RESEARCH
26 SEPTEMBER 2014 • VOL 345 ISSUE 6204 1579 SCIENCE
sciencemag.org
INTRODUCTION: Trained immunity refers
to the memory characteristics of the innate
immune system. Memory traits of innate
immunity have been reported in plants and
invertebrates, as well as in mice lacking
functional T and B cells that are protected
against secondary infections after exposure to certain infections or vaccinations.
The underlying mechanism of trained immunity is represented by epigenetic programming through histone modifications,
leading to stronger gene transcription
upon restimulation. However, the specific
mTOR- and HIF-1α–mediated aerobic
glycolysis as metabolic basis for
trained immunity
IMMUNOGENETICS
Shih-Chin Cheng, Jessica Quintin, Robert A. Cramer, Kelly M. Shepardson, Sadia Saeed,
Vinod Kumar, Evangelos J. Giamarellos-Bourboulis, Joost H. A. Martens,
Nagesha Appukudige Rao, Ali Aghajanirefah, Ganesh R. Manjeri, Yang Li,
Daniela C. Ifrim, Rob J. W. Arts, Brian M. J. W. van der Meer, Peter M. T. Deen,
Colin Logie, Luke A. O’Neill, Peter Willems, Frank L. van de Veerdonk,
Jos W. M. van der Meer, Aylwin Ng, Leo A. B. Joosten, Cisca Wijmenga,
Hendrik G. Stunnenberg, Ramnik J. Xavier, Mihai G. Netea*
Aerobic glycolysis as metabolic basis for trained immunity. In naïve macrophages during aerobic conditions, glucose metabolism is mainly geared toward oxidative phosphorylation
providing adenosine triphosphate (ATP) as the energy source. In contrast, long-term functional
reprogramming during trained immunity requires a metabolic shift toward aerobic glycolysis
and is induced through a dectin-1–Akt–m TOR–HIF-1α pathway.
Glucose Glucose
Pyruvate Pyruvate
Lactate
Lactate Oxidative
phosphorylation
Aerobic glycolysis
( Warburg efect) Oxidative
phosphorylation
Naïve monocyte
(resting monocyte)
Akt mTor
HIF-1α
trained monocyte
Susceptible Protected
Dead
C. albicans
S. aureus sepsis S. aureus sepsis
Dectin-1
β-glucan
cellular processes that mediate trained
immunity in monocytes or macrophages
are poorly understood.
METHODS: We studied a model of trained
immunity, induced by the β-glucan com-
ponent of Candida albicans, that was
previously shown to induce nonspecific
protection against both infections and ma-
lignancies. Genome-wide transcriptome
and histone modification profiles were
performed and pathway analysis was ap-
plied to identify the cellular processes
induced during monocyte training. Biolog-
ical validations were performed in human
primary monocytes and in two experimen-
tal models in vivo.
RESULTS: In addition to immune signaling
pathways, glycolysis genes were strongly up-regulated in terms of histone modification
profiling, and this was validated by RNA
sequencing of cells from β-glucan–treated
mice. The biochemical characterizations of
the β-glucan–trained monocytes revealed
elevated aerobic glycolysis with reduced
basal respiration rate, increased glucose
consumption and lactate production, and
higher intracellular ratio of nicotinamide
adenine dinucleotide (NAD+) to its reduced
form (NADH). The dectin-1–Akt–mTOR–
HIF-1α pathway (m TOR, mammalian target
of rapamycin; HIF-1α, hypoxia-inducible
factor–1α) was responsible for the metabolic shift induced by β-glucan. Trained
immunity was completely abrogated in
monocytes from dectin-1–deficient patients.
Blocking of the m TOR–HIF-1α pathway by
chemical inhibitors inhibited trained immunity. Mice receiving
metformin, an adenosine monophosphate–
activated protein kinase
(AMPK) activator that
subsequently inhibits
mTOR, lost the trained
immunity–induced protection against lethal C. albicans infection. The role of the
mTOR–HIF-1α pathway for β-glucan–
induced innate immune memory was further validated in myeloid-specific HIF-1α
knockout (mHIF-1α KO) mice that, unlike
wild-type mice, were not protected against
Staphylococcus aureus sepsis.
DISCUSSION: The shift of central glucose
metabolism from oxidative phosphorylation to aerobic glycolysis (the “Warburg
effect”) meets the spiked need for energy
and biological building blocks for rapid
proliferation during carcinogenesis or
clonal expansion in activated lymphocytes.
We found that an elevated glycolysis is the
metabolic basis for trained immunity as
well, providing the energy and metabolic
substrates for the increased activation of
trained immune cells. The identification
of glycolysis as a fundamental process in
trained immunity further highlights a
key regulatory role for metabolism in innate host defense and defines a potential
therapeutic target in both infectious and
inflammatory diseases. ■
The list of author affiliations is available in the full article online.
*Corresponding author. E-mail: mihal.netea@radboudumc.nl
Cite this article as S.-C. Cheng et al., Science 345, 1250684
(2014). DOI: 10.1126/science.1250684
Read the full article
at http://dx.doi
.org/10.1126/
science.1250684
ON OUR WEB SITE
