Loss of TLR3 and its downstream signaling accelerates acinar cell damage in the acute phase of pancreatitis

Regel, Ivonne; Raulefs, Susanne; Benitz, Simone; Mihaljevic, Charlotte; Rieder, Simon; Leinenkugel, Georg; Steiger, Katja; Schlitter, Anna Melissa; Espósito, Irene; Mayerle, Julia; Kong, Bo; Kleeff, Jörg; Michalski, Christoph

doi:10.1016/j.pan.2018.12.005

Cited by 6 publications

(6 citation statements)

References 26 publications

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“…In AP, loss of TRIF accelerates AP. And the TRIF depletion favors acinar cell necrosis to apoptosis ( 36 ). Thus, TRIF could affect the severity of AP.…”

Section: Discussionmentioning

confidence: 99%

MyD88 deficiency aggravates the severity of acute pancreatitis by promoting MyD88-independent TRIF pathway-mediated necrosis

Yang¹,

Wang²,

Fu³

et al. 2022

Ann Transl Med

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Background: With uncontrolled inflammatory progression, acute pancreatitis (AP) can progress to severe acute pancreatitis (SAP). Inflammation and parenchymal cell death are key pathologic responses of AP.Toll-like receptor 4 (TLR4) plays a pro-inflammatory role in AP. Myeloid differentiation primary response protein 88 (MyD88) is the most essential utilized adaptor of TLR4, but its role in AP remains unclear. We investigated the potential role of MyD88 in the pathogenesis of AP.

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“…In AP, loss of TRIF accelerates AP. And the TRIF depletion favors acinar cell necrosis to apoptosis ( 36 ). Thus, TRIF could affect the severity of AP.…”

Section: Discussionmentioning

confidence: 99%

MyD88 deficiency aggravates the severity of acute pancreatitis by promoting MyD88-independent TRIF pathway-mediated necrosis

Yang¹,

Wang²,

Fu³

et al. 2022

Ann Transl Med

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“…We add a cautionary note that most of the above conclusions were drawn from immunofluorescence observations. Noteworthy, whilst all TLR antibodies used were knockout validated (Ilvesaro et al 2008, Stridh et al 2011, Uthaya Kumar et al 2016, Regel et al 2019, the TLR5 antibody was not. However, previous studies had used this same antibody for detecting TLR5 in various tissues (Ha et al 2008, Uchida et al 2014.…”

Section: Discussionmentioning

confidence: 99%

“…html). The datasets were analysed with Seurat 3 (Stuart et al 2019), including normalisation, variable feature identification and anchored dataset integration Dako (Agilent) A056401 (#10088287) 1:400 TLR-1 (rabbit) (Stridh et al 2011) Novus Biologicals NBP1-77244 (#3639-0503) 1:100 TLR-2 (T2.5) (mouse) (Stridh et al 2011) Novus Biologicals NBP2-31222 (#12023M0812A) 1:100 TLR-3 (mouse) (Regel et al 2019) Novus Biologicals NBP2-24875 (40C1285.6/#AB101606A-06) 1:100 TLR-4 (mouse) (Uthaya Kumar et al 2016) Santa Cruz SC-293072 (25/#E0614) 1:100 TLR-5 (mouse) (Uchida et al 2014) Novus Biologicals NBP2-24787 (#3694-0503) 1:100 TLR-9 (mouse) (Ilvesaro et al 2008) Novus Biologicals NBP2-24729 (26C593.2/#A-6) 1:100 using default parameters, unless otherwise specified. The variable features used for anchoring were identified using the default cut-off of the top 2000 variable genes, as determined by the standardised gene dispersion estimates across all cell types and across the four datasets, plus all TLRs; TLR4 and TLR8 were the only two TLRs identified in top 2000 variable genes.…”

Section: Single-cell Rna Sequencing Analysismentioning

confidence: 99%

“…To test our hypothesis that islet cells other than β-cells express TLRs, we immunostained paraformaldehydefixed, mouse pancreatic sections (lean, non-diabetic heterozygotes of B6.BKS(D)-Leprdb/J line) with insulin and different TLRs, specifically TLR1, 2, 3, 4, 5 and 9, with validated commercially available antibodies (Ilvesaro et al 2008, Stridh et al 2011, Uchida et al 2014, Uthaya Kumar et al 2016, Regel et al 2019. These TLR antibodies tested positive for cells of either the mouse spleen or liver (Supplementary Fig.…”

Section: Tlrs Are Expressed In Mouse Pancreatic Islets But Do Not Co-localise With β-Cellsmentioning

confidence: 99%

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TLR4 signals through islet macrophages to alter cytokine secretion during diabetes

