Inducible, Dose-Adjustable and Time-Restricted Reconstitution of Stat1 Deficiency In Vivo

Leitner, Nicole R.; Lassnig, Caroline; Rom, Rita; Heider, Susanne; Bagó-Horváth, Zsuzsanna; Eferl, Robert; Müller, Simone; Kolbe, Thomas; Kenner, Lukas; Rülicke, Thomas; Strobl, Birgit; Müller, Mathias

doi:10.1371/journal.pone.0086608

Cited by 10 publications

(18 citation statements)

References 75 publications

(92 reference statements)

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“…The STAT1 signaling is essential to all three types of IFN pathways and therefore plays an important role in immunosurveillance ( Tymoszuk et al , 2014 ). Specifically, IFN-induced STAT1 activation leads to its binding either to the interferon response elements or Gamma-activated sites, further activating the interferon-induced genes ( Leitner et al , 2014 ). Studies in mice with defective STAT1 activation have shown increased tumour incidence attributed to its tumour-suppressive role in breast tumourigenesis ( Levy and Gilliland, 2000 ; Koromilas and Sexl, 2013 ).…”

Section: Discussionmentioning

confidence: 99%

A distinct pre-existing inflammatory tumour microenvironment is associated with chemotherapy resistance in high-grade serous epithelial ovarian cancer

Koti

Clément

et al. 2015

Br J Cancer

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Background:Chemotherapy resistance is a major determinant of poor overall survival rates in high-grade serous ovarian cancer (HGSC). We have previously shown that gene expression alterations affecting the NF-κB pathway characterise chemotherapy resistance in HGSC, suggesting that the regulation of an immune response may be associated with this phenotype.Methods:Given that intrinsic drug resistance pre-exists and is governed by both tumour and host factors, the current study was performed to examine the cross-talk between tumour inflammatory microenvironment and cancer cells, and their roles in mediating differential chemotherapy response in HGSC patients. Expression profiling of a panel of 184 inflammation-related genes was performed in 15 chemoresistant and 19 chemosensitive HGSC tumours using the NanoString nCounter platform.Results:A total of 11 significantly differentially expressed genes were found to distinguish the two groups. As STAT1 was the most significantly differentially expressed gene (P=0.003), we validated the expression of STAT1 protein by immunohistochemistry using an independent cohort of 183 (52 resistant and 131 sensitive) HGSC cases on a primary tumour tissue microarray. Relative expression levels were subjected to Kaplan–Meier survival analysis and Cox proportional hazard regression models.Conclusions:This study confirms that higher STAT1 expression is significantly associated with increased progression-free survival and that this protein together with other mediators of tumour–host microenvironment can be applied as a novel response predictive biomarker in HGSC. Furthermore, an overall underactive immune microenvironment suggests that the pre-existing state of the tumour immune microenvironment could determine response to chemotherapy in HGSC.

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Section: Discussionmentioning

confidence: 99%

A distinct pre-existing inflammatory tumour microenvironment is associated with chemotherapy resistance in high-grade serous epithelial ovarian cancer

Koti

Clément

et al. 2015

Br J Cancer

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“…To confirm the role of STAT1 that was predicted by our model, we tested cytokine gene expression in wild-type and STAT1 knockout BMDMs derived from STAT1-inducible ( Stat1 ind ) mice without doxycycline treatment (43). We found that the amounts of Il6 and Il12b mRNAs were decreased in the STAT1 knockout cells compared to those in the wild-type cells when they were treated under the I 8 R and I 24 R conditions (Fig.…”

Section: Resultsmentioning

confidence: 93%

“…To gather experimental support for this biphasic response, we tested cytokine mRNA production in response to various amounts of STAT1 in experiments with cells from Stat1 ind mice (43). We first demonstrated the incremental induction of STAT1 abundance in BMDMs derived from Stat1 ind mice and pretreated with doxycycline (0, 0.03125, 0.0625, 0.125, 0.25, and 0.5 μg/ml) (fig.…”

Section: Resultsmentioning

confidence: 99%

Innate immune memory and homeostasis may be conferred through crosstalk between the TLR3 and TLR7 pathways

Liu

Yang

et al. 2016

Sci. Signal.

