title: CD46 accelerates macrophage-mediated host susceptibility to meningococcal sepsis in a murine model.
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.
authors: Department of Molecular Biosciences, the Wenner-Gren Institute, Stockholm University, Stockholm, Sweden.
authors: Xiao
authors: X
authors: Wang
authors: College of Animal Science and Veterinary Medicine, Shanxi Agricultural University, Taigu, China.
authors: Ding
authors: D
authors: Zhang
authors: Department of Molecular Biosciences, the Wenner-Gren Institute, Stockholm University, Stockholm, Sweden.
authors: Mikael
authors: M
authors: Sjölinder
authors: Department of Molecular Biosciences, the Wenner-Gren Institute, Stockholm University, Stockholm, Sweden.
authors: Yi
authors: Y
authors: Wan
authors: Department of Molecular Biosciences, the Wenner-Gren Institute, Stockholm University, Stockholm, Sweden.|Cancer Center, Mälar Hospital, Eskilstuna, Sweden.
authors: Hong
authors: H
authors: Sjölinder
mesh_terms: D019264:Adoptive Transfer; D017398:Alternative Splicing; D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000276:immunology; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D004198:Disease Susceptibility; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D054884:Host-Pathogen Interactions / Q000235:genetics / Q000276:immunology; D006801:Humans; D016130:Immunophenotyping; D018836:Inflammation Mediators / Q000378:metabolism; D008070:Lipopolysaccharides / Q000276:immunology; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism*; D017737:Macrophages, Peritoneal / Q000276:immunology / Q000378:metabolism; D051916:Membrane Cofactor Protein / Q000235:genetics* / Q000378:metabolism; D008589:Meningococcal Infections / Q000235:genetics* / Q000276:immunology* / Q000382:microbiology / Q000401:mortality; D051379:Mice; D008822:Mice, Transgenic; D009345:Neisseria meningitidis / Q000276:immunology*; D010587:Phagocytosis / Q000276:immunology; D010641:Phenotype; D018805:Sepsis; D015398:Signal Transduction
chemical_list: D016207:Cytokines; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D051916:Membrane Cofactor Protein
keywords: CD46; LPS; Macrophages; Neisseria meningitidis; Sepsis