The Cytokine Response to Lipopolysaccharide Does Not Predict the Host Response to Infection.

Fensterheim BA, Guo Y, Sherwood ER, Bohannon JK
J Immunol. 2017 198 (8): 3264-3273

PMID: 28275139 · PMCID: PMC5380530 · DOI:10.4049/jimmunol.1602106

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 a infection. Mice primed with protective TLR ligands, including CpG-ODN, showed reduced plasma cytokines during infection. 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.

Copyright © 2017 by The American Association of Immunologists, Inc.

MeSH Terms (15)

Animals Cytokines Disease Models, Animal Flow Cytometry Ligands Lipid A Lipopolysaccharides Male Mice Mice, Inbred BALB C Mice, Inbred C57BL Poly I-C Pseudomonas aeruginosa Pseudomonas Infections Toll-Like Receptors

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