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Cutting Edge: Mycobacterium tuberculosis
Induces Aerobic Glycolysis in Human
Alveolar Macrophages That Is Required for
Control of Intracellular Bacillary Replication
Laura E. Gleeson, Frederick J. Sheedy, Eva M.
Palsson-McDermott, Denise Triglia, Seonadh M. O'Leary,
Mary P. O'Sullivan, Luke A. J. O'Neill and Joseph Keane
Supplementary
Material
http://www.jimmunol.org/content/suppl/2016/02/11/jimmunol.150161
2.DCSupplemental
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Copyright © 2016 by The American Association of
Immunologists, Inc. All rights reserved.
Print ISSN: 0022-1767 Online ISSN: 1550-6606.
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J Immunol published online 12 February 2016
http://www.jimmunol.org/content/early/2016/02/11/jimmun
ol.1501612
Published February 12, 2016, doi:10.4049/jimmunol.1501612
The
Cutting Edge
Journal of
Immunology
Cutting Edge: Mycobacterium tuberculosis Induces
Aerobic Glycolysis in Human Alveolar Macrophages
That Is Required for Control of Intracellular
Bacillary Replication
Laura E. Gleeson,* Frederick J. Sheedy,* Eva M. Palsson-McDermott,†
Denise Triglia,* Seonadh M. O’Leary,* Mary P. O’Sullivan,* Luke A. J. O’Neill,† and
Joseph Keane*
T
mune function (5, 6). Macrophages stimulated with the TLR4
agonist LPS undergo a shift in glucose metabolism, similar to
that seen in cancer cells, termed the Warburg effect (or aerobic glycolysis) (6). This involves increased rates of glycolysis
and reduced oxidative phosphorylation via the tricarboxylic
acid cycle, with concurrent accumulation of tricarboxylic acid
intermediates, such as succinate. Increased succinate results in
impaired activity of prolylhydroxylases, allowing stabilization
of the transcription factor hypoxia inducible factor-1a and
leading to transcription of Il-1b and production of mature IL1b (6, 7). Molecular determinants of this significant change
in metabolism are being investigated as potential targets for
manipulation in this important pathway (7).
In this work, we demonstrate for the first time, to our
knowledge, that M. tuberculosis infection induces a metabolic
shift toward aerobic glycolysis in primary human alveolar
macrophages (AM) and monocyte-derived macrophages (MDM)
and that this shift is required for optimal production of IL-1b, as
well as for suppression of the anti-inflammatory cytokine IL-10.
We further demonstrate that this alteration in host glucose
metabolism, through its induction of IL-1b, is required for
control of bacillary intracellular replication. This work highlights host AM glucose metabolism as a potential target for
host-directed adjunctive therapies.
Materials and Methods
he innate immune response to Mycobacterium tuberculosis infection in the human lung is crucial in
determining the outcome of infection (1). Mice deficient in the innate cytokine IL-1b signaling display increased susceptibility to infection (2, 3), supporting a critical
role for this cytokine in the host response to the bacterium.
IL-1b also induces differentiation of human monocytes into
macrophages, with enhanced phagocytic and Ag-presentation
functions in M. tuberculosis infection (4).
Recently, metabolic reprogramming in stimulated host
immune cells was implicated in the regulation of innate im-
Human AM were retrieved at bronchoscopy after informed consent, as approved by the Research Ethics Committee of St. James’s Hospital (Dublin,
Ireland), and prepared and cultured as previously reported (8, 9). Cells were
cultured for 24 h prior to experimentation.
Human MDM were isolated from peripheral blood buffy coats (obtained
from the Irish Blood Transfusion Services) by density gradient centrifugation
and adherence to plastic or immune-magnetic separation using CD14-positive
magnetic beads (STEMCELL Technologies). Cells were cultured for 7–10 d to
allow differentiation prior to experimentation.
CS57BL/6 (Harlan) mice and IL-1R2/2 mice (CS57BL/6 background;
The Jackson Laboratory), kindly donated by Prof. Kingston Mills (School of
Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity
*Department of Clinical Medicine, School of Medicine, Institute of Molecular Medicine, Trinity College Dublin, Dublin 8, Ireland; and †School of Biochemistry and
Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2,
Ireland
Address correspondence and reprint requests to Dr. Laura E. Gleeson, Institute of
Molecular Medicine, Trinity College Dublin, Rm 1.14 Trinity Centre for Health
Sciences, St James’s Hospital, James’s Street, Dublin 8, Ireland. E-mail address:
[email protected]
Received for publication July 27, 2015. Accepted for publication January 15, 2016.
