Functional expression of TLR5 in murine salivary gland epithelial cells

Iwasa, Satoko; Ota, Hirotaka; Nishio, Kensuke; Ohtsu, Mariko; Kusunoki, Masafumi; Gojoubori, Takahiro; Shirakawa, Tetsuo; Asano, Masaharu

doi:10.2334/josnusd.15-0588

Cited by 4 publications

(4 citation statements)

References 25 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%

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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%

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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“…TLR5 expression is decreased in PBMCs from pSS patients as compared to healthy controls [63], although the significance of this finding remains to be determined. It is interesting to speculate that TLR5 activation may promote sialadenitis and autoantibody production in pSS patients, as is suggested by studies in mice ( vide supra ), although this has not been examined in humans to date [44, 64]. Further studies of TLR5 in peripheral blood samples and salivary tissue of pSS patients may reveal an important role for this poorly understood receptor in autoimmunity.…”

Section: Tlrs Are Dysregulated In Human Ssmentioning

confidence: 97%

Current and Emerging Evidence for Toll-Like Receptor Activation in Sjögren’s Syndrome

Kiripolsky

Kramer

2018

Journal of Immunology Research

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While the importance of Toll-like receptor (TLR) signaling is well established in many autoimmune diseases, the role of TLR activation in Sjögren's syndrome (SS) is poorly understood. Studies in mice and humans reveal that TLRs are potent mediators of inflammation in SS. TLRs are expressed and functional in salivary tissue, and TLRs in peripheral blood cells of SS patients are also upregulated and hyperresponsive to ligation. In this review, we will detail observations in mouse models regarding the importance of TLR activation in both local and systemic disease. We will then discuss studies in SS patients that provide evidence of the importance of TLR-mediated signaling in disease. While the ligands that activate TLRs in the context of SS are unknown, emerging data suggest that damage-associated molecular patterns (DAMPs) may be significant drivers of the chronic and unremitting inflammation that is characteristic of SS. We will discuss putative DAMPs that may be of clinical significance in disease. Therapies that target TLR signaling cascades will likely reduce both exocrine-specific and systemic manifestations of SS.

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“…In submandibular glands obtained from NOD mice, Tlr1 , Tlr ‐ 2, Tlr‐4 , and Tlr ‐ 9 mRNA levels at 16 weeks were higher compared with 4‐week‐old control NOD mice (Shimizu et al , ). Likewise, in C57BL/6 mice, it was reported that SGEC responded to flagellin by elevated expression of TLR5 and CXCL1, suggesting that the pattern of TLR expression depends on the mouse strain (Iwasa et al , ). Stimulation of TLR3 with poly I:C was documented to be associated with disease progression in an SS mouse model (Nandula et al , ).…”

Section: Discussionmentioning

confidence: 98%

Flagellar filament structural protein induces Sjögren's syndrome‐like sialadenitis in mice

et al. 2017

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Functional expression of TLR5 in murine salivary gland epithelial cells

Cited by 4 publications

References 25 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

Current and Emerging Evidence for Toll-Like Receptor Activation in Sjögren’s Syndrome

Flagellar filament structural protein induces Sjögren's syndrome‐like sialadenitis in mice

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