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.

scholarly journals The myeloid type I interferon response to myocardial infarction begins in bone marrow and is regulated by Nrf2-activated macrophages

2020 ◽  
Vol 5 (51) ◽  
pp. eaaz1974 ◽  
Author(s):  
David M. Calcagno ◽  
Richard P. Ng ◽  
Avinash Toomu ◽  
Claire Zhang ◽  
Kenneth Huang ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Bone Marrow ◽  
Steady State ◽  
Type I Interferon ◽  
Tissue Injury ◽  
Transcriptional Regulators ◽  
Innate Immune ◽  
Interferon Response ◽  
Type I ◽  
Molecular Patterns

Sterile tissue injury is thought to locally activate innate immune responses via damage-associated molecular patterns (DAMPs). Whether innate immune pathways are remotely activated remains relatively unexplored. Here, by analyzing ~145,000 single-cell transcriptomes at steady state and after myocardial infarction (MI) in mice and humans, we show that the type I interferon (IFN) response, characterized by expression of IFN-stimulated genes (ISGs), begins far from the site of injury, in neutrophil and monocyte progenitors within the bone marrow. In the peripheral blood of patients, we observed defined subsets of ISG-expressing neutrophils and monocytes. In the bone marrow and blood of mice, ISG expression was detected in neutrophils and monocytes and their progenitors, intensified with maturation at steady-state and after MI, and was controlled by Tet2 and Irf3 transcriptional regulators. Within the infarcted heart, ISG-expressing cells were negatively regulated by Nrf2 activation in Ccr2− steady-state cardiac macrophages. Our results show that IFN signaling begins in the bone marrow, implicate multiple transcriptional regulators (Tet2, Irf3, and Nrf2) in governing ISG expression, and provide a clinical biomarker (ISG score) for studying IFN signaling in patients.

scholarly journals Role of NLRs in the Regulation of Type I Interferon Signaling, Host Defense and Tolerance to Inflammation

2021 ◽  
Vol 22 (3) ◽  
pp. 1301
Author(s):  
Ioannis Kienes ◽  
Tanja Weidl ◽  
Nora Mirza ◽  
Mathias Chamaillard ◽  
Thomas A. Kufer
Keyword(s):  
Viral Infections ◽  
Type I Interferon ◽  
Tissue Injury ◽  
Interferon Response ◽  
Type I ◽  
Interferon Signaling ◽  
Microbial Products ◽  
Interferon Responses

Type I interferon signaling contributes to the development of innate and adaptive immune responses to either viruses, fungi, or bacteria. However, amplitude and timing of the interferon response is of utmost importance for preventing an underwhelming outcome, or tissue damage. While several pathogens evolved strategies for disturbing the quality of interferon signaling, there is growing evidence that this pathway can be regulated by several members of the Nod-like receptor (NLR) family, although the precise mechanism for most of these remains elusive. NLRs consist of a family of about 20 proteins in mammals, which are capable of sensing microbial products as well as endogenous signals related to tissue injury. Here we provide an overview of our current understanding of the function of those NLRs in type I interferon responses with a focus on viral infections. We discuss how NLR-mediated type I interferon regulation can influence the development of auto-immunity and the immune response to infection.

Anemoside B4 inhibits enterovirus 71 propagation in mice through upregulating 14-3-3 expression and type I interferon responses

2021 ◽  
Author(s):  
Nai-xin Kang ◽  
Yue Zou ◽  
Qing-hua Liang ◽  
Yan-er Wang ◽  
Yan-li Liu ◽  
...  
Keyword(s):  
Type I Interferon ◽  
Enterovirus 71 ◽  
Type I ◽  
Interferon Responses

scholarly journals Investigation of type I interferon responses in ANCA-associated vasculitis

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Isabella Batten ◽  
Mark W. Robinson ◽  
Arthur White ◽  
Cathal Walsh ◽  
Barbara Fazekas ◽  
...  
Keyword(s):  
Protein Expression ◽  
Type I Interferon ◽  
Contributory Factor ◽  
Type I ◽  
Healthy Controls ◽  
Type I Ifn ◽  
Serum Samples ◽  
Anca Associated Vasculitis ◽  
Clinical Measurements ◽  
Interferon Responses

AbstractType I interferon (IFN) dysregulation is a major contributory factor in the development of several autoimmune diseases, termed type I interferonopathies, and is thought to be the pathogenic link with chronic inflammation in these conditions. Anti-neutrophil cytoplasmic antibody (ANCA)-Associated Vasculitis (AAV) is an autoimmune disease characterised by necrotising inflammation of small blood vessels. The underlying biology of AAV is not well understood, however several studies have noted abnormalities in type I IFN responses. We hypothesised that type I IFN responses are systemically dysregulated in AAV, consistent with features of a type I interferonopathy. To investigate this, we measured the expression of seven interferon regulated genes (IRGs) (ISG15, SIGLEC1, STAT1, RSAD2, IFI27, IFI44L and IFIT1) in peripheral blood samples, as well as three type I IFN regulated proteins (CXCL10, MCP-1 and CCL19) in serum samples from AAV patients, healthy controls and disease controls. We found no difference in type I IFN regulated gene or protein expression between AAV patients and healthy controls. Furthermore, IRG and IFN regulated protein expression did not correlate with clinical measurements of disease activity in AAV patients. Thus, we conclude that systemic type I IFN responses are not key drivers of AAV pathogenesis and AAV should not be considered a type I interferonopathy.

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

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.

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 P200 family protein IFI204 negatively regulates type I interferon responses by targeting IRF7 in nucleus

2019 ◽  
Vol 15 (10) ◽  
pp. e1008079 ◽  
Author(s):  
Liu Cao ◽  
Yanxi Ji ◽  
Lanyi Zeng ◽  
Qianyun Liu ◽  
Zhen Zhang ◽  
...  
Keyword(s):  
Type I Interferon ◽  
Type I ◽  
Family Protein ◽  
Interferon Responses
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