scholarly journals Stat2 loss disrupts damage signalling and is protective in acute pancreatitis

2019 ◽  
Author(s):  
Helen Heath ◽  
Gary Britton ◽  
Hiromi Kudo ◽  
George Renney ◽  
Malcolm Ward ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Pancreatitis ◽  
Type I Interferon ◽  
Pancreatic Tissue ◽  
Sterile Inflammation ◽  
Mitogen Activated Protein Kinase ◽  
Type I ◽  
Label Free ◽  
Bone Marrow Chimera ◽  
Interferon Signalling

ABSTRACTSeverity of sterile inflammation, as seen in acute pancreatitis, is determined by damage-sensing receptors, signalling cascades and cytokine production. Stat2 is a type I interferon signalling mediator that also has interferon-independent roles in murine lipopolysaccharide-induced NF-κB-mediated sepsis. However its role in sterile inflammation is unknown. We hypothesised that Stat2 determines severity of non-infective inflammation in the pancreas.Wild type (WT) and Stat2−/− mice were injected intraperitoneally with cerulein or L-arginine. Specific cytokine-blocking antibodies were used in some experiments. Pancreata and blood were harvested 1h and 24h after the final dose of cerulein and up to 96h post L-arginine. Whole-tissue phosphoproteomic changes were assessed using label-free mass spectrometry. Tissue-specific Stat2 effects were studied in WT/Stat2−/− bone-marrow chimera and using Cre-lox recombination to delete Stat2 in pancreatic and duodenal homeobox 1(Pdx1)-expressing cells.Stat2−/− mice were protected from cerulein- and L-arginine-induced pancreatitis. Protection was independent of type I interferon signalling. Stat2−/− mice had lower cytokine levels including TNFα and IL-10 and reduced NF-kB nuclear localisation in pancreatic tissue compared to WT. Inhibition of TNFα improved (inhibition of IL-10 worsened) cerulein-induced pancreatitis in WT but not Stat2−/− mice. Phosphoproteomics showed down-regulation of mitogen-activated protein kinase (MAPK) mediators but accumulation of Ser412-phosphorylated Tak1. Stat2 deletion in Pdx1-expressing acinar cells (Stat2flox/Pdx1-cre) reduced pancreatic TNFα expression, but not histological injury or serum amylase. WT/Stat2−/− bone-marrow chimera were protected from pancreatitis irrespective of host or recipient genotype.Stat2 loss results in disrupted signalling in pancreatitis, upstream of NF-κB in non-acinar and/or bone marrow derived cells.

scholarly journals Adipose type I interferon signalling protects against metabolic dysfunction

2017 ◽  
Vol 66 (1) ◽  
pp. S609
Author(s):  
T. Adolph ◽  
V. Wieser ◽  
C. Grander ◽  
F. Grabherr ◽  
B. Enrich ◽  
...  
Keyword(s):  
Type I Interferon ◽  
Type I ◽  
Metabolic Dysfunction ◽  
Interferon Signalling

scholarly journals Type I interferon responses to ischemic injury begin in the bone marrow of mice and humans and depend on Tet2, Nrf2, and Irf3

2019 ◽  
Author(s):  
David M. Calcagno ◽  
Richard P. Ng ◽  
Avinash Toomu ◽  
Claire Zhang ◽  
Kenneth Huang ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Type I Interferon ◽  
Tissue Injury ◽  
Type I ◽  
Blood Neutrophils ◽  
Clinical Biomarker ◽  
Acute Mi ◽  
Molecular Patterns ◽  
Interferon Responses ◽  
Myeloid Progenitors

AbstractSterile tissue injury locally activates innate immune responses via interactions with damage associated molecular patterns (DAMPs). Here, by analyzing ∼120K single cell transcriptomes after myocardial infarction (MI) in mice and humans, we show neutrophil and monocyte subsets induce type I interferon (IFN) stimulated genes (ISGs) in myeloid progenitors of the bone marrow, far from the site of injury. In patients with acute MI, peripheral blood neutrophils and monocytes express ISGs at levels far beyond healthy individuals and comparable to patients with lupus. In the bone marrow of Tet2-/- mice, ISGs are spontaneously induced in myeloid progenitors and their progeny. In the heart, IFN responses are negatively regulated by Ccr2- resident macrophages in a Nrf2-dependent fashion. Our results show post-MI IFN signaling begins in the bone marrow, implicate multiple transcription factors in its regulation (Tet2, Irf3, Nrf2), and provide a clinical biomarker (ISG score) for studying post-MI IFN signaling in patients.