The online version of this article contains supplemental material.
This work was supported by the Health Research Board, a Health Professionals fellowship, and the Royal City of Dublin Hospital Trust.
Copyright Ó 2016 by The American Association of Immunologists, Inc. 0022-1767/16/$30.00
www.jimmunol.org/cgi/doi/10.4049/jimmunol.1501612
Cell culture
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Recent advances in immunometabolism link metabolic
changes in stimulated macrophages to production of
IL-1b, a crucial cytokine in the innate immune response to Mycobacterium tuberculosis. To investigate
this pathway in the host response to M. tuberculosis,
we performed metabolic and functional studies on human alveolar macrophages, human monocyte-derived
macrophages, and murine bone marrow–derived macrophages following infection with the bacillus in vitro.
M. tuberculosis infection induced a shift from oxidative
phosphorylation to aerobic glycolysis in macrophages.
Inhibition of this shift resulted in decreased levels of
proinflammatory IL-1b and decreased transcription of
PTGS2, increased levels of anti-inflammatory IL-10,
and increased intracellular bacillary survival. Blockade
or absence of IL-1R negated the impact of aerobic
glycolysis on intracellular bacillary survival, demonstrating that infection-induced glycolysis limits M. tuberculosis survival in macrophages through induction
of IL-1b. Drugs that manipulate host metabolism may
be exploited as adjuvants for future therapeutic and
vaccination strategies. The Journal of Immunology,
2016, 196: 000–000.
2
CUTTING EDGE: M. TUBERCULOSIS INDUCES GLYCOLYSIS IN HUMAN MACROPHAGES
College Dublin), were bred under specific pathogen–free conditions, and
BMDM were isolated and cultured as previously described (6, 7). Cells were
differentiated until day 5, after which they were lifted using 10 mM EDTA
and plated for experimentation. All experiments were carried out with prior
ethical approval from the Trinity College Dublin Animal Research Ethics
Committee.
Human cells were cultured in glucose-deprived RPMI 40 (Sigma-Aldrich)
supplemented with 10 mM glucose or 10 mM galactose for 24 h prior to, and
for the duration of, infection. Murine BMDM were treated 3 h prior to, and for
the duration of, infection with 5 mM 2-deoxyglucose (2DG; Sigma-Aldrich).
Recombinant human IL-1b/IL-1F2 Ab (R&D Systems) was used at
0.1 mg/ml.
Mycobacterial culture and infection of macrophages
Metabolic measurements
Lactate concentration in supernatants was measured by colorimetric assay
(Sigma-Aldrich) and read at 570 nm using an Epoch Microplate Spectrophotometer with Gen5 Data Analysis software (BioTek Instruments).
The bioenergetic profile of cells was determined using an XF24 Extracellular
Flux analyzer (Seahorse Biosciences). Oxygen consumption rate and extracellular acidification rate were assessed in Seahorse Media supplemented with
10 mM glucose and 2 mM L-glutamine. Results were normalized to cell
number using a Crystal Violet dye extraction growth assay.
FIGURE 1. M. tuberculosis infection induces glycolysis in macrophages. Secreted lactate concentration
from human MDM (A, B, and D), human AM (A, E,
and F), or murine BMDM (A) at 24 h p.i. (A and D–
F) or at the indicated times p.i. (B). (C) Ratio of
glycolysis (extracellular acidification rate)/oxidative
phosphorylation (oxygen consumption rate) in human AM p.i. Data are mean 6 SEM of six [human
AM (A)], two [human MDM (A and B)], three
[murine BMDM (A), human AM (D)], four (C),
seven (E), and eight (F) individual donors. *p , 0.05,
**p , 0.01, ***p , 0.001.
RNA extraction was performed using the RNeasy Mini Kit (QIAGEN), and
cDNA was generated using the Applied Biosystems High-Capacity cDNA
Archive Kit. Real-time PCR was performed using TaqMan primers. Data were
normalized to GAPDH, and mRNA expression fold-change relative to uninfected was calculated using the 22DDCt method.
Cytokine concentration in supernatants was measured by ELISA (TNF-a,
IL-10 [both from eBioscience]; IL-1b [R&D Systems]).
Intracellular bacillary survival assay
Following a 3-h wash to remove extracellular bacteria, as described above,
infected macrophages were lysed in 0.1% Triton-X at 3 or 72 h postinfection
(p.i.), and serial dilutions were performed and plated on 7H10 Middlebrook
Agar in triplicate. CFU were enumerated at 14–28 d.
