scholarly journals Tumor PD-L1 selectively suppresses type I interferon in myeloid cells to suppress CTL recruitment to promote lung metastasis

2021 ◽  
Author(s):  
John D Klement ◽  
Priscilla S Redd ◽  
Chunwan Lu ◽  
Alyssa D Merting ◽  
Dakota B Poschel ◽  
...  
Keyword(s):  
Tumor Cells ◽  
Lung Metastasis ◽  
Immune Suppression ◽  
Type I Interferon ◽  
Lung Metastases ◽  
Myeloid Cells ◽  
Type I ◽  
Intermediate Cell ◽  
Dependent Manner ◽  
Human Patient

The mechanism underlying tumor cell PD-L1 (tPD-L1) induction of immune suppression through T cell PD-1 is well-known, but the mechanism underlying tPD-L1 induction of immune suppression via an intermediate cell is incompletely understood. We report here that tPD-L1 does not suppress cytotoxic T lymphocyte (CTL) activation and lytic function when only tumor cells and CTLs are present. Strikingly, knocking out PD-L1 in tumor cells has no effect on primary tumor growth, but significantly decreases lung metastasis in a CTL-dependent manner. Depletion of myeloid cells impaired tPD-L1 promotion of lung metastasis. Single-cell RNA sequencing revealed that tPD-L1 engages myeloid PD-1 (mPD-1) to antagonize type I interferon (IFN-I) and STAT1 signaling to repress Cxcl9 and Cxcl10 expression to impair CTL recruitment to lung metastases. Human patient response to PD-1 blockade immunotherapy correlates with IFN-I response in myeloid cells. Our data determines that the tPD-L1/mPD-1/IFN-I/STAT1/Cxcl9/10 axis controls CTL tumor infiltration in lung metastasis.

scholarly journals Protection against RNA-induced liver damage by myeloid cells requires type I interferon and IL-1 receptor antagonist in mice

Hepatology ◽  
2014 ◽  
Vol 59 (4) ◽  
pp. 1555-1563 ◽  
Author(s):  
Elea Conrad ◽  
Theresa K. Resch ◽  
Patricia Gogesch ◽  
Ulrich Kalinke ◽  
Ingo Bechmann ◽  
...  
Keyword(s):  
Receptor Antagonist ◽  
Liver Damage ◽  
Type I Interferon ◽  
Myeloid Cells ◽  
Type I

scholarly journals 435 Autocrine IFN-k maintains baseline type I interferon responses in keratinocytes in a Tyk2 dependent manner

2016 ◽  
Vol 136 (9) ◽  
pp. S234
Author(s):  
M. Sarkar ◽  
L.C. Tsoi ◽  
X. Xing ◽  
L. Yun ◽  
P. Harms ◽  
...  
Keyword(s):  
Type I Interferon ◽  
Type I ◽  
Dependent Manner ◽  
Interferon Responses

Abstract MP153: TET2 Regulates Type I Interferon Signaling in the Hematopoietic Response to Myocardial Infarction

2020 ◽  
Vol 127 (Suppl_1) ◽  
Author(s):  
Claire Zhang ◽  
David M Calcagno ◽  
Avinash Toomu ◽  
Kenneth M Huang ◽  
Zhenxing Fu ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Heart Failure ◽  
Bone Marrow ◽  
Cardiac Remodeling ◽  
Type I Interferon ◽  
Myeloid Cells ◽  
Type I ◽  
Type I Ifn ◽  
Clonal Hematopoiesis ◽  
Hematopoietic Response

Myocardial infarction (MI) elicits a rapid and vigorous reaction from the bone marrow hematopoietic compartment, inducing a massive efflux of myeloid first responders into the bloodstream. These cells traffic to the infarct, where they mediate cardiac remodeling and repair through inflammatory signaling and recruitment of additional immune cells to the injured myocardium. A hyperinflammatory myeloid compartment, as is produced by mutations in epigenetic regulator TET2 associated with clonal hematopoiesis, can thus drive adverse cardiac remodeling after MI and accelerate progression to heart failure. Whether loss of TET2 alters the transcriptional landscape of MI-induced myelopoiesis remains to be investigated in an unbiased fashion. Here, we performed single-cell RNA sequencing of >16,000 bone marrow myeloid cells isolated from wild-type and Tet2 -/- mice after MI to characterize the emergency hematopoietic response in the presence and absence of TET2. Our data capture distinct transitional states of myeloid lineage commitment and maturation, originating from myeloid progenitors and progressing along divergent granulocytic and monocytic differentiation trajectories. Additionally, we delineate a subpopulation of interferon (IFN)-activated myeloid progenitors, monocytes, and neutrophils characterized by the concerted upregulation of various Type I IFN-stimulated genes, and find the fraction of IFN-activated cells, as well as the degree of activation, to be markedly higher in Tet2 -/- mice. We have previously described activation of this pathway after MI in mice, and demonstrated cardioprotective effects of its genetic or pharmacological inhibition. Our findings reveal heightened activation of the antiviral Type I interferon response among bone marrow myeloid cells of Tet2 -/- mice during MI-induced emergency hematopoiesis. This highlights IFN signaling as a potential candidate driver of cardiovascular pathologies (including atherosclerosis, myocardial infarction, and heart failure) associated with TET2-mediated clonal hematopoiesis. Further studies are necessary to investigate whether Tet2 -/- mice exhibit enhanced response to blockade of Type I IFN signaling after MI, and to determine whether myeloid cells of TET2 -mutant humans are similarly activated.

