The Flagellin:Allergen Fusion Protein rFlaA:Betv1 Induces a MyD88− and MAPK-Dependent Activation of Glucose Metabolism in Macrophages
Abstract
:1. Introduction
2. Materials and Methods
2.1. Generation of Recombinant Proteins
2.2. Determination of Beta-Glucans
2.3. Mice
2.4. In Vitro Generation of Mouse Bone Marrow-Derived Macrophages, Stimulation, and Flow Cytometry
2.5. Preparation of BMDM:CD4+ T Cell Co-Cultures
2.6. Inhibitors
2.7. Western Blotting
2.8. Analysis of Cell Metabolic State
2.9. Metabolic Flux Analysis
2.10. RNA-Seq and Bioinformatics
2.11. Statistical Analysis
3. Results
3.1. Activation of BMDM Metabolism by rFlaA:Betv1 Is Accompanied by Both Pro- and Anti-inflammatory Cytokine Secretion
3.2. rFlaA:Betv1 Triggers a Pronounced Shift Towards Glycolysis in BMDMs
3.3. rFlaA:Betv1-Induced BMDM Metabolism and Inflammatory Cytokine Secretion Depend on MyD88 While Only Being Partially TLR5-Dependent
3.4. rFlaA:Betv1 Induces MAPK, NFκB, and mTOR Signaling in BMDMs
3.5. Activation of BMDM Metabolism and IL-10 Secretion are Partly mTOR-Dependent while Pro-Inflammatory Cytokine Secretion Is mTOR-Independent
3.6. MAP Kinase Signaling Contributes to rFlaA:Betv1-Induced Activation of BMDM Metabolism as well as Both Pro- and Anti-Inflammatory Cytokine Secretion
3.7. rFlaA:Betv1 Suppresses Th2 Responses from Bet v 1-specific CD4+ T Cells In Vitro
3.8. rFlaA:Betv1 Induces a Transcriptional Shift Towards HIF-1a-Mediated Glycolytic Metabolism in BMDMs
4. Discussion
4.1. rFlaA:Betv1 Induces a Partly TLR5-Dependent Activation of BMDMs Characterized by Both Pro- and Anti-Inflammatory Cytokine Secretion
4.2. rFlaA:Betv1-Stimulated BMDMs Efficiently Modulate Allergen-Specific T Cell Responses
4.3. rFlaA:Betv1 Activates Both Glycolytic Metabolism and HIF-1a Signaling in BMDMs
4.4. MAPK, NFκB, and mTOR Signaling Contribute to rFlaA:Betv1-Mediated BMDM Activation
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Abbreviations
2-DG | 2-deoxy-glucose |
ACO2 | Aconitase 2 |
BMDM | Bone marrow-derived macrophage |
CD | Cluster of differentiation |
C/EBPβ | CCAAT enhancer-binding protein |
ECAR | Extracellular acidification rate |
GM-CSF | Granulocyte-macrophage colony-stimulating factor |
IFN-γ | Interferon gamma |
IL | Interleukin |
Ipaf | ICE-protease activating factor |
MAP(K) | Mitogen-activated protein (kinase) |
(m)DC | (Myeloid) Dendritic cell |
mTOR | Mammalian target of rapamycin |
mTORC1 | mTOR complex 1 |
MyD88 | Myeloid differentiation primary response 88 |
NFκB | Nuclear factor ‘kappa-light-chain-enhancer’ of activated B-cells |
OCR | Oxygen consumption rate |
PI3K | Phosphatidylinositol 3 kinase |
PDK:1 | Pyruvate dehydrogenase kinase 1 |
PFK | Phospho-fructo-kinase |
PFKFB3 | 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 |
PGM | Phosphoglycerate mutase |
PKM | Pyruvate kinase isozyme |
rBet v 1 | Recombinant major birch pollen allergen number one from Betula verrucosa |
rFlaA | Recombinant Listeria monocytogenes flagellin A |
rFlaA:Betv1 | Recombinant fusion protein of FlaA and Bet v 1 |
rmM-CSF | Recombinant mouse macrophage colony-stimulating factor |
RAPTOR | Regulatory associated protein of mTOR |
TSC | Tuberous sclerosis complex |
Rot/AA | Rotenone/ antimycin A |
SAP/JNK MAPK | Stress-activated protein kinase/c-Jun NH2-terminal kinase |
Th1/2 | T helper 1/2 cell |
TLR | Toll-like receptor |
TNF-α | Tumor necrosis factor alpha |
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Oligo Name | Sequence |
---|---|
NNSR_RT | gctcttccgatctctNNNNNN |
NNSR_2 | gctcttccgatctgaNNNNNN |
NNSRnest_ind_N | CAAGCAGAAGACGGCATACGAGATNNNNNNGTGACTGGAGTTCAGACGTGTGCTCTTCCGATCTGA (N stands for a 6mer TruSeq index (Illumina)) |
NNSR_Illumina | AATGATACGGCGACCACCGAGATCTACACTCTTTCCCTACACGACGCTCTTCCGATCTCT |
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Lin, Y.-J.; Papp, G.; Miskey, C.; Fiedler, A.; Goretzki, A.; Wolfheimer, S.; Zimmermann, J.; Crauwels, P.; Ivics, Z.; van Zandbergen, G.; Vieths, S.; Scheurer, S.; Schülke, S. The Flagellin:Allergen Fusion Protein rFlaA:Betv1 Induces a MyD88− and MAPK-Dependent Activation of Glucose Metabolism in Macrophages. Cells 2021, 10, 2614. https://doi.org/10.3390/cells10102614
Lin Y-J, Papp G, Miskey C, Fiedler A, Goretzki A, Wolfheimer S, Zimmermann J, Crauwels P, Ivics Z, van Zandbergen G, Vieths S, Scheurer S, Schülke S. The Flagellin:Allergen Fusion Protein rFlaA:Betv1 Induces a MyD88− and MAPK-Dependent Activation of Glucose Metabolism in Macrophages. Cells. 2021; 10(10):2614. https://doi.org/10.3390/cells10102614
Chicago/Turabian StyleLin, Yen-Ju, Garibald Papp, Csaba Miskey, Anna Fiedler, Alexandra Goretzki, Sonja Wolfheimer, Jennifer Zimmermann, Peter Crauwels, Zoltán Ivics, Ger van Zandbergen, Stefan Vieths, Stephan Scheurer, and Stefan Schülke. 2021. "The Flagellin:Allergen Fusion Protein rFlaA:Betv1 Induces a MyD88− and MAPK-Dependent Activation of Glucose Metabolism in Macrophages" Cells 10, no. 10: 2614. https://doi.org/10.3390/cells10102614