Statistical analysis
Results are expressed as mean 6 SEM. The data were analyzed by GraphPad
Prism (La Jolla, CA) using the unpaired Student t test for all murine
experiments and the paired Student t test for all human experiments. A
p value , 0.05 was considered statistically significant.
Results
First, we undertook to establish the impact of M. tuberculosis
infection on macrophage glucose metabolism. Lactate, generated from the reduction of pyruvate by the enzyme lactate
dehydrogenase, represents the end-product of the glycolytic
pathway. Lactate exits the cell via the monocarboxylate
transport protein system (10); therefore, increases in secreted
lactate reflect increases in intracellular glycolytic activity.
Human AM, human MDM, and murine BMDM demonstrated increased lactate production when infected with
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M. tuberculosis strains H37Ra (ATCC 2517) and H37Rv (ATCC 25618)
(American Type Culture Collection, Manassas, VA) were propagated in
Middlebrook 7H9 medium to log phase. M. tuberculosis strain H37Rv,
gamma-irradiated whole cells, NR-49098 (BEI Resources, National Institute
of Allergy and Infectious Diseases, National Institutes of Health) was prepared according to the supplier’s instructions. Bacteria were resuspended, and
multiplicity of infection (MOI) was determined for each donor as previously
described (8, 9). Cells were infected at MOI 1–5 bacilli/cell for 3 h, extracellular bacteria were removed, and fresh media were applied to allow incubation for specified times.
Cytokine measurements
The Journal of Immunology
FIGURE 2. Infection-induced glycolysis promotes
IL-1b, suppresses IL-10, and induces PTGS2. Relative expression (A) and secreted cytokine level (B) in
human MDM 24 h p.i. with H37Ra in glucose or
galactose. (C) Secreted cytokine level in murine
BMDM 24 h p.i. with H37Ra in the presence or
absence of 2DG. Relative expression of PTGS2
mRNA in human MDM in the presence or absence
of anti-IL-1R–IgG (D) and Ptgs2 mRNA in WT and
IL-1R2/2 murine BMDM (E) 24 h p.i. with H37Ra.
(F) Relative expression of PTGS2 mRNA in human
MDM in glucose or galactose. Data are mean 6 SEM
of three (A–C and F) or two (D and E) individual
experiments. **p , 0.01, ***p , 0.001. ns, not significant.
IL-1b–dependent host resistance to M. tuberculosis infection was linked to production of eicosanoids through induction of the enzyme cyclooxygenase-2 (gene known as Ptgs2)
(13). We confirmed that blockade or absence of IL-1R signaling in murine and human macrophages is associated with
reduced PTGS2 induction (Fig. 2D, 2E) and further demonstrated a trend towards reduced PTGS2 transcription following inhibition of glycolytic metabolism in M. tuberculosis–
infected human MDM (Fig. 2F).
To investigate the functional implications of this metabolic shift, we measured intracellular bacillary killing in the
presence and absence of glycolytic inhibitors described above.
Inhibition of glycolysis impaired bacillary killing by macrophages, suggesting that this metabolic shift is required for
optimal control of the bacillus (Fig. 3). The presence or
absence of glycolytic inhibitors did not impact M. tuberculosis replication in macrophage-free culture (Supplemental
Fig. 1D). Bacillary killing was impaired to a similar extent
in murine BMDM cultured in the presence of a glycolytic
inhibitor and those deficient in IL-1R (IL-1R2/2); the impact of inhibiting glycolysis was not seen in macrophages
from IL1R2/2 mice (Fig. 4A), suggesting that this effect of
glycolysis is mediated through its induction of IL-1b. Similarly, in human MDM, pretreatment with anti-IL-1R–IgG
impaired bacillary killing to a similar extent as galactose
treatment (Fig. 4B).
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M. tuberculosis, and this was dependent on the MOI (Fig. 1A,
1B, Supplemental Fig. 1A). Extracellular flux analyses also
demonstrated a shift toward glycolytic metabolism in
iH37Rv-infected AM, with similar kinetics as observed for
lactate secretion (Fig. 1C). Use of gamma-irradiated M. tuberculosis strain iH37Rv allowed examination of macrophage
metabolism in isolation, and results were confirmed using live
H73Ra and H37Rv in human MDM (Fig. 1D) and human
AM (Fig. 1E, 1F).
The metabolic shift toward glycolysis is required for optimal
production of IL-1b in murine macrophages (6); thus, we
next sought to determine the effect of this metabolic shift on
human macrophage cytokine profiles. Cells grown in glucosedeprived galactose-containing media are forced to generate
ATP from glutamine-driven oxidative metabolism, effectively
inhibiting the glycolytic pathway (11, 12). Inhibition of glycolysis resulted in decreased levels of IL-1b, but not IL-1a, at
the transcriptional and mature protein levels (Fig. 2A, 2B).
