The Flagellin:Allergen Fusion Protein rFlaA:Betv1 Induces a MyD88− and MAPK-Dependent Activation of Glucose Metabolism in Macrophages
| Autor: | Jennifer Zimmermann, Peter Crauwels, Alexandra Goretzki, Stefan Schülke, Garibald Papp, Ger van Zandbergen, Stephan Scheurer, Csaba Miskey, Anna H. Fiedler, Yen-Ju Lin, Stefan Vieths, Sonja Wolfheimer, Zoltán Ivics |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
MAPK/ERK pathway
Chemokine QH301-705.5 Recombinant Fusion Proteins flagellin Article TLR5 immune metabolism metabolism Bet v 1 fusion protein HIF-1a Warburg allergen Pollenallergie Mice Bacterial Proteins Animals Biology (General) PI3K/AKT/mTOR pathway Cells Cultured Plant Proteins Mice Knockout Antigens Bacterial Mice Inbred BALB C biology Chemistry Macrophages General Medicine Allergens Antigens Plant Cell biology Mice Inbred C57BL Glucose biology.protein Pollen Tumor necrosis factor alpha Cytokine secretion Cell activation Flagellin |
| Zdroj: | Cells Cells, 10(10):2614 Volume 10 Issue 10 Cells, Vol 10, Iss 2614, p 2614 (2021) |
| ISSN: | 2073-4409 |
| Popis: | TLR5 ligand flagellin-containing fusion proteins are potential vaccine candidates for many diseases. A recombinant fusion protein of flagellin A and the major birch pollen allergen Bet v 1 (rFlaA:Betv1) modulates immune responses in vitro and in vivo. We studied the effects of rFlaA:Betv1 on bone marrow-derived macrophages (BMDMs). BMDMs differentiated from BALB/c, C57BL/6, TLR5−/−, or MyD88−/− mice were pre-treated with inhibitors, stimulated with rFlaA:Betv1 or respective controls, and analyzed for activation, cytokine secretion, metabolic state, RNA transcriptome, and modulation of allergen-specific Th2 responses. Stimulation of BMDMs with rFlaA:Betv1 resulted in MyD88-dependent production of IL-1β, IL-6, TNF-α, IL-10, CD69 upregulation, and a pronounced shift towards glycolysis paralleled by activation of MAPK, NFκB, and mTOR signaling. Inhibition of either mTOR (rapamycin) or SAP/JNK-MAPK signaling (SP600125) resulted in dose-dependent metabolic suppression. In BMDM and T cell co-cultures, rFlaA:Betv1 stimulation suppressed rBet v 1-induced IL-5 and IL-13 secretion while inducing IFN-γ production. mRNA-Seq analyses showed HIF-1a, JAK, STAT, phagosome, NLR, NFκB, TNF, TLR, and chemokine signaling to participate in the interplay of cell activation, glycolysis, and immune response. rFlaA:Betv1 strongly activated BMDMs, resulting in MyD88−, MAPK−, and mTOR-dependent enhancement of glucose metabolism. Our results suggest macrophages are important target cells to consider during restauration of allergen tolerance during AIT. |
| Databáze: | OpenAIRE |
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