ER stress and its regulator X‐box‐binding protein‐1 enhance polyIC‐induced innate immune response in dendritic cells

Hu, Fanlei; Yu, Xiaofei; Wang, Hongxia; Zuo, Daming; Guo, Chunqing; Yi, Huanfa; Tirosh, Boaz; Subjeck, John R.; Qiu, Xiaoyan; Wang, Xiangyang

doi:10.1002/eji.201040831

Cited by 85 publications

(88 citation statements)

References 39 publications

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“…Therefore, the outcome of the pro-or anti-inflammatory effects of XBP1 in β-cells seems to be context dependent and defined by the balance between its anti-apoptotic/ anti-oxidative responses versus its direct pro-inflammatory signaling. This is in agreement with data obtained in other tissues showing that while XBP1 deficiency may stimulate inflammation (Kaser et al 2008), XBP-1 signaling may also directly induce pro-inflammatory responses (Smith et al 2008, Martinon et al 2010, Zeng et al 2010, Hu et al 2011, Ziogas et al 2015.…”

Section: Er Stress-induced Inflammation In Pancreatic β-Cells Er Stresupporting

confidence: 93%

Endoplasmic reticulum stress and the unfolded protein response in pancreatic islet inflammation

Meyerovich

Ortis

Allagnat

et al. 2016

Journal of Molecular Endocrinology

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Insulin-secreting pancreatic β-cells are extremely dependent on their endoplasmic reticulum (ER) to cope with the oscillatory requirement of secreted insulin to maintain normoglycemia. Insulin translation and folding rely greatly on the unfolded protein response (UPR), an array of three main signaling pathways designed to maintain ER homeostasis and limit ER stress. However, prolonged or excessive UPR activation triggers alternative molecular pathways that can lead to β-cell dysfunction and apoptosis. An increasing number of studies suggest a role of these pro-apoptotic UPR pathways in the downfall of β-cells observed in diabetic patients. Particularly, the past few years highlighted a cross talk between the UPR and inflammation in the context of both type 1 (T1D) and type 2 diabetes (T2D). In this article, we describe the recent advances in research regarding the interplay between ER stress, the UPR, and inflammation in the context of β-cell apoptosis leading to diabetes.

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Section: Er Stress-induced Inflammation In Pancreatic β-Cells Er Stresupporting

confidence: 93%

Endoplasmic reticulum stress and the unfolded protein response in pancreatic islet inflammation

Meyerovich

Ortis

Allagnat

et al. 2016

Journal of Molecular Endocrinology

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“…Previous reports have shown that ER stress results in IRF3 activation in mouse embryonic fibroblast and that Xbp1 splicing enhances the IFN-␤ response in immune cells (17,18). In our study, acute administration of CCl 4 led to an early activation of IRF3, a pro-apoptotic BH3-only protein, as seen by the phosphorylation in whole cell liver lysates (Fig.…”

Section: Irf3 Deficiency Attenuates Chronic CCL 4 -Mediated Liversupporting

confidence: 71%

“…However, there are multiple lines of evidence suggesting that IRF3 activation can result from other forms of noninfectious cell damage that involve Xbp1 splicing (17,18,36).…”

Section: Discussionmentioning

confidence: 99%

Endoplasmic Reticulum Stress-induced Hepatocellular Death Pathways Mediate Liver Injury and Fibrosis via Stimulator of Interferon Genes

