WNT6/ACC2-induced storage of triacylglycerols in macrophages is exploited by Mycobacterium tuberculosis
Julius Brandenburg, … , Dominik Schwudke, Norbert Reiling
Julius Brandenburg, … , Dominik Schwudke, Norbert Reiling
Published July 13, 2021
Citation Information: J Clin Invest. 2021;131(16):e141833. https://doi.org/10.1172/JCI141833.
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Research Article Infectious disease Metabolism

WNT6/ACC2-induced storage of triacylglycerols in macrophages is exploited by Mycobacterium tuberculosis

Abstract

In view of emerging drug-resistant tuberculosis (TB), host-directed adjunct therapies are urgently needed to improve treatment outcomes with currently available anti-TB therapies. One approach is to interfere with the formation of lipid-laden “foamy” macrophages in the host, as they provide a nutrient-rich host cell environment for Mycobacterium tuberculosis (Mtb). Here, we provide evidence that Wnt family member 6 (WNT6), a ligand of the evolutionarily conserved Wingless/Integrase 1 (WNT) signaling pathway, promotes foam cell formation by regulating key lipid metabolic genes including acetyl-CoA carboxylase 2 (ACC2) during pulmonary TB. Using genetic and pharmacological approaches, we demonstrated that lack of functional WNT6 or ACC2 significantly reduced intracellular triacylglycerol (TAG) levels and Mtb survival in macrophages. Moreover, treatment of Mtb-infected mice with a combination of a pharmacological ACC2 inhibitor and the anti-TB drug isoniazid (INH) reduced lung TAG and cytokine levels, as well as lung weights, compared with treatment with INH alone. This combination also reduced Mtb bacterial numbers and the size of mononuclear cell infiltrates in livers of infected mice. In summary, our findings demonstrate that Mtb exploits WNT6/ACC2-induced storage of TAGs in macrophages to facilitate its intracellular survival, a finding that opens new perspectives for host-directed adjunctive treatment of pulmonary TB.

Authors

Julius Brandenburg, Sebastian Marwitz, Simone C. Tazoll, Franziska Waldow, Barbara Kalsdorf, Tim Vierbuchen, Thomas Scholzen, Annette Gross, Svenja Goldenbaum, Alexandra Hölscher, Martina Hein, Lara Linnemann, Maja Reimann, Andreas Kispert, Michael Leitges, Jan Rupp, Christoph Lange, Stefan Niemann, Jochen Behrends, Torsten Goldmann, Holger Heine, Ulrich E. Schaible, Christoph Hölscher, Dominik Schwudke, Norbert Reiling

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Figure 2

WNT6 drives the accumulation of TAG-rich lipid droplets.

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WNT6 drives the accumulation of TAG-rich lipid droplets. (A) Visualizati...
(A) Visualization of neutral lipids in WNT6-overexpressing (WNT6) or control (LacZ) NIH 3T3 cells by fluorescence microscopy. Nuclei (blue, DAPI); neutral lipids (green, BODIPY 493/503). A representative staining from 2 independent experiments is shown. (B) Quantification of neutral lipids by flow cytometry (same cells as in A; arithmetic mean fluorescence intensity [aMFI] of BODIPY signals); n = 3. (C) Mass spectrometry–based quantification of TAGs (same cells as in A); n = 3. (D) Visualization of neutral lipids in BMDMs from Wnt6+/+ or Wnt6–/– mice incubated for 24 hours in the absence (Ctrl) or presence of oleic acid (oleate-BSA, 200 μM) by fluorescence microscopy. A representative staining from 2 independent experiments is shown. (E) Mass spectrometry–based quantification of TAGs in BMDMs from Wnt6+/+ or Wnt6–/– mice incubated for 24 hours in the absence (Ctrl, BSA) or presence of oleic acid (oleate-BSA, 200 μM); n = 2. (F) Oxygen consumption rate (OCR) of BMDMs incubated for 24 hours in the absence (Ctrl, BSA) or presence of oleic acid (oleate-BSA, 200 μM) as determined on an extracellular flux analyzer; n = 2. (G and H) Visualization (G) and quantification (H) of neutral lipids in uninfected and Mtb-infected (MOI 0.1:1) Wnt6+/+ and Wnt6–/– peritoneal macrophages after 24 hours by fluorescence microscopy. mCherry-Mtb (red); nuclei (blue, DAPI); neutral lipids (green, BODIPY); n = 5. Statistical analyses were carried out using 1-way ANOVA with Holm-Šidák’s multiple-comparison test. *P ≤ 0.05, **P ≤ 0.01. Data are depicted as mean ± SEM, except in E, where mean ± SD is shown. Scale bars: 20 μm.