TY - JOUR
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.
N1 - Funding Information:
Disclosure of potential conflict of interest: S. C. Gale has received research support from the US Public Health Service . S. E. Calvano and S. Corbett have received research support from the National Institutes of Health (NIH) . K. C. Barnes has received research support from the NIH ; is a board member for Genentech and a member of the American Academy of Allergy, Asthma & Immunology (AAAAI)/American College of Allergy, Asthma & Immunology (ACAAI) Joint Board; has received consultancy fees from Sanofi-Aventis, Sirius Genomics, and Merck; is employed by JHU; has received research support from the NIH/National Heart, Lung, and Blood Institute (NHLBI) ; has received lecture fees from Northwestern University; and has received royalties from UpToDate. The rest of the authors declare that they have no relevant conflicts of interest.
Funding Information:
Supported by R01 GM-34695 (U.S. PHS), R01 HL089807-01 (to M.M.W.), HL 73994 (to K.C.B.), and the Intramural Research Program of the NIH , National Institute of Environmental Health Sciences ( Z01 ES102005-08 ). K.C.B. was supported in part by the Mary Beryl Patch Turnbull Scholar Program .
PY - 2014/7
Y1 - 2014/7
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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U2 - 10.1016/j.jaci.2014.01.032
DO - 10.1016/j.jaci.2014.01.032
M3 - Article
C2 - 24655576
AN - SCOPUS:84903743112
SN - 0091-6749
VL - 134
SP - 127-134.e9
JO - Journal of Allergy and Clinical Immunology
JF - Journal of Allergy and Clinical Immunology
IS - 1
ER -