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

doi:10.1016/j.jaci.2014.01.032

Journal of Allergy and Clinical Immunology

Volume 134, Issue 1, July 2014, Pages 127-134.e9

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https://doi.org/10.1016/j.jaci.2014.01.032 Get rights and content

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.

Section snippets

Human ex vivo whole-blood assay of TLR-induced cytokines

Healthy subjects were identified by APOE genotype by using the National Institute of Environmental Health Sciences (NIEHS) Environmental Polymorphisms Registry¹¹ and enrolled in accordance with an NIEHS institutional review board (IRB)–approved protocol. Exclusion criteria included age of less than 18 years, active smoking, use of anti-inflammatory (eg, nonsteroidal anti-inflammatory drugs) or immunosuppressive (eg, corticosteroids) agents, confirmed/suspected immunodeficiency, and recent

Blood from APOε4⁺ patients displays enhanced responses in multiple TLR cascades

To first define whether APOε4 is associated with an altered human innate immune response, we collected peripheral blood from 7 APOε3/APOε3 and 7 APOε3/APOε4 healthy adult volunteers and stimulated it ex vivo with a panel of TLR ligands.¹² Whole blood was selected rather than isolated leukocyte populations as a model of the integrated human in vivo innate immune response given that ApoE is expressed in circulating monocytes and present in serum. Total leukocyte counts, monocyte percentages,

Discussion

APOε4 has been associated in many reports with increased risk for diseases that are thought to arise in part from chronic inflammation, most notably atherosclerotic cardiovascular disease and Alzheimer disease. For the first time, we show, using primary ex vivo and in vivo human systems, that a single-copy APOε4 is associated with marked augmentation of the human innate immune response. This enhancement extends across several plasma membrane–localized TLR pathways (TLR1, TLR2, TLR4, and TLR5)

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: 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.

: 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.

^∗: These authors contributed equally to this work.

^‡: Stephen C. Gale is currently affiliated with the Department of Surgery, Trauma Services, East Texas Medical Center, Tyler, Texas.

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Immune deficiencies, infection, and systemic immune disordersAPOε4 is associated with enhanced in vivo innate immune responses in human subjects

Background

Objective

Methods

Results

Conclusions

Section snippets

Human ex vivo whole-blood assay of TLR-induced cytokines

Blood from APOε4+ patients displays enhanced responses in multiple TLR cascades

Discussion

J Biol Chem

J Lipid Res

J Biol Chem

Trends Biochem Sci

Biochem Biophys Res Commun

J Biol Chem

Lancet

J Thorac Cardiovasc Surg

Thromb Res

J Thromb Haemost

J Biol Chem

Thromb Res

Blood

Ann Epidemiol

J Biol Chem

J Biol Chem

Apolipoprotein E-deficient mice have an impaired immune response to Klebsiella pneumoniae

Eur J Clin Invest

Apolipoprotein E induces antiinflammatory phenotype in macrophages

Arterioscler Thromb Vasc Biol

Human recombinant apolipoprotein E redirects lipopolysaccharide from Kupffer cells to liver parenchymal cells in rats In vivo

J Clin Invest

Apolipoprotein E: far more than a lipid transport protein

Annu Rev Genomics Hum Genet

APOE genotype affects outcome in a murine model of sepsis: implications for a new treatment strategy

Anaesth Intensive Care

The Environmental Polymorphism Registry: a unique resource that facilitates translational research of environmental disease

Environ Health Perspect

Toll-like receptor 1 polymorphisms affect innate immune responses and outcomes in sepsis

Am J Respir Crit Care Med

Immune deficiencies, infection, and systemic immune disorders
APOε4 is associated with enhanced in vivo innate immune responses in human subjects

Blood from APOε4⁺ patients displays enhanced responses in multiple TLR cascades