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The TLR4 Agonist Monophosphoryl Lipid A Drives Broad Resistance to Infection via
Dynamic Reprogramming of Macrophage Metabolism.
Fensterheim BA, Young JD, Luan L, Kleinbard RR, Stothers CL, Patil NK,
McAtee-Pereira AG, Guo Y, Trenary I, Hernandez A, Fults JB, Williams DL,
Sherwood ER, Bohannon JK
Submitted Externally on 6/4/2018
Journal of immunology (Baltimore, Md. : 1950)
Volume : Pages
200 : 3777 - 3789
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.
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