Interestingly, inhibiting glycolysis increased production of the
anti-inflammatory cytokine IL-10, despite low levels of IL10
mRNA at the times points analyzed (Fig. 2B). Similar to
earlier observations with LPS-stimulated murine macrophages,
TNF-a production was unchanged (6). Inhibition of glycolysis
did not impact IL-18 or IL-12 transcription (Supplemental
Fig. 1B, 1C). Similar results were seen in murine BMDM
treated with glycolytic inhibitor 2DG (Fig. 2C).
3
4
CUTTING EDGE: M. TUBERCULOSIS INDUCES GLYCOLYSIS IN HUMAN MACROPHAGES
Discussion
Immunometabolism is an exciting new field with the potential
for novel therapeutic targets for infection and autoimmune
disease (14). Key innate immunity defense mechanisms in
M. tuberculosis infection, such as proinflammatory cytokine
secretion and autophagy, as well as development of trained
immunity, have been linked to intracellular metabolism (6,
15, 16). Aerobic glycolysis, long described in cancer cells,
recently was observed to occur in innate immune cells stimulated with TLR agonists (5, 6). Our data demonstrate a shift
toward aerobic glycolysis in primary human cells infected
with M. tuberculosis, including primary human AM that
represent the first line of defense against M. tuberculosis
in vivo.
We further demonstrate that this shift toward glycolysis is
crucial for the production of proinflammatory IL-1b, and
suppression of anti-inflammatory IL-10, a cytokine that assists
the bacillus in evading host immune responses (8). We previously reported similar alterations in IL-1b and IL-10
through manipulation of the glycolytic enzyme PKM2 in
TLR-stimulated murine BMDM (7). Our observations are
supported by increased cytokine production in response to
M. tuberculosis lysate in PBMC cultured in media with high
glucose concentration (17). Although our results demonstrate
that TNF-a production is not directly impacted by glycolytic
reprogramming, IL-1b was shown to augment TNF-a signaling in M. tuberculosis infection (18); thus, glycolysis may
also affect this cytokine indirectly at later time points. Taken
together, these data suggest that host macrophage glucose
metabolism plays a demonstrable role in the cytokine signature generated in response to infection with the bacillus.
Although direct alterations in extracellular glucose concentration do not impact upon bacillary replication in macrophages (17), we show that the metabolic pathway through
which intracellular glucose is used by the macrophage plays a
major role in facilitating elimination of M. tuberculosis in
primary human cells. Although other investigators suggested
that glycolysis may facilitate macrophage survival and, hence,
permit bacillary replication, these studies were performed in
the primarily glycolytic THP1 cell line (19). As our data illustrate, the metabolic shift induced in primary human cells
(which are not dependent upon glycolysis for survival, in
contrast to the THP1 cell line) is crucial for key innate immune functions, specifically those mediated through IL-1b.
Sher and colleagues (13) reported that IL-1b–dependent resistance to M. tuberculosis infection was mediated, in part,
through induction of Ptgs2. We confirmed, in primary human
cells, that optimal PTGS2 transcription requires IL-1 signaling in M. tuberculosis infection. Furthermore, inhibition of
the infection-induced switch to glycolysis results in decreased
PTGS2, in parallel with decreased IL-1b production. Interestingly, Chen et al. (20) reported reduced PTGS2 induction
in response to virulent H37Rv compared with avirulent
H37Ra, which, combined with our observations, may im-
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FIGURE 3. Infection-induced glycolysis is required
for optimal control of bacillary intracellular replication by the macrophage. Fold change in H37Ra
CFU/ml at 72 h (A, C, and E) and relative to glucose
control (B, D, and F) in human MDM (A and B),
human AM (C and D), and murine BMDM (E and F)
in the presence or absence of galactose (A–D) or 2DG
(E and F). Data depict nine (A and B), three (C and
D), and five (E and F) individual donors. Error bars
depict SEM. *p , 0.05, **p , 0.01, ***p , 0.001.
The Journal of Immunology
5
metabolism toward aerobic glycolysis, such as the antiemetic
agent meclizine; thus, they may warrant investigation as potential therapeutic adjuncts in the setting of M. tuberculosis
infection (23). Additionally, reported links between immunometabolism and trained immunity may be specifically relevant
to enhancing M. tuberculosis vaccination strategies in the future
(16).
Disclosures
The authors have no financial conflicts of interest.
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FIGURE 4. Impact of glycolysis on bacillary replication is mediated through
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