Journal
EUROPEAN JOURNAL OF IMMUNOLOGY
Volume 47, Issue 1, Pages 119-130Publisher
WILEY
DOI: 10.1002/eji.201646397
Keywords
CD46; LPS; Macrophages; Neisseria meningitidis; Sepsis
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Funding
- Swedish Research Council [2008-2572, 2008-3367]
- Swedish Society of Medicine [SLS-327941]
- Clas Groschinskys Minnesfond [M12212]
- China Scholarship Council (CSC)
- Stockholm University
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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 homozygousmice (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-1 beta 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.
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