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Toll-like receptors (TLRs) recognize pathogen-associated molecular patterns (PAMPs) and stimulate the innate immune response through the production of cytokines. The innate immune response depends on the timing of encountering PAMPs, suggesting a short-term “memory.” In particular, activation of TLR3 appears to prime macrophages for the subsequent activation of TLR7, which leads to synergistically increased production of cytokines. By developing a calibrated mathematical model for the kinetics of TLR3 and TLR7 pathway crosstalk and providing experimental validation, we demonstrated the involvement of the Janus-activated kinase (JAK)–signal transducer and activator of transcription (STAT) pathway in controlling the synergistic production of cytokines. Signaling through this pathway played a dual role: It mediated the synergistic production of cytokines, thus boosting the immune response, and it also maintained homeostasis to avoid an excessive inflammatory response. Thus, we propose that the JAK-STAT pathway provides a cytokine rheostat mechanism, which enables macrophages to fine-tune their responses to multiple, temporally separated infection events involving the TLR3 and TLR7 pathways.

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“…The type III IFNs are involved in multiple downstream signaling cascades that could affect the abundance of nasal flora through the action of antimicrobial peptides, cytokines that alter barrier function and immune cells recruited across the mucosal surface. The effects of type III IFNs are mediated by JAK/STAT signaling, initiated by phosphorylation of STAT1 ( 28 , 29 ). The relative induction of STAT1 and STAT3 phosphorylation in WT and Il28r −/− mutant mice, exposed to influenza virus or phosphate-buffered saline (PBS), were compared, and Ifnar −/− mutant mice were included as a control for the type I IFNs ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Lambda Interferon Restructures the Nasal Microbiome and Increases Susceptibility to Staphylococcus aureus Superinfection

Planet

Parker

Cohen

et al. 2016

mBio

103

101

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Much of the morbidity and mortality associated with influenza virus respiratory infection is due to bacterial coinfection with pathogens that colonize the upper respiratory tract such as methicillin-resistant Staphylococcus aureus (MRSA) and Streptococcus pneumoniae. A major component of the immune response to influenza virus is the production of type I and III interferons. Here we show that the immune response to infection with influenza virus causes an increase and restructuring of the upper respiratory microbiota in wild-type (WT) mice but not in Il28r−/− mutant mice lacking the receptor for type III interferon. Mice lacking the IL-28 receptor fail to induce STAT1 phosphorylation and expression of its regulator, SOCS1. Il28r−/− mutant mice have increased expression of interleukin-22 (IL-22), as well as Ngal and RegIIIγ, in the nasal cavity, the source of organisms that would be aspirated to cause pneumonia. Proteomic analysis reveals changes in several cytoskeletal proteins that contribute to barrier function in the nasal epithelium that may contribute to the effects of IL-28 signaling on the microbiota. The importance of the effects of IL-28 signaling in the pathogenesis of MRSA pneumonia after influenza virus infection was confirmed by showing that WT mice nasally colonized before or after influenza virus infection had significantly higher levels of infection in the upper airways, as well as significantly greater susceptibility to MRSA pneumonia than Il28r−/− mutant mice did. Our results suggest that activation of the type III interferon in response to influenza virus infection has a major effect in expanding the upper airway microbiome and increasing susceptibility to lower respiratory tract infection.

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Inducible, Dose-Adjustable and Time-Restricted Reconstitution of Stat1 Deficiency In Vivo

Cited by 10 publications

References 75 publications

A distinct pre-existing inflammatory tumour microenvironment is associated with chemotherapy resistance in high-grade serous epithelial ovarian cancer

A distinct pre-existing inflammatory tumour microenvironment is associated with chemotherapy resistance in high-grade serous epithelial ovarian cancer

Innate immune memory and homeostasis may be conferred through crosstalk between the TLR3 and TLR7 pathways

Lambda Interferon Restructures the Nasal Microbiome and Increases Susceptibility to Staphylococcus aureus Superinfection

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