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.

AXL promotes Zika virus infection in astrocytes by antagonizing type I interferon signalling

2018 ◽  
Vol 3 (3) ◽  
pp. 302-309 ◽  
Author(s):  
Jian Chen ◽  
Yi-feng Yang ◽  
Yu Yang ◽  
Peng Zou ◽  
Jun Chen ◽  
...  
Keyword(s):  
Virus Infection ◽  
Zika Virus ◽  
Type I Interferon ◽  
Type I ◽  
Zika Virus Infection ◽  
Interferon Signalling

scholarly journals Sustained Inflammatory Signalling through Stat1/Stat2/IRF9 Is Associated with Amoeboid Phenotype of Melanoma Cells

Cancers ◽  
2020 ◽  
Vol 12 (9) ◽  
pp. 2450
Author(s):  
Aneta Gandalovičová ◽  
Anna-Marie Šůchová ◽  
Vladimír Čermák ◽  
Ladislav Merta ◽  
Daniel Rösel ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Type I Interferon ◽  
Tumour Progression ◽  
Tumour Microenvironment ◽  
Melanoma Cells ◽  
Interferon Response ◽  
Type I ◽  
Expression Of Genes ◽  
Interferon Signalling ◽  
Inflammatory Signalling

The invasive behaviour of cancer cells underlies metastatic dissemination; however, due to the large plasticity of invasion modes, it is challenging to target. It is now widely accepted that various secreted cytokines modulate the tumour microenvironment and pro-inflammatory signalling can promote tumour progression. Here, we report that cells after mesenchymal–amoeboid transition show the increased expression of genes associated with the type I interferon response. Moreover, the sustained activation of type I interferon signalling in response to IFNβ mediated by the Stat1/Stat2/IRF9 complex enhances the round amoeboid phenotype in melanoma cells, whereas its downregulation by various approaches promotes the mesenchymal invasive phenotype. Overall, we demonstrate that interferon signalling is associated with the amoeboid phenotype of cancer cells and suggest a novel role of IFNβ in promoting cancer invasion plasticity, aside from its known role as a tumour suppressor.

Isolation of a Common Natural Type-I Interferon Producing Cell and Dendritic Cell Progenitor Population in Mouse Bone Marrow.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1653-1653
Author(s):  
Nobuyuki Onai ◽  
Aya Onai ◽  
Markus G. Manz
Keyword(s):  
Bone Marrow ◽  
Steady State ◽  
Type I Interferon ◽  
Receptor Expression ◽  
Mouse Bone Marrow ◽  
Type I ◽  
Differentiation Potential ◽  
Hematopoietic Stem ◽  
Gm Csf

