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Humanized Mouse Model to Study Bacterial Infections Targeting the Microvasculature
Published on: April 1, 2014
CD46 accelerates macrophage-mediated host susceptibility to meningococcal sepsis in a murine model
Xiao Wang1, Ding Zhang2, Mikael Sjölinder1
1Department of Molecular Biosciences, the Wenner-Gren Institute, Stockholm University, Stockholm, Sweden.
Abstract:
CD46, a membrane cofactor expressed on all nucleated human cells, plays an essential role in suppressing autoimmune reactions and protecting host cells from complement-mediated attack. Human transgenic CD46 homozygous mice (CD46+/+ ) are prone to lethal sepsis upon infection with Neisseria meningitidis (N. meningitidis). However, the underlying mechanisms are poorly understood. Here, we determined thatCD46+/+ mice produce large numbers of M1 type macrophages with enhanced surface expression of MHC II and production of pro-inflammatory mediators such as IL-6, TNF, IL-12, and IL-1β In the presence of M-CSF or GM-CSF, CD46 signaling enhances monocyte-macrophage differentiation. Additionally, CD46+/+ macrophages rapidly undergo apoptosis upon LPS challenge or meningococcal infection, which could contribute to uncontrolled bacterial dissemination in vivo. Adoptive transfer of CD46+/+ peritoneal macrophages aggravated septic responses in wild-type mice, but the depletion of macrophages partially alleviated septic reactions in CD46+/+ mice after N. meningitidis infection. Our findings reveal a novel role of CD46 in accelerating inflammatory responses upon meningococcal infection or LPS stimulation by regulating the functional polarization and survival of macrophages.
Insights
CD46 (membrane cofactor protein) exacerbates sepsis by promoting M1 macrophage polarization and survival. This leads to increased inflammation and bacterial spread during Neisseria meningitidis infections.
Area of Science:
- Immunology
- Cell Biology
Background:
- CD46 (membrane cofactor protein) is crucial for immune regulation and host protection.
- CD46 homozygous mice (CD46+/+) are susceptible to lethal sepsis from Neisseria meningitidis.
Purpose of the Study:
- To elucidate the mechanisms by which CD46 influences sepsis pathogenesis.
- To investigate the role of CD46 in macrophage function during infection.
Main Methods:
- Analysis of macrophage populations (M1 type) in CD46+/+ mice.
- Assessment of macrophage differentiation, apoptosis, and cytokine production.
- In vivo studies using adoptive transfer and macrophage depletion.
Main Results:
- CD46+/+ mice exhibit increased M1 macrophages with enhanced pro-inflammatory mediator production (IL-6, TNF, IL-12, IL-1β).
- CD46 signaling promotes monocyte-macrophage differentiation and enhances macrophage survival upon LPS or N. meningitidis challenge.
- Macrophage dysfunction in CD46+/+ mice contributes to uncontrolled bacterial dissemination and sepsis severity.
Conclusions:
- CD46 plays a significant role in accelerating inflammatory responses during meningococcal infection and LPS stimulation.
- CD46 regulates macrophage functional polarization and survival, impacting sepsis outcomes.
- Targeting CD46-mediated macrophage responses may offer therapeutic strategies for sepsis.