Iracheta-Vellve

Petrášek

Gyöngyösi

et al. 2016

Journal of Biological Chemistry

124

119

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Edited by Jeffrey PessinFibrosis, driven by inflammation, marks the transition from benign to progressive stages of chronic liver diseases. Although inflammation promotes fibrogenesis, it is not known whether other events, such as hepatocyte death, are required for the development of fibrosis. Interferon regulatory factor 3 (IRF3) regulates hepatocyte apoptosis and production of type I IFNs. In the liver, IRF3 is activated via Toll-like receptor 4 (TLR4) signaling or the endoplasmic reticulum (ER) adapter, stimulator of interferon genes (STING). We hypothesized that IRF3-mediated hepatocyte death is an independent determinant of chemically induced liver fibrogenesis. To test this, we performed acute or chronic CCl 4 administration to WT and IRF3-, Toll/ Interleukin-1R (TIR) domain-containing adapter-inducing interferon-␤ (TRIF)-, TRIF-related adaptor molecule (TRAM)-, and STING-deficient mice. We report that acute CCl 4 administration to WT mice resulted in early ER stress, activation of IRF3, and type I IFNs, followed by hepatocyte apoptosis and liver injury, accompanied by liver fibrosis upon repeated administration of CCl 4 . Deficiency of IRF3 or STING prevented hepatocyte death and fibrosis both in acute or chronic CCl 4 . In contrast, mice deficient in type I IFN receptors or in TLR4 signaling adaptors, TRAM or TRIF, upstream of IRF3, were not protected from hepatocyte death and/or fibrosis, suggesting that the proapoptotic role of IRF3 is independent of TLR signaling in fibrosis. Hepatocyte death is required for liver fibrosis with causal involvement of STING and IRF3. Thus, our results identify that IRF3, by its association with STING in the presence of ER stress, couples hepatocyte apoptosis with liver fibrosis and indicate that innate immune signaling regulates outcomes of liver fibrosis via modulation of hepatocyte death in the liver.

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“…Data from other tissues have already indicated a possible crosstalk between type I IFNs and ER stress: ER stress enhances IFNβ induction in PIC-treated macrophages [39] and potentiates PIC-induced expression of IFNβ and other inflammatory cytokines in dendritic cells [40]. Furthermore, PICinduced overexpression of ISGs triggers ER stress in HeLa cells [41].…”

Section: Discussionmentioning

confidence: 97%

Interferon-α mediates human beta cell HLA class I overexpression, endoplasmic reticulum stress and apoptosis, three hallmarks of early human type 1 diabetes

et al. 2017

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Aims/hypothesis Three hallmarks of the pancreatic islets in early human type 1 diabetes are overexpression of HLA class I, endoplasmic reticulum (ER) stress and beta cell apoptosis. The mediators of these phenomena remain to be defined. The type I interferon IFNα is expressed in human islets from type 1 diabetes patients and mediates HLA class I overexpression. We presently evaluated the mechanisms involved in IFNα-induced HLA class I expression in human beta cells and determined whether this cytokine contributes to ER stress and apoptosis. Methods IFNα-induced inflammation, ER stress and apoptosis were evaluated by RT-PCR, western blot, immunofluorescence and nuclear dyes, and proteins involved in type I interferon signalling were inhibited by small interfering RNAs. All experiments were performed in human islets or human EndoC-βH1 cells.Results IFNα upregulates HLA class I, inflammation and ER stress markers in human beta cells via activation of the candidate gene TYK2, and the transcription factors signal transducer and activator of transcription 2 and IFN regulatory factor 9. Furthermore, it acts synergistically with IL-1β to induce beta cell apoptosis. Conclusions/interpretation The innate immune effects induced by IFNα may induce and amplify the adaptive immune response against human beta cells, indicating that IFNα has a central role in the early phases of diabetes.

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ER stress and its regulator X‐box‐binding protein‐1 enhance polyIC‐induced innate immune response in dendritic cells

Cited by 85 publications

References 39 publications

Endoplasmic reticulum stress and the unfolded protein response in pancreatic islet inflammation

Endoplasmic reticulum stress and the unfolded protein response in pancreatic islet inflammation

Endoplasmic Reticulum Stress-induced Hepatocellular Death Pathways Mediate Liver Injury and Fibrosis via Stimulator of Interferon Genes

Interferon-α mediates human beta cell HLA class I overexpression, endoplasmic reticulum stress and apoptosis, three hallmarks of early human type 1 diabetes

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