mTOR-driven glycolysis governs induction of innate immune responses by bronchial epithelial cells exposed to the bacterial component flagellin

Ramirez‐Moral, Ivan; Yu, Xiao; Butler, Joe; Weeghel, Michel van; Otto, Natasja A.; Ferreira, Bianca Lima; Maele, Laurye Van; Sirard, Jean‐Claude; Vos, Alex F. de; Jong, Menno D. de; Houtkooper, Riekelt H.; Poll, Tom van der

doi:10.1038/s41385-021-00377-8

Cited by 14 publications

(35 citation statements)

References 43 publications

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“…In the present study, we analyzed the immune modulating properties of a flagellin:antigen fusion protein on epithelial cells. While the effects of flagellin on epithelial cells are well-known [ 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 ] and the interaction of flagellin with epithelial cells has often been described as a key factor for its adjuvant activity [ 52 ], our study is the first to characterize the response of epithelial cells to a flagellin:antigen fusion protein. We could show that, upon stimulation with a flagellin:antigen fusion protein, epithelial cells can modulate pro-inflammatory mDC responses by a both p38 MAPK- and COX2-dependent production of PGE 2 .…”

Section: Discussionmentioning

confidence: 99%

“…Several studies reported flagellin to induce the secretion of chemokines (IL-8, CXCL1, and CCL20) and cytokines (TGF-β1, G-CSF, GM-CSF, and IL-6) from both airway and intestinal epithelial cells [ 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 ]. Mechanistically, flagellin-induced CCL20, TGF-β1, IL-8, and IL-6 production from epithelial cells were shown to be both MAPK- [ 44 , 45 , 50 , 53 ] and at least in part NF κ B-dependent [ 51 , 53 , 54 ].…”

Section: Discussionmentioning

confidence: 99%

“…Mechanistically, flagellin-induced CCL20, TGF-β1, IL-8, and IL-6 production from epithelial cells were shown to be both MAPK- [ 44 , 45 , 50 , 53 ] and at least in part NF κ B-dependent [ 51 , 53 , 54 ]. Moreover, Ramirez-Moral et al found that Pseudomonas aeruginosa flagellin induced a mTOR-dependent activation of glycolysis, paralleled by the secretion of CXCL1, CXCL8, CCL20, and G-CSF in primary human bronchial epithelial cells [ 48 ]. Interestingly, a recent publication investigated the role of flagellin type C (FliC) from Salmonella enterica as a vaccine adjuvant.…”

Section: Discussionmentioning

confidence: 99%

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The Fusion Protein rFlaA:Betv1 Modulates DC Responses by a p38-MAPK and COX2-Dependent Secretion of PGE2 from Epithelial Cells

Lin

Flaczyk

Wolfheimer

et al. 2021

Cells

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Developing new adjuvants/vaccines and better understanding their mode-of-action is an important task. To specifically improve birch pollen allergy treatment, we designed a fusion protein consisting of major birch pollen allergen Betv1 conjugated to the TLR5-ligand flagellin (rFlaA:Betv1). This study investigates the immune-modulatory effects of rFlaA:Betv1 on airway epithelial cells. LA-4 mouse lung epithelial cells were stimulated with rFlaA:Betv1 in the presence/absence of various inhibitors with cytokine- and chemokine secretion quantified by ELISA and activation of intracellular signaling cascades demonstrated by Western blot (WB). Either LA-4 cells or LA-4-derived supernatants were co-cultured with BALB/c bone marrow-derived myeloid dendritic cells (mDCs). Compared to equimolar amounts of flagellin and Betv1 provided as a mixture, rFlaA:Betv1 induced higher secretion of IL-6 and the chemokines CCL2 and CCL20 from LA-4 cells and a pronounced MAPK- and NFκB-activation. Mechanistically, rFlaA:Betv1 was taken up more strongly and the induced cytokine production was inhibited by NFκB-inhibitors, while ERK- and p38-MAPK-inhibitors only suppressed IL-6 and CCL2 secretion. In co-cultures of LA-4 cells with mDCs, rFlaA:Betv1-stimulated LA-4 cells p38-MAPK- and COX2-dependently secreted PGE2, which modulated DC responses by suppressing pro-inflammatory IL-12 and TNF-α secretion. Taken together, these results contribute to our understanding of the mechanisms underlying the strong immune-modulatory effects of flagellin-containing fusion proteins.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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The Fusion Protein rFlaA:Betv1 Modulates DC Responses by a p38-MAPK and COX2-Dependent Secretion of PGE2 from Epithelial Cells