Chittezhath

Wai

Tay

et al. 2020

Journal of Endocrinology

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Toll-like receptors (TLRs), particularly TLR4, may act as immune sensors for metabolic stress signals such as lipids and link tissue metabolic changes to innate immunity. TLR signalling is not only tissue dependent but also cell-type dependent and recent studies suggest that TLRs are not restricted to innate immune cells alone. Pancreatic islets, a hub of metabolic hormones and cytokines, respond to TLR signalling. However, the source of TLR signalling within the islet remain poorly understood. Uncovering the specific cell source and its role in mediating TLR signalling especially within the type-2 diabetes (T2D) islet will yield new targets to tackle islet inflammation, hormone secretion dysregulation and ultimately diabetes. In the present study, we immuno-characterized TLRs linked to pancreatic islets in both healthy and obese diabetic mice. We found that while TLRs1-4 and TLR9 were expressed in mouse islets, these TLRs did not co-localise with insulin-producing β-cells. β-cells from obese diabetic mice were also devoid of these TLRs. While TLR immuno-reactivity in obese mice islets increased, this was driven mostly by increased islet endothelial cell and islet macrophage presence. Analysis of human islet single-cell RNA-seq databases revealed that macrophages were an important source of islet TLRs. However, only TLR4 and TLR8 showed variation and cell-type specificity in their expression patterns. Cell depletion experiments in isolated mouse islets showed that TLR4 signalled through macrophages to alter islet cytokine secretome. Together, these studies suggest that islet macrophages are a dominant source of TLR4-mediated signalling in both healthy and diabetic islets.

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“…TLR3 synthetic ligand poly-ICLC with sorafenib significantly reduces tumor growth, both in vitro and in vivo in hepatocellular carcinoma (18). The mechanism of the antitumorigenic effect of TLR3 is well-established, wherein the TRIF-dependent classical pathway induces apoptosis in cancer cells through the endosomal compartment (49,50).…”

Section: Discussionmentioning

confidence: 99%

Myeloid Differentiation Primary Response 88–Cyclin D1 Signaling in Breast Cancer Cells Regulates Toll-Like Receptor 3-Mediated Cell Proliferation

2020

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Toll-like receptor 3 (TLR3)-mediated apoptotic changes in cancer cells are well-documented, and hence, several synthetic ligands of TLR3 are being used for adjuvant therapy, but there are reports showing a contradictory effect of TLR3 signaling, which include our previous report that had shown cell proliferation following surface localization of TLR 3. However, the underlying mechanism of cell surface localization of TLR3 and subsequent cell proliferation lacks clarity. This study addresses the TLR3 ligand-mediated signaling cascade that regulates a proliferative effect in breast cancer cells (MDA-MB-231 and T47D) challenged with TLR3 ligand in the presence of myeloid differentiation primary response 88 (MyD88) inhibitor. Evidences were obtained using immunoblotting, coimmunoprecipitation, confocal microscopy, immunocytochemistry, ELISA, and flow cytometry. Results had revealed that TLR3 ligand treatment significantly enhanced breast cancer cell proliferation marked by an upregulated expression of cyclinD1, but the same was suppressed by the addition of MyD88 inhibitor. Also, expression of interleukin 1 receptor-associated kinase 1 (IRAK1)-TNF receptor-associated factor 6 (TRAF6)-transforming growth factor beta-activated kinase 1 (TAK1) was altered in the given TLR3-signaling pathway. Inhibition of MyD88 disrupted the downstream adaptor complex and mediated signaling through the TLR3-MyD88-NF-κB (p65)-IL-6-cyclin D1 pathway. TLR3-mediated alternative signaling of the TLR3-MyD88-IRAK1-TRAF6-TAK1-TAB1-NF-κB axis leads to upregulation of IL6 and cyclin D1. This response is hypothesized to be via the MyD88 gateway that culminates in the proliferation of breast cancer cells. Overall, this study provides first comprehensive evidence on the involvement of canonical signaling of TLR3 using MyD88-cyclin D1-mediated breast cancer cell proliferation. The findings elucidated herein will provide valuable insights into understanding the TLR3-mediated adjuvant therapy in cancer.

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Loss of TLR3 and its downstream signaling accelerates acinar cell damage in the acute phase of pancreatitis

Cited by 6 publications

References 26 publications

MyD88 deficiency aggravates the severity of acute pancreatitis by promoting MyD88-independent TRIF pathway-mediated necrosis

MyD88 deficiency aggravates the severity of acute pancreatitis by promoting MyD88-independent TRIF pathway-mediated necrosis

TLR4 signals through islet macrophages to alter cytokine secretion during diabetes

Myeloid Differentiation Primary Response 88–Cyclin D1 Signaling in Breast Cancer Cells Regulates Toll-Like Receptor 3-Mediated Cell Proliferation

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