APOε4 is associated with enhanced in vivo innate immune responses in human subjects

Stephen C. Gale, Li Gao, Carmen Mikacenic, Susette M. Coyle, Nicholas Rafaels, Tanda Murray Dudenkov, Jennifer H. Madenspacher, David W. Draper, William Ge, Jim J. Aloor, Kathleen M. Azzam, Lihua Lai, Perry J. Blackshear, Steven E. Calvano, Kathleen C. Barnes, Stephen F. Lowry, Siobhan Corbett, Mark M. Wurfel, Michael B. Fessler

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
JournalThe Journal of Allergy and Clinical Immunology
Volume134
Issue number1
DOIs
StatePublished - 2014
Externally publishedYes

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Innate Immunity
Sepsis
Apolipoproteins E
Wounds and Injuries
Cytokines
Ligands
Lipids
Toll-Like Receptor 2
Toll-Like Receptors
Medical Genetics
Protein Transport
Hypothermia
Monocytes
Volunteers
Interleukin-6
Fever
Alleles
Macrophages
Lymphocytes
Apoptosis

Keywords

  • Apolipoprotein
  • LPS
  • Toll-like receptor

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Medicine(all)

Cite this

APOε4 is associated with enhanced in vivo innate immune responses in human subjects. / Gale, Stephen C.; Gao, Li; Mikacenic, Carmen; Coyle, Susette M.; Rafaels, Nicholas; Murray Dudenkov, Tanda; Madenspacher, Jennifer H.; Draper, David W.; Ge, William; Aloor, Jim J.; Azzam, Kathleen M.; Lai, Lihua; Blackshear, Perry J.; Calvano, Steven E.; Barnes, Kathleen C.; Lowry, Stephen F.; Corbett, Siobhan; Wurfel, Mark M.; Fessler, Michael B.

In: The Journal of Allergy and Clinical Immunology, Vol. 134, No. 1, 2014.

Research output: Contribution to journalArticle

Gale, SC, Gao, L, Mikacenic, C, Coyle, SM, Rafaels, N, Murray Dudenkov, T, Madenspacher, JH, Draper, DW, Ge, W, Aloor, JJ, Azzam, KM, Lai, L, Blackshear, PJ, Calvano, SE, Barnes, KC, Lowry, SF, Corbett, S, Wurfel, MM & Fessler, MB 2014, 'APOε4 is associated with enhanced in vivo innate immune responses in human subjects', The Journal of Allergy and Clinical Immunology, vol. 134, no. 1. https://doi.org/10.1016/j.jaci.2014.01.032
Gale, Stephen C. ; Gao, Li ; Mikacenic, Carmen ; Coyle, Susette M. ; Rafaels, Nicholas ; Murray Dudenkov, Tanda ; Madenspacher, Jennifer H. ; Draper, David W. ; Ge, William ; Aloor, Jim J. ; Azzam, Kathleen M. ; Lai, Lihua ; Blackshear, Perry J. ; Calvano, Steven E. ; Barnes, Kathleen C. ; Lowry, Stephen F. ; Corbett, Siobhan ; Wurfel, Mark M. ; Fessler, Michael B. / APOε4 is associated with enhanced in vivo innate immune responses in human subjects. In: The Journal of Allergy and Clinical Immunology. 2014 ; Vol. 134, No. 1.
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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.",
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T1 - APOε4 is associated with enhanced in vivo innate immune responses in human subjects

AU - Gale, Stephen C.

AU - Gao, Li

AU - Mikacenic, Carmen

AU - Coyle, Susette M.

AU - Rafaels, Nicholas

AU - Murray Dudenkov, Tanda

AU - Madenspacher, Jennifer H.

AU - Draper, David W.

AU - Ge, William

AU - Aloor, Jim J.

AU - Azzam, Kathleen M.

AU - Lai, Lihua

AU - Blackshear, Perry J.

AU - Calvano, Steven E.

AU - Barnes, Kathleen C.

AU - Lowry, Stephen F.

AU - Corbett, Siobhan

AU - Wurfel, Mark M.

AU - Fessler, Michael B.

PY - 2014

Y1 - 2014

N2 - 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.

AB - 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.

KW - Apolipoprotein

KW - LPS

KW - Toll-like receptor

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