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

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 (epsilon 3) and disease-associated (epsilon 2 and epsilon 4) alleles, but its connection to human innate immunity is undefined. Objective: We sought to define the relationship of APO epsilon 4 to the human innate immune response. Methods: We evaluated APO epsilon 4 in several functional models of the human innate immune response, including intravenous LPS challenge in human subjects, and assessed APO epsilon 4 association to organ injury in patients with severe sepsis, a disease driven by dysregulated innate immunity. Results: Whole blood from healthy APO epsilon 3/APO epsilon 4 volunteers induced higher cytokine levels on ex vivo stimulation with Toll-like receptor (TLR) 2, TLR4, or TLR5 ligands than blood from APO epsilon 3/APO epsilon 3 patients, whereas TLR7/8 responses were similar. This was associated with increased lipid rafts in APO epsilon 3/APO epsilon 4 monocytes. By contrast, APO epsilon 3/APO epsilon 3 and APO epsilon 3/APO epsilon 4 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, APO epsilon 3/APO epsilon 4 patients had higher hyperthermia and plasma TNF-alpha levels and earlier plasma IL-6 than APO epsilon 3/APO epsilon 3 patients. APO epsilon 4-targeted replacement mice displayed enhanced hypothermia, plasma cytokines, and hepatic injury and altered splenic lymphocyte apoptosis after systemic LPS compared with APO epsilon 3 counterparts. In a cohort of 828 patients with severe sepsis, APO epsilon 4 was associated with increased coagulation system failure among European American patients. Conclusions: APO epsilon 4 is a determinant of the human innate immune response to multiple TLR ligands and associates with altered patterns of organ injury in human sepsis.