scholarly journals O-GlcNAc transferase promotes influenza A virus–induced cytokine storm by targeting interferon regulatory factor–5

2020 ◽  
Vol 6 (16) ◽  
pp. eaaz7086 ◽  
Author(s):  
Qiming Wang ◽  
Peining Fang ◽  
Rui He ◽  
Mengqi Li ◽  
Haisheng Yu ◽  
...  
Keyword(s):  
Influenza A Virus ◽  
Influenza A ◽  
Cytokine Production ◽  
Interferon Regulatory Factor ◽  
Clinical Samples ◽  
Cytokine Storm ◽  
Regulatory Factor ◽  
Interferon Regulatory Factor 5 ◽  
Key Enzyme ◽  
Glcnac Transferase

In this study, we demonstrated an essential function of the hexosamine biosynthesis pathway (HBP)–associated O-linked β-N-acetylglucosamine (O-GlcNAc) signaling in influenza A virus (IAV)–induced cytokine storm. O-GlcNAc transferase (OGT), a key enzyme for protein O-GlcNAcylation, mediated IAV-induced cytokine production. Upon investigating the mechanisms driving this event, we determined that IAV induced OGT to bind to interferon regulatory factor–5 (IRF5), leading to O-GlcNAcylation of IRF5 on serine-430. O-GlcNAcylation of IRF5 is required for K63-linked ubiquitination of IRF5 and subsequent cytokine production. Analysis of clinical samples revealed that IRF5 is O-GlcNAcylated, and higher levels of proinflammatory cytokines correlated with higher levels of blood glucose in IAV-infected patients. We identified a molecular mechanism by which HBP-mediated O-GlcNAcylation regulates IRF5 function during IAV infection, highlighting the importance of glucose metabolism in IAV-induced cytokine storm.

scholarly journals Interferon Regulatory Factor‐5 in Resident Macrophage Promotes Polycystic Kidney Disease

Kidney360 ◽  
2020 ◽  
Vol 1 (3) ◽  
pp. 179-190
Author(s):  
Kurt A. Zimmerman ◽  
Jifeng Huang ◽  
Lan He ◽  
Dustin Z. Revell ◽  
Zhang Li ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Polycystic Kidney Disease ◽  
Cytokine Production ◽  
Interferon Regulatory Factor ◽  
Cystic Disease ◽  
Regulatory Factor ◽  
Polycystic Kidney ◽  
Qrt Pcr ◽  
Interferon Regulatory Factor 5 ◽  
Stat3 Phosphorylation

BackgroundAutosomal dominant polycystic kidney disease is caused by genetic mutations in PKD1 or PKD2. Macrophages and their associated inflammatory cytokines promote cyst progression; however, transcription factors within macrophages that control cytokine production and cystic disease are unknown.MethodsIn these studies, we used conditional Pkd1 mice to test the hypothesis that macrophage-localized interferon regulatory factor-5 (IRF5), a transcription factor associated with production of cyst-promoting cytokines (TNFα, IL-6), is required for accelerated cyst progression in a unilateral nephrectomy (1K) model. Analyses of quantitative real-time PCR (qRT-PCR) and flow-cytometry data 3 weeks post nephrectomy, a time point before the onset of severe cystogenesis, indicate an accumulation of inflammatory infiltrating and resident macrophages in 1K Pkd1 mice compared with controls. qRT-PCR data from FACS cells at this time demonstrate that macrophages from 1K Pkd1 mice have increased expression of Irf5 compared with controls. To determine the importance of macrophage-localized Irf5 in cyst progression, we injected scrambled or IRF5 antisense oligonucleotide (ASO) in 1K Pkd1 mice and analyzed the effect on macrophage numbers, cytokine production, and renal cystogenesis 6 weeks post nephrectomy.ResultsAnalyses of qRT-PCR and IRF5 ASO treatmentsignificantly reduced macrophage numbers, Irf5 expression in resident—but not infiltrating—macrophages, and the severity of cystic disease. In addition, IRF5 ASO treatment in 1K Pkd1 mice reduced Il6 expression in resident macrophages, which was correlated with reduced STAT3 phosphorylation and downstream p-STAT3 target gene expression.ConclusionsThese data suggest that Irf5 promotes inflammatory cytokine production in resident macrophages resulting in accelerated cystogenesis.

scholarly journals Involvement of Interleukin-1 Receptor-Associated Kinase 4 and Interferon Regulatory Factor 5 in the Immunopathogenesis of SARS-CoV-2 Infection: Implications for the Treatment of COVID-19

2021 ◽  
Vol 12 ◽  
Author(s):  
Nicholas Stoy
Keyword(s):  
Interleukin 1 ◽  
Interferon Regulatory Factor ◽  
Innate Immune ◽  
Cytokine Storm ◽  
Regulatory Factor ◽  
Microbial Infection ◽  
Severe Morbidity ◽  
Interferon Regulatory Factor 5 ◽  
Cytokines And Chemokines ◽  
Endosomal Membranes

Interleukin-1 receptor-associated kinase 4 (IRAK4) and interferon regulatory factor 5 (IRF5) lie sequentially on a signaling pathway activated by ligands of the IL-1 receptor and/or multiple TLRs located either on plasma or endosomal membranes. Activated IRF5, in conjunction with other synergistic transcription factors, notably NF-κB, is crucially required for the production of proinflammatory cytokines in the innate immune response to microbial infection. The IRAK4-IRF5 axis could therefore have a major role in the induction of the signature cytokines and chemokines of the hyperinflammatory state associated with severe morbidity and mortality in COVID-19. Here a case is made for considering IRAK4 or IRF5 inhibitors as potential therapies for the “cytokine storm” of COVID-19.

101 The role of interferon regulatory factor 3 and p38 in influenza a virus induced pro-inflammatory cytokines

Cytokine ◽  
2008 ◽  
Vol 43 (3) ◽  
pp. 259
Author(s):  
Kenrie P. Hui ◽  
Suki M. Lee ◽  
Chung-yan Cheung ◽  
Iris H.Y. Ng ◽  
Leo L.M. Poon ◽  
...  
Keyword(s):  
Influenza A Virus ◽  
Inflammatory Cytokines ◽  
Influenza A ◽  
Interferon Regulatory Factor ◽  
Regulatory Factor ◽  
Interferon Regulatory Factor 3 ◽  
Pro Inflammatory Cytokines

scholarly journals Association of a haplotype in the promoter region of the interferon regulatory factor 5 gene with rheumatoid arthritis

2007 ◽  
Vol 56 (7) ◽  
pp. 2202-2210 ◽  
Author(s):  
Snaevar Sigurdsson ◽  
Leonid Padyukov ◽  
Fina A. S. Kurreeman ◽  
Ulrika Liljedahl ◽  
Ann-Christin Wiman ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Promoter Region ◽  
Interferon Regulatory Factor ◽  
Regulatory Factor ◽  
Interferon Regulatory Factor 5

Associations between interferon regulatory factor 5 polymorphisms and rheumatoid arthritis: a meta-analysis

2012 ◽  
Vol 40 (2) ◽  
pp. 1791-1799 ◽  
Author(s):  
Young Ho Lee ◽  
Sang-Cheol Bae ◽  
Sung Jae Choi ◽  
Jong Dae Ji ◽  
Gwan Gyu Song
Keyword(s):  
Rheumatoid Arthritis ◽  
Meta Analysis ◽  
Interferon Regulatory Factor ◽  
Regulatory Factor ◽  
Interferon Regulatory Factor 5

scholarly journals Interferon