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J Immunol. 2018 Jun 1;200(11):3777-3789. doi: 10.4049/jimmunol.1800085. Epub 2018 Apr 23.

The TLR4 Agonist Monophosphoryl Lipid A Drives Broad Resistance to Infection via Dynamic Reprogramming of Macrophage Metabolism.

Author information

1
Department of Pathology, Microbiology, and Immunology, Vanderbilt University, Nashville, TN 37212.
2
Department of Chemical and Biomolecular Engineering, Vanderbilt University, Nashville, TN 37235.
3
Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN 37212.
4
Department of Anesthesiology, Vanderbilt University Medical Center, Nashville, TN 37232; and.
5
Department of Surgery, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN 37614.
6
Department of Anesthesiology, Vanderbilt University Medical Center, Nashville, TN 37232; and julia.k.bohannon@vanderbilt.edu.

Abstract

Monophosphoryl lipid A (MPLA) is a clinically used TLR4 agonist that has been found to drive nonspecific resistance to infection for up to 2 wk. However, the molecular mechanisms conferring protection are not well understood. In this study, we found that MPLA prompts resistance to infection, in part, by inducing a sustained and dynamic metabolic program in macrophages that supports improved pathogen clearance. Mice treated with MPLA had enhanced resistance to infection with Staphylococcus aureus and Candida albicans that was associated with augmented microbial clearance and organ protection. Tissue macrophages, which exhibited augmented phagocytosis and respiratory burst after MPLA treatment, were required for the beneficial effects of MPLA. Further analysis of the macrophage phenotype revealed that early TLR4-driven aerobic glycolysis was later coupled with mitochondrial biogenesis, enhanced malate shuttling, and increased mitochondrial ATP production. This metabolic program was initiated by overlapping and redundant contributions of MyD88- and TRIF-dependent signaling pathways as well as downstream mTOR activation. Blockade of mTOR signaling inhibited the development of the metabolic and functional macrophage phenotype and ablated MPLA-induced resistance to infection in vivo. Our findings reveal that MPLA drives macrophage metabolic reprogramming that evolves over a period of days to support a macrophage phenotype highly effective at mediating microbe clearance and that this results in nonspecific resistance to infection.

PMID:
29686054
PMCID:
PMC5964009
[Available on 2019-06-01]
DOI:
10.4049/jimmunol.1800085
[Indexed for MEDLINE]

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