherichia coli i.v. to examine the effects of Mkp-1 deficiency on animal survival, bacterial clearance, metabolic activity, and cytokine production. We found that Mkp-1 deficiency predisposed animals to accelerated mortality and was associated with more robust production of TNF-alpha, IL-6 and IL-10, greater bacterial burden, altered cyclooxygenase-2 and iNOS expression, and substantial changes in the mobilization of energy stores. Likewise, knockout of Mkp-1 also sensitized mice to sepsis caused by cecal ligation and puncture. IL-10 inhibition by neutralizing Ab or genetic deletion alleviated increased bacterial burden. Treatment with the bactericidal antibiotic gentamicin, given 3 h after Escherichia coli infection, protected Mkp-1(+/+) mice from septic shock but had no effect on Mkp-1(-/-) mice. Thus, during Gram-negative bacterial sepsis Mkp-1 not only plays a critical role in the regulation of cytokine production but also orchestrates the bactericidal activities of the innate immune system and controls the metabolic response to stress.
Insights
MAPK phosphatase 1 (Mkp-1) deficiency worsens Gram-negative bacterial sepsis by increasing inflammatory cytokines and bacterial load. Mkp-1 is essential for innate immune response and metabolic control during infection.
Area of Science:
- Immunology
- Microbiology
- Molecular Biology
Background:
- Mitogen-activated protein kinases (MAPKs) regulate inflammatory cytokine production in innate immune cells.
- MAPK phosphatase 1 (Mkp-1) inhibits p38 and JNK, thereby suppressing inflammatory responses.
- Previous studies showed Mkp-1 deficiency exacerbates inflammation in response to LPS and heat-killed bacteria.
Purpose of the Study:
- To investigate the role of Mkp-1 in host defense against live Gram-negative bacterial infection (Escherichia coli).
- To determine the impact of Mkp-1 deficiency on survival, bacterial clearance, metabolism, and cytokine production during sepsis.
Main Methods:
- Challenging wild-type (Mkp-1(+/+)) and knockout (Mkp-1(-/-)) mice with live Escherichia coli intravenously.
- Assessing animal survival, bacterial burden, cytokine levels (TNF-alpha, IL-6, IL-10), cyclooxygenase-2 and iNOS expression.
- Evaluating metabolic changes and response to cecal ligation and puncture (CLP) sepsis model.
- Investigating the effect of IL-10 inhibition and antibiotic treatment (gentamicin).
Main Results:
- Mkp-1 deficiency led to accelerated mortality, increased TNF-alpha, IL-6, and IL-10 production, and higher bacterial burden.
- Mkp-1 knockout mice showed altered cyclooxygenase-2 and iNOS expression and significant metabolic disturbances.
- Mkp-1 deficiency sensitized mice to CLP-induced sepsis.
- IL-10 inhibition reduced bacterial burden, while gentamicin failed to protect Mkp-1(-/-) mice from septic shock.
Conclusions:
- Mkp-1 plays a critical role in regulating cytokine production during Gram-negative bacterial sepsis.
- Mkp-1 orchestrates innate immune bactericidal activity and controls metabolic responses to stress.
- Mkp-1 deficiency impairs host defense mechanisms, leading to increased susceptibility to sepsis.
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