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

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.

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

10.1101/765404 ◽

2019 ◽

Cited By ~ 1

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.

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

Cells ◽

10.3390/cells9051205 ◽

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.

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

PLoS Pathogens ◽

10.1371/journal.ppat.1008079 ◽

2019 ◽

Vol 15 (10) ◽

pp. e1008079 ◽

Cited By ~ 3

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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Synthetic rewiring and boosting type I interferon responses for visualization and counteracting viral infections

Nucleic Acids Research ◽

10.1093/nar/gkaa961 ◽

2020 ◽

Vol 48 (20) ◽

pp. 11799-11811

Author(s):

Natascha Gödecke ◽

Jan Riedel ◽

Sabrina Herrmann ◽

Sara Behme ◽

Ulfert Rand ◽

...

Keyword(s):

Positive Feedback ◽

Viral Infections ◽

Type I Interferon ◽

Type I ◽

First Line ◽

Initial Stimulus ◽

Sensor Actuator ◽

Actuator System ◽

Interferon Responses ◽

Robust Sensing

Abstract Mammalian first line of defense against viruses is accomplished by the interferon (IFN) system. Viruses have evolved numerous mechanisms to reduce the IFN action allowing them to invade the host and/or to establish latency. We generated an IFN responsive intracellular hub by integrating the synthetic transactivator tTA into the chromosomal Mx2 locus for IFN-based activation of tTA dependent expression modules. The additional implementation of a synthetic amplifier module with positive feedback even allowed for monitoring and reacting to infections of viruses that can antagonize the IFN system. Low and transient IFN amounts are sufficient to trigger these amplifier cells. This gives rise to higher and sustained—but optionally de-activatable—expression even when the initial stimulus has faded out. Amplification of the IFN response induced by IFN suppressing viruses is sufficient to protect cells from infection. Together, this interfaced sensor/actuator system provides a toolbox for robust sensing and counteracting viral infections.

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