APO[epsilon]4is associated with enhancedin vivoinnate 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 ([straight epsilon]3) and disease-associated ([straight epsilon]2 and [straight epsilon]4) alleles, but its connection to human innate immunity is undefined. Objective We sought to define the relationship ofAPO[straight epsilon]4to the human innate immune response. Methods We evaluatedAPO[straight epsilon]4in several functional models of the human innate immune response, including intravenous LPS challenge in human subjects, and assessedAPO[straight epsilon]4association to organ injury in patients with severe sepsis, a disease driven by dysregulated innate immunity. Results Whole blood from healthyAPO[straight epsilon]3/APO[straight epsilon]4volunteers induced higher cytokine levels onex vivostimulation with Toll-like receptor (TLR) 2, TLR4, or TLR5 ligands than blood fromAPO[straight epsilon]3/APO[straight epsilon]3patients, whereas TLR7/8 responses were similar. This was associated with increased lipid rafts inAPO[straight epsilon]3/APO[straight epsilon]4monocytes. By contrast,APO[straight epsilon]3/APO[straight epsilon]3andAPO[straight epsilon]3/APO[straight epsilon]4serum neutralized LPS equivalently and supported similar LPS responses inApoe-deficient macrophages, arguing against a differential role for secretory APOE4 protein. After intravenous LPS,APO[straight epsilon]3/APO[straight epsilon]4patients had higher hyperthermia and plasma TNF-[alpha] levels and earlier plasma IL-6 thanAPO[straight epsilon]3/APO[straight epsilon]3patients. 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,APO[straight epsilon]4was associated with increased coagulation system failure among European American patients. Conclusions APO[straight epsilon]4is a determinant of the human innate immune response to multiple TLR ligands and associates with altered patterns of organ injury in human sepsis.