title: APOε4 is associated with enhanced in vivo innate immune responses in human subjects.
abstract: BACKGROUND
  The genetic determinants of the human innate immune response are poorly understood. Apolipoprotein (Apo) E, a lipid-trafficking protein that affects inflammation, has well-described wild-type (ε3) and disease-associated (ε2 and ε4) alleles, but its connection to human innate immunity is undefined.
  
  
  OBJECTIVE
  We sought to define the relationship of APOε4 to the human innate immune response.
  
  
  METHODS
  We evaluated APOε4 in several functional models of the human innate immune response, including intravenous LPS challenge in human subjects, and assessed APOε4 association to organ injury in patients with severe sepsis, a disease driven by dysregulated innate immunity.
  
  
  RESULTS
  Whole blood from healthy APOε3/APOε4 volunteers induced higher cytokine levels on ex vivo stimulation with Toll-like receptor (TLR) 2, TLR4, or TLR5 ligands than blood from APOε3/APOε3 patients, whereas TLR7/8 responses were similar. This was associated with increased lipid rafts in APOε3/APOε4 monocytes. By contrast, APOε3/APOε3 and APOε3/APOε4 serum neutralized LPS equivalently and supported similar LPS responses in Apoe-deficient macrophages, arguing against a differential role for secretory APOE4 protein. After intravenous LPS, APOε3/APOε4 patients had higher hyperthermia and plasma TNF-α levels and earlier plasma IL-6 than APOε3/APOε3 patients. APOE4-targeted replacement mice displayed enhanced hypothermia, plasma cytokines, and hepatic injury and altered splenic lymphocyte apoptosis after systemic LPS compared with APOE3 counterparts. In a cohort of 828 patients with severe sepsis, APOε4 was associated with increased coagulation system failure among European American patients.
  
  
  CONCLUSIONS
  APOε4 is a determinant of the human innate immune response to multiple TLR ligands and associates with altered patterns of organ injury in human sepsis.
authors.affiliation: Department of Surgery, UMDNJ-Robert Wood Johnson Medical School, New Brunswick, NJ.
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Gale
authors.affiliation: Department of Medicine, Johns Hopkins University, Baltimore, Md.
authors.forename: Li
authors.initials: L
authors.lastname: Gao
authors.affiliation: Department of Medicine, University of Washington, Seattle, Wash.
authors.forename: Carmen
authors.initials: C
authors.lastname: Mikacenic
authors.affiliation: Department of Surgery, UMDNJ-Robert Wood Johnson Medical School, New Brunswick, NJ.
authors.forename: Susette M
authors.initials: SM
authors.lastname: Coyle
authors.affiliation: Department of Medicine, Johns Hopkins University, Baltimore, Md.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Rafaels
authors.affiliation: Department of Medicine, Johns Hopkins University, Baltimore, Md.
authors.forename: Tanda
authors.initials: T
authors.lastname: Murray Dudenkov
authors.affiliation: Laboratory of Respiratory Biology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC.
authors.forename: Jennifer H
authors.initials: JH
authors.lastname: Madenspacher
authors.affiliation: Laboratory of Respiratory Biology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC.
authors.forename: David W
authors.initials: DW
authors.lastname: Draper
authors.affiliation: Laboratory of Respiratory Biology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC.
authors.forename: William
authors.initials: W
authors.lastname: Ge
authors.affiliation: Laboratory of Respiratory Biology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC.
authors.forename: Jim J
authors.initials: JJ
authors.lastname: Aloor
authors.affiliation: Laboratory of Respiratory Biology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC.
authors.forename: Kathleen M
authors.initials: KM
authors.lastname: Azzam
authors.affiliation: Laboratory of Respiratory Biology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC.
authors.forename: Lihua
authors.initials: L
authors.lastname: Lai
authors.affiliation: Laboratory of Signal Transduction, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC.
authors.forename: Perry J
authors.initials: PJ
authors.lastname: Blackshear
authors.affiliation: Department of Surgery, UMDNJ-Robert Wood Johnson Medical School, New Brunswick, NJ.
authors.forename: Steven E
authors.initials: SE
authors.lastname: Calvano
authors.affiliation: Department of Medicine, Johns Hopkins University, Baltimore, Md.
authors.forename: Kathleen C
authors.initials: KC
authors.lastname: Barnes
authors.affiliation: Department of Surgery, UMDNJ-Robert Wood Johnson Medical School, New Brunswick, NJ.
authors.forename: Stephen F
authors.initials: SF
authors.lastname: Lowry
authors.affiliation: Department of Surgery, UMDNJ-Robert Wood Johnson Medical School, New Brunswick, NJ.
authors.forename: Siobhan
authors.initials: S
authors.lastname: Corbett
authors.affiliation: Department of Medicine, University of Washington, Seattle, Wash.
authors.forename: Mark M
authors.initials: MM
authors.lastname: Wurfel
authors.affiliation: Laboratory of Respiratory Biology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC. Electronic address: fesslerm@niehs.nih.gov.
authors.forename: Michael B
authors.initials: MB
authors.lastname: Fessler
mesh_terms: D000328:Adult; D000818:Animals; D053318:Apolipoprotein E3 / Q000235:genetics / Q000276:immunology; D053327:Apolipoprotein E4 / Q000235:genetics / Q000276:immunology*; D002478:Cells, Cultured; D015870:Gene Expression; D006801:Humans; D007113:Immunity, Innate; D015850:Interleukin-6 / Q000235:genetics / Q000276:immunology; D008024:Ligands; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D008822:Mice, Transgenic; D009000:Monocytes / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D018805:Sepsis / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D051195:Toll-Like Receptor 2 / Q000235:genetics / Q000276:immunology; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000276:immunology; D051198:Toll-Like Receptor 5 / Q000235:genetics / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000276:immunology
chemical_list: D053318:Apolipoprotein E3; D053327:Apolipoprotein E4; C508600:IL6 protein, human; D015850:Interleukin-6; D008024:Ligands; D008070:Lipopolysaccharides; C495342:TLR2 protein, human; C495345:TLR4 protein, human; C495346:TLR5 protein, human; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051198:Toll-Like Receptor 5; D014409:Tumor Necrosis Factor-alpha
keywords: Apolipoprotein; LPS; Toll-like receptor