Abstract Most type-I interferon producing cells (IPCs) and dendritic cells (DCs) are non-dividing cells with a short in vivo half-live of several days, and thus need to be continuously replaced. A common differentiation pathway for IPCs and DCs, and accordingly, the existence of common IPC and DC progenitors remains controversial. Flt3-ligand (Flt3L) is a non-redundant cytokine for in vivo IPC and DC development: IPC and DC differentiation potential is confined to Flt3+-hematopoietic progenitors; Flt3L KO mice show massively reduced IPCs and DCs. In contrast to Flt3, the “myeloid” cytokines GM-CSF and M-CSF seem to be less relevant in steady-state IPC and DC differentiation, however, they might be critically important in inflammatory conditions. To identify a candidate common IPC and DC progenitor population, we evaluated Flt3 and “myeloid” cytokine receptor expression in mouse bone marrow. We found that c-kitintlin− cells contained a Flt3+M-CSFR+ fraction that in Flt3L supplemented cultures gave rise to about 95% pure CD11c+MHC class II+ cells, consisting of both CD11c+B220+ IPCs and CD11c+B220− DCs, at a efficiency comparable to that of hematopoietic stem cells. In the presence of GM-CSF, Flt3+M-CSFR+c-kitintlin− cells gave rise to CD11c+CD11b+ DCs but not CD11c−CD11b+ macrophages/monocytes. Furthermore, Flt3+M-CSFR+c-kitintlin− cells possessed very poor, if any activity in myeloid colony forming assays, and lacked pre-B cell colony forming activity. In both, lethally and sub-lethally irradiated mice, transferred Flt3+M-CSFR+c-kitintlin− cells differentiated into CD11c+B220+ IPCs, CD11c+CD8α+, and CD11c+CD8α− conventional DC subsets, while no other hematopoietic cells were detectable. In vivo reconstitution and CFSE-labeling experiments showed that Flt3+M-CSFR+c-kitintlin− cells extensively proliferate in the lethally irradiated mice, reaching peak progeny levels of IPC and DC at day 10 after transplantation, indicating high proliferative, but limited self-renewal capacity of these cells. Quantitative RT-PCR analysis revealed high expression of DC and IPC-development affiliated genes (such as PU.1, STAT3, GM-CSFR, and CX3CR1), but no lymphoid- and erythroid-development affiliated gene transcription. These data suggest the existence of common developmental intermediates for both IPCs and DCs in mouse bone marrow, and thus might provide new insights into the regulation of IPC and DC differentiation in steady-state and inflammation.

scholarly journals Helicase Domain of West Nile Virus NS3 Protein Plays a Role in Inhibition of Type I Interferon Signalling

Viruses ◽  
2017 ◽  
Vol 9 (11) ◽  
pp. 326 ◽  
Author(s):  
Yin Setoh ◽  
Parthiban Periasamy ◽  
Nias Peng ◽  
Alberto Amarilla ◽  
Andrii Slonchak ◽  
...  
Keyword(s):  
West Nile Virus ◽  
Type I Interferon ◽  
Helicase Domain ◽  
Type I ◽  
West Nile ◽  
Ns3 Protein ◽  
Interferon Signalling

Type I interferon signalling is not required for the induction of endotoxin tolerance

Cytokine ◽  
2017 ◽  
Vol 95 ◽  
pp. 7-11 ◽  
Author(s):  
Yalda Karimi ◽  
Sophie M. Poznanski ◽  
Fatemeh Vahedi ◽  
Branson Chen ◽  
Marianne V. Chew ◽  
...  
Keyword(s):  
Type I Interferon ◽  
Endotoxin Tolerance ◽  
Type I ◽  
Interferon Signalling

scholarly journals The X proteins of bornaviruses interfere with type I interferon signalling

2013 ◽  
Vol 94 (2) ◽  
pp. 263-269 ◽  
Author(s):  
Jonas Johansson Wensman ◽  
Muhammad Munir ◽  
Srinivas Thaduri ◽  
Katarina Hörnaeus ◽  
Muhammad Rizwan ◽  
...  
Keyword(s):  
Type I Interferon ◽  
Rna Virus ◽  
Luciferase Reporter ◽  
Type I ◽  
Type I Ifn ◽  
X Protein ◽  
Wide Range ◽  
Reporter Assays ◽  
Interferon Signalling

Borna disease virus (BDV) is a neurotropic, negative-stranded RNA virus causing persistent infection and progressive neurological disorders in a wide range of warm-blooded animals. The role of the small non-structural X protein in viral pathogenesis is not completely understood. Here we investigated whether the X protein of BDV and avian bornavirus (ABV) interferes with the type I interferon (IFN) system, similar to other non-structural proteins of negative-stranded RNA viruses. In luciferase reporter assays, we found that the X protein of various bornaviruses interfered with the type I IFN system at all checkpoints investigated, in contrast to previously reported findings, resulting in reduced type I IFN secretion.

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