Lin

Flaczyk

Wolfheimer

et al. 2021

Cells

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“…A pathologist resected the healthy tracheobronchial tissue distant from tumorous tissue and assessed the absence of malignant cells via microscopy. HBE cells were isolated according to Fulcher's protocol [12], as described before [10]. Briefly, passage 2 (P2) to P4 cells were used for differentiation in 24-well Transwell inserts (Corning, Corning, NY, USA) treated with human type IV placental collagen in submerged PneumaCult-Ex Plus media (StemCell Technologies, Vancouver, BC, Canada).…”

Section: Hbe Cell Differentiationmentioning

confidence: 99%

“…We recently demonstrated that, besides different leukocyte subsets, primary human bronchial epithelial (HBE) cells also utilize glycolysis to produce immune mediators after stimulation with flagellin [10]. Here, we aimed to investigate the impact of HIF1α stabilization on the metabolism and function of primary HBE cells in response to flagellin.…”

Section: Introductionmentioning

confidence: 99%

HIF-1α Stabilization in Flagellin-Stimulated Human Bronchial Cells Impairs Barrier Function

Ramirez‐Moral

Ferreira

Butler

et al. 2022

Cells

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The respiratory epithelium provides a first line of defense against pathogens. Hypoxia-inducible factor (HIF)1α is a transcription factor which is stabilized in hypoxic conditions through the inhibition of prolyl-hydroxylase (PHD)2, the enzyme that marks HIF1α for degradation. Here, we studied the impact of HIF1α stabilization on the response of primary human bronchial epithelial (HBE) cells to the bacterial component, flagellin. The treatment of flagellin-stimulated HBE cells with the PHD2 inhibitor IOX2 resulted in strongly increased HIF1α expression. IOX2 enhanced the flagellin-induced expression of the genes encoding the enzymes involved in glycolysis, which was associated with the intracellular accumulation of pyruvate. An untargeted pathway analysis of RNA sequencing data demonstrated the strong inhibitory effects of IOX2 toward key innate immune pathways related to cytokine and mitogen-activated kinase signaling cascades in flagellin-stimulated HBE cells. Likewise, the cell–cell junction organization pathway was amongst the top pathways downregulated by IOX2 in flagellin-stimulated HBE cells, which included the genes encoding claudins and cadherins. This IOX2 effect was corroborated by an impaired barrier function, as measured by dextran permeability. These results provide a first insight into the effects associated with HIF1α stabilization in the respiratory epithelium, suggesting that HIF1α impacts properties that are key to maintaining homeostasis upon stimulation with a relevant bacterial agonist.

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Liensinine alleviates LPS-induced acute lung injury by blocking autophagic flux via PI3K/AKT/mTOR signaling pathway

Wang,

Zou,

Diao

et al. 2023

Biomedicine & Pharmacotherapy

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mTOR-driven glycolysis governs induction of innate immune responses by bronchial epithelial cells exposed to the bacterial component flagellin

Cited by 14 publications

References 43 publications

The Fusion Protein rFlaA:Betv1 Modulates DC Responses by a p38-MAPK and COX2-Dependent Secretion of PGE2 from Epithelial Cells

The Fusion Protein rFlaA:Betv1 Modulates DC Responses by a p38-MAPK and COX2-Dependent Secretion of PGE2 from Epithelial Cells

HIF-1α Stabilization in Flagellin-Stimulated Human Bronchial Cells Impairs Barrier Function

Liensinine alleviates LPS-induced acute lung injury by blocking autophagic flux via PI3K/AKT/mTOR signaling pathway

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