scholarly journals Type I interferon modulates Langerhans cell ADAM17 to promote photosensitivity in lupus

2021 ◽  
Author(s):  
Thomas M Li ◽  
Keila R Veiga ◽  
Noa Schwartz ◽  
Yurii Chinenov ◽  
David J Oliver ◽  
...  
Keyword(s):  
Type I Interferon ◽  
Organ Damage ◽  
Skin Lesions ◽  
Type I ◽  
Dependent Manner ◽  
Skin Injury ◽  
Murine Lupus ◽  
Potential Therapeutic Target ◽  
Inflammatory Conditions ◽  
Egfr Ligands

Type I IFN (IFN-I) mediates autoimmune and inflammatory conditions, and better understanding IFN-I-driven pathogenesis could expand therapeutic possibilities. Lupus is an autoimmune disease characterized by photosensitivity, inflammatory skin lesions, and systemic organ damage. Patients have an IFN-I signature in blood and tissues and anifrolumab (anti-IFNAR1), developed for lupus and recently FDA-approved, underscores the importance of IFN-I in pathogenesis. Anifrolumab is especially efficacious for cutaneous disease, but mechanisms are poorly understood. Langerhans cells (LCs) normally limit UVR-induced skin injury via ADAM17, a metalloprotease that clips from the cell membrane and activates skin-protective EGFR ligands. Downregulation of LC ADAM17 mRNA and activity in lupus models contributes to photosensitivity, and here we link IFN-I pathogenesis with LC dysfunction. We show that murine model and human lupus non-lesional skin have IFN-I signatures and that IFN-I reduces ADAM17 sheddase activity in LCs. Furthermore, anti-IFNAR1 in multiple murine lupus models restores LC ADAM17 function and reduces photosensitivity in an EGFR and LC ADAM17-dependent manner. These results suggest that IFN-I contributes to photosensitivity in lupus by downregulating LC ADAM17 function, providing mechanisms for IFN-I pathogenesis and anifrolumab efficacy and highlighting the importance of LCs as a potential therapeutic target.

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 Erratum: Beneficial effect of novel proteasome inhibitors in murine lupus via dual inhibition of type I interferon and autoantibody-secreting cells

2012 ◽  
Vol 64 (3) ◽  
pp. 939-939
Author(s):  
H. Travis Ichikawa ◽  
Thomas Conley ◽  
Tony Muchamuel ◽  
Jing Jiang ◽  
Susan Lee ◽  
...  
Keyword(s):  
Beneficial Effect ◽  
Type I Interferon ◽  
Proteasome Inhibitors ◽  
Type I ◽  
Murine Lupus ◽  
Dual Inhibition

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 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

PS1-021. Nuclear receptor PPAR-γ interacts with IRF7 to negatively regulate TLR7/9-mediated type I interferon production and the development of murine lupus

Cytokine ◽  
2011 ◽  
Vol 56 (1) ◽  
pp. 22
Author(s):  
Barry Ripley ◽  
Minoru Fujimoto ◽  
Amy Han ◽  
David Millrine ◽  
Soyoung Lee ◽  
...  
Keyword(s):  
Nuclear Receptor ◽  
Type I Interferon ◽  
Type I ◽  
Interferon Production ◽  
Murine Lupus ◽  
Ppar Γ

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 MicroRNA-130b Ameliorates Murine Lupus Nephritis Through Targeting the Type I Interferon Pathway on Renal Mesangial Cells

2016 ◽  
Vol 68 (9) ◽  
pp. 2232-2243 ◽  
Author(s):  
Xiao Han ◽  
Yan Wang ◽  
Xiaoyan Zhang ◽  
Yuting Qin ◽  
Bo Qu ◽  
...  
Keyword(s):  
Lupus Nephritis ◽  
Mesangial Cells ◽  
Type I Interferon ◽  
Type I ◽  
Murine Lupus ◽  
Interferon Pathway

scholarly journals Mosaic Tetrasomy 9p Associated With Inflammatory Bowel Disease

2019 ◽  
Vol 13 (11) ◽  
pp. 1474-1478 ◽  
Author(s):  
Luis Sifuentes-Dominguez ◽  
Petro Starokadomskyy ◽  
Jacob Welch ◽  
Bhaskar Gurram ◽  
Jason Y Park ◽  
...  
Keyword(s):  
Inflammatory Bowel Disease ◽  
Bowel Disease ◽  
Intestinal Inflammation ◽  
Type I Interferon ◽  
Organ Damage ◽  
Genomic Region ◽  
Chromosome 9 ◽  
Type I ◽  
First Case ◽  
Inflammatory Bowel

Abstract The genetic basis of inflammatory bowel disease remains to be elucidated completely. Here we report on a patient with inflammatory bowel disease who has mosaic tetrasomy of the short arm of chromosome 9, a genomic region that harbours the type I interferon gene cluster. We show that increased interferon activation is present in peripheral blood and intestinal tissue from this patient, similar to previous reports of autoinflammatory organ damage driven by interferon activation in other patients with this chromosomal abnormality. To our knowledge, this is the first case of tetrasomy 9p-associated interferonopathy driving intestinal inflammation and highlights the role that type-I interferon pathways can play in the pathogenesis of intestinal inflammation.

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