PMID- 34685593
OWN - NLM
STAT- MEDLINE
DCOM- 20211213
LR  - 20211214
IS  - 2073-4409 (Electronic)
IS  - 2073-4409 (Linking)
VI  - 10
IP  - 10
DP  - 2021 Oct 1
TI  - The Flagellin:Allergen Fusion Protein rFlaA:Betv1 Induces a MyD88- and 
      MAPK-Dependent Activation of Glucose Metabolism in Macrophages.
LID - 10.3390/cells10102614 [doi]
LID - 2614
AB  - 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-1beta, IL-6, TNF-alpha, IL-10, CD69 upregulation, and a pronounced shift towards 
      glycolysis paralleled by activation of MAPK, NFkappaB, 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-gamma production. mRNA-Seq analyses showed HIF-1a, JAK, STAT, phagosome, NLR, 
      NFkappaB, 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.
FAU - Lin, Yen-Ju
AU  - Lin YJ
AD  - Vice Presidents Research Group 1: Molecular Allergology, Paul-Ehrlich-Institut, 
      63225 Langen, Germany.
FAU - Papp, Garibald
AU  - Papp G
AD  - Vice Presidents Research Group 1: Molecular Allergology, Paul-Ehrlich-Institut, 
      63225 Langen, Germany.
FAU - Miskey, Csaba
AU  - Miskey C
AUID- ORCID: 0000-0002-7566-9556
AD  - Medical Biotechnology, Paul-Ehrlich-Institut, 63225 Langen, Germany.
FAU - Fiedler, Anna
AU  - Fiedler A
AD  - Vice Presidents Research Group 1: Molecular Allergology, Paul-Ehrlich-Institut, 
      63225 Langen, Germany.
FAU - Goretzki, Alexandra
AU  - Goretzki A
AD  - Vice Presidents Research Group 1: Molecular Allergology, Paul-Ehrlich-Institut, 
      63225 Langen, Germany.
FAU - Wolfheimer, Sonja
AU  - Wolfheimer S
AD  - Vice Presidents Research Group 1: Molecular Allergology, Paul-Ehrlich-Institut, 
      63225 Langen, Germany.
FAU - Zimmermann, Jennifer
AU  - Zimmermann J
AD  - Vice Presidents Research Group 1: Molecular Allergology, Paul-Ehrlich-Institut, 
      63225 Langen, Germany.
FAU - Crauwels, Peter
AU  - Crauwels P
AD  - Immunology, Paul-Ehrlich-Institut, 63225 Langen, Germany.
FAU - Ivics, Zoltan
AU  - Ivics Z
AUID- ORCID: 0000-0002-7803-6658
AD  - Medical Biotechnology, Paul-Ehrlich-Institut, 63225 Langen, Germany.
FAU - van Zandbergen, Ger
AU  - van Zandbergen G
AD  - Immunology, Paul-Ehrlich-Institut, 63225 Langen, Germany.
AD  - Institute of Immunology, University Medical Center of the Johannes Gutenberg 
      University of Mainz, 55122 Mainz, Germany.
AD  - Research Center for Immunotherapy (FZI), University Medical Center, Johannes 
      Gutenberg-University Mainz, 55122 Mainz, Germany.
FAU - Vieths, Stefan
AU  - Vieths S
AD  - Vice Presidents Research Group 1: Molecular Allergology, Paul-Ehrlich-Institut, 
      63225 Langen, Germany.
FAU - Scheurer, Stephan
AU  - Scheurer S
AUID- ORCID: 0000-0002-2859-562X
AD  - Vice Presidents Research Group 1: Molecular Allergology, Paul-Ehrlich-Institut, 
      63225 Langen, Germany.
FAU - Schulke, Stefan
AU  - Schulke S
AUID- ORCID: 0000-0002-9674-5116
AD  - Vice Presidents Research Group 1: Molecular Allergology, Paul-Ehrlich-Institut, 
      63225 Langen, Germany.
LA  - eng
GR  - DFG SCHE637/4-1/Deutsche Forschungsgemeinschaft/
GR  - DFG SCHU2951/4/Deutsche Forschungsgemeinschaft/
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20211001
PL  - Switzerland
TA  - Cells
JT  - Cells
JID - 101600052
RN  - 0 (Allergens)
RN  - 0 (Antigens, Bacterial)
RN  - 0 (Antigens, Plant)
RN  - 0 (Bacterial Proteins)
RN  - 0 (Plant Proteins)
RN  - 0 (Recombinant Fusion Proteins)
RN  - 12777-81-0 (Flagellin)
RN  - IY9XDZ35W2 (Glucose)
SB  - IM
MH  - Allergens/*immunology
MH  - Animals
MH  - Antigens, Bacterial/*immunology
MH  - Antigens, Plant/*immunology
MH  - Bacterial Proteins/immunology
MH  - Cells, Cultured
MH  - Flagellin/*immunology
MH  - Glucose/metabolism
MH  - Macrophages
MH  - Mice
MH  - Mice, Inbred BALB C
MH  - Mice, Inbred C57BL
MH  - Mice, Knockout
MH  - Plant Proteins/immunology
MH  - Pollen/immunology
MH  - Recombinant Fusion Proteins/*immunology
PMC - PMC8534024
OTO - NOTNLM
OT  - Bet v 1
OT  - HIF-1a
OT  - TLR5
OT  - Warburg
OT  - allergen
OT  - flagellin
OT  - fusion protein
OT  - immune metabolism
OT  - metabolism
COIS- The authors declare no conflict of interest.
EDAT- 2021/10/24 06:00
MHDA- 2021/12/15 06:00
PMCR- 2021/10/01
CRDT- 2021/10/23 01:22
PHST- 2021/06/22 00:00 [received]
PHST- 2021/09/15 00:00 [revised]
PHST- 2021/09/21 00:00 [accepted]
PHST- 2021/10/23 01:22 [entrez]
PHST- 2021/10/24 06:00 [pubmed]
PHST- 2021/12/15 06:00 [medline]
PHST- 2021/10/01 00:00 [pmc-release]
AID - cells10102614 [pii]
AID - cells-10-02614 [pii]
AID - 10.3390/cells10102614 [doi]
PST - epublish
SO  - Cells. 2021 Oct 1;10(10):2614. doi: 10.3390/cells10102614.