scholarly journals UBQLN2 Promotes the Production of Type I Interferon via the TBK1-IRF3 Pathway

Cells ◽  
2020 ◽  
Vol 9 (5) ◽  
pp. 1205
Author(s):  
Tianhong Chen ◽  
Wenjuan Zhang ◽  
Bo Huang ◽  
Xuan Chen ◽  
Cao Huang
Keyword(s):  
Inflammatory Cytokines ◽  
Type I Interferon ◽  
Complete Loss ◽  
Functional Assay ◽  
Type I ◽  
Dependent Manner ◽  
Frontotemporal Degeneration ◽  
Dose Dependent ◽  
Lateral Sclerosis ◽  
Pro Inflammatory Cytokines

Mutations of Ubiquilin 2 (UBQLN2) or TANK-binding kinase 1 (TBK1) are associated with amyotrophic lateral sclerosis and frontotemporal degeneration (ALS/FTD). However, the mechanisms whereby UBQLN2 or TBK1 mutations lead to ALS and FTD remain unclear. Here, we explored the effect of UBQLN2 on TBK1 in HEK-293T cells or in CRISPR–Cas9-mediated IRF3 and IRF7 knockout (KO) cells. We found an interaction between TBK1 and UBQLN2, which was affected by ALS/FTD-linked mutations in TBK1 or UBQLN2. Co-expression of UBQLN2 with TBK1 elevated the protein level of TBK1 as well as the phosphorylation of TBK1 and IRF3 in a UBQLN2 dose-dependent manner, and this phosphorylation was reduced by mutant UBQLN2. In addition, the cellular production of IFN1 and related pro-inflammatory cytokines was substantially elevated when UBQLN2 and TBK1 were co-expressed, which was also decreased by mutant UBQLN2. Functional assay revealed that mutant UBQLN2 significantly reduced the binding affinity of TBK1 for its partners, including IRF3, (SQSTM1)/p62 and optineurin (OPTN). Moreover, complete loss of IRF3 abolished the induction of IFN1 and related pro-inflammatory cytokines enhanced by UBQLN2 in HEK-293T cells, whereas no significant change in IRF7 knockout cells was observed. Thus, our findings suggest that UBQLN2 promotes IRF3 phosphorylation via TBK1, leading to enhanced IFN1 induction, and also imply that the dysregulated TBK1-IRF3 pathway may play a role in UBQLN2-related neurodegeneration.

scholarly journals Cancer Vaccine Immunotherapy with RNA-Loaded Liposomes

2018 ◽  
Vol 19 (10) ◽  
pp. 2890 ◽  
Author(s):  
Elias Sayour ◽  
Hector Mendez-Gomez ◽  
Duane Mitchell
Keyword(s):  
Immune Suppression ◽  
Cancer Vaccines ◽  
Type I Interferon ◽  
Type I ◽  
Toll Like Receptor ◽  
Adaptive Responses ◽  
Receptor Stimulation ◽  
Delivery Vehicles ◽  
Therapeutic Settings

Cancer vaccines may be harnessed to incite immunity against poorly immunogenic tumors, however they have failed in therapeutic settings. Poor antigenicity coupled with systemic and intratumoral immune suppression have been significant drawbacks. RNA encoding for tumor associated or specific epitopes can serve as a more immunogenic and expeditious trigger of anti-tumor immunity. RNA stimulates innate immunity through toll like receptor stimulation producing type I interferon, and it mediates potent adaptive responses. Since RNA is inherently unstable, delivery systems have been developed to protect and deliver it to intended targets in vivo. In this review, we discuss liposomes as RNA delivery vehicles and their role as cancer vaccines.

scholarly journals Rabies Virus Infection Induces Type I Interferon Production in an IPS-1 Dependent Manner While Dendritic Cell Activation Relies on IFNAR Signaling

2010 ◽  
Vol 6 (7) ◽  
pp. e1001016 ◽  
Author(s):  
Elizabeth J. Faul ◽  
Celestine N. Wanjalla ◽  
Mehul S. Suthar ◽  
Michael Gale ◽  
Christoph Wirblich ◽  
...  
Keyword(s):  
Dendritic Cell ◽  
Virus Infection ◽  
Rabies Virus ◽  
Cell Activation ◽  
Type I Interferon ◽  
Type I ◽  
Dependent Manner ◽  
Interferon Production ◽  
Dendritic Cell Activation ◽  
Rabies Virus Infection

scholarly journals Double-stranded RNA analog and type I interferon regulate expression of Trem paired receptors in murine myeloid cells

