title: The Cytokine Response to Lipopolysaccharide Does Not Predict the Host Response to Infection.
abstract: The magnitude of the LPS-elicited cytokine response is commonly used to assess immune function in critically ill patients. A suppressed response, known as endotoxin tolerance, is associated with worse outcomes, yet endotoxin tolerance-inducing TLR4 ligands are known to protect animals from infection. Thus, it remains unknown whether the magnitude of the LPS-elicited cytokine response provides an accurate assessment of antimicrobial immunity. To address this, the ability of diverse TLR ligands to modify the LPS-elicited cytokine response and resistance to infection were assessed. Priming of mice with LPS, monophosphoryl lipid A (MPLA), or poly(I:C) significantly reduced plasma LPS-elicited proinflammatory cytokines, reflecting endotoxin tolerance, whereas CpG-ODN-primed mice showed augmented cytokine production. In contrast, LPS, MPLA, and CpG-ODN, but not poly(I:C), improved the host response to aPseudomonas aeruginosainfection. Mice primed with protective TLR ligands, including CpG-ODN, showed reduced plasma cytokines duringP. aeruginosainfection. The protection imparted by TLR ligands persisted for up to 15 d yet was independent of the adaptive immune system. In bone marrow-derived macrophages, protective TLR ligands induced a persistent metabolic phenotype characterized by elevated glycolysis and oxidative metabolism as well as augmented size, granularity, phagocytosis, and respiratory burst. Sustained augmentation of glycolysis in TLR-primed cells was dependent, in part, on hypoxia-inducible factor 1-α and was essential for increased phagocytosis. In conclusion, the magnitude of LPS-elicited cytokine production is not indicative of antimicrobial immunity after exposure to TLR ligands. Additionally, protective TLR ligands induce sustained augmentation of phagocyte metabolism and antimicrobial function.
authors.affiliation: Department of Pathology, Microbiology, and Immunology, Vanderbilt University, Nashville, TN 37235; and.
authors.forename: Benjamin A
authors.initials: BA
authors.lastname: Fensterheim
authors.affiliation: Department of Pathology, Microbiology, and Immunology, Vanderbilt University, Nashville, TN 37235; and.
authors.forename: Yin
authors.initials: Y
authors.lastname: Guo
authors.affiliation: Department of Pathology, Microbiology, and Immunology, Vanderbilt University, Nashville, TN 37235; and.|Anesthesiology Research Division, Department of Anesthesiology, Vanderbilt University Medical Center, Nashville, TN 37212.
authors.forename: Edward R
authors.identifier: 0000-0002-9505-7178
authors.initials: ER
authors.lastname: Sherwood
authors.affiliation: Anesthesiology Research Division, Department of Anesthesiology, Vanderbilt University Medical Center, Nashville, TN 37212 julia.k.bohannon@vanderbilt.edu.
authors.forename: Julia K
authors.identifier: 0000-0003-0460-9377
authors.initials: JK
authors.lastname: Bohannon
mesh_terms: D000818:Animals; D016207:Cytokines / Q000096:biosynthesis / Q000276:immunology*; D004195:Disease Models, Animal; D005434:Flow Cytometry; D008024:Ligands; D008050:Lipid A / Q000031:analogs & derivatives / Q000276:immunology; D008070:Lipopolysaccharides / Q000276:immunology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D011070:Poly I-C / Q000276:immunology; D011552:Pseudomonas Infections / Q000276:immunology*; D011550:Pseudomonas aeruginosa; D051193:Toll-Like Receptors / Q000037:antagonists & inhibitors / Q000276:immunology
chemical_list: D016207:Cytokines; D008024:Ligands; D008050:Lipid A; D008070:Lipopolysaccharides; D051193:Toll-Like Receptors; C048436:monophosphoryl lipid A; D011070:Poly I-C