2016 ◽  
Vol 17 (1) ◽  
Author(s):  
Jun Kasamatsu ◽  
Mengyao Deng ◽  
Masahiro Azuma ◽  
Kenji Funami ◽  
Hiroaki Shime ◽  
...  
Keyword(s):  
Type I Interferon ◽  
Myeloid Cells ◽  
Type I ◽  
Double Stranded Rna

scholarly journals Molecular Insight Into the IRE1α-Mediated Type I Interferon Response Induced by Proteasome Impairment in Myeloid Cells of the Brain

2019 ◽  
Vol 10 ◽  
Author(s):  
Maja Studencka-Turski ◽  
Gonca Çetin ◽  
Heike Junker ◽  
Frédéric Ebstein ◽  
Elke Krüger
Keyword(s):  
Type I Interferon ◽  
Myeloid Cells ◽  
Interferon Response ◽  
Type I ◽  
The Brain ◽  
Insight Into

scholarly journals PP2A Facilitates Porcine Reproductive and Respiratory Syndrome Virus Replication by Deactivating irf3 and Limiting Type I Interferon Production

Viruses ◽  
2019 ◽  
Vol 11 (10) ◽  
pp. 948 ◽  
Author(s):  
Jiayu Xu ◽  
Lu Zhang ◽  
Yunfei Xu ◽  
He Zhang ◽  
Junxin Gao ◽  
...  
Keyword(s):  
Virus Infection ◽  
Therapeutic Target ◽  
Type I Interferon ◽  
Negative Regulator ◽  
Host Cells ◽  
Respiratory Syndrome Virus ◽  
Target Cells ◽  
Type I ◽  
Dependent Manner ◽  
Pp2a Activity

Protein phosphatase 2A (PP2A), a major serine/threonine phosphatase in mammalian cells, is known to regulate the kinase-driven intracellular signaling pathways. Emerging evidences have shown that the PP2A phosphatase functions as a bona-fide therapeutic target for anticancer therapy, but it is unclear whether PP2A affects a porcine reproductive and respiratory syndrome virus infection. In the present study, we demonstrated for the first time that inhibition of PP2A activity by either inhibitor or small interfering RNA duplexes in target cells significantly reduced their susceptibility to porcine reproductive and respiratory syndrome virus (PRRSV) infection. Further analysis revealed that inhibition of PP2A function resulted in augmented production of type I interferon (IFN). The mechanism is that inhibition of PP2A activity enhances the levels of phosphorylated interferon regulatory factor 3, which activates the transcription of IFN-stimulated genes. Moreover, inhibition of PP2A activity mainly blocked PRRSV replication in the early stage of viral life cycle, after virus entry but before virus release. Using type I IFN receptor 2 specific siRNA in combination with PP2A inhibitor, we confirmed that the effect of PP2A on viral replication within target cells was an interferon-dependent manner. Taken together, these findings demonstrate that PP2A serves as a negative regulator of host cells antiviral responses and provides a novel therapeutic target for virus infection.

scholarly journals Milk-derived exosomes (MDEs) have a different biological effect on normal fetal colon epithelial cells compared to colon tumor cells in a miRNA-dependent manner

2019 ◽  
Vol 17 (1) ◽  
Author(s):  
Shimon Reif ◽  
Yaffa Elbaum Shiff ◽  
Regina Golan-Gerstl
Keyword(s):  
Epithelial Cells ◽  
Protein Expression ◽  
Human Milk ◽  
Tumor Cells ◽  
Expression Profiles ◽  
Biological Effects ◽  
Biologically Active ◽  
Type I ◽  
Dependent Manner ◽  
Mesenchymal Transformation

Abstract Background Breastfeeding is the ideal source of infant nutrition. Human milk consists not only of nutrients but also biologically active components. Among these latter compounds, exosomes contain proteins, lipids, mRNAs and miRNAs. Methods To elucidate the biological effects of milk-derived exosomes (MDEs) on normal colonic epithelial cells compared to colonic tumor cells, we incubated cells with MDEs. MDEs were able to enter into normal and tumor cells and change their miRNA expression profiles. Proliferation, cell morphology and protein expression were analyzed in these cells. Results Human milk-derived exosomes induced proliferation- and epithelial mesenchymal transformation-related changes, such as collagen type I and twist expression, in normal but not in tumor cells. PTEN, a target of miRNA-148a, was downregulated in normal but not in tumor cells following incubation with MDEs. Moreover, miRNA-148a-3p knockdown cells were used to demonstrate the importance of miRNA in the effect of exosomes on cell proliferation and protein expression. MDEs inhibited proliferation and DNMT1 expression in cells with knockdown of miRNA-148a. Conclusions In conclusion, the positive effect of exosomes on normal cells without affecting tumor cells may presents an aspect of their safety when considering it use as a nutritional supplement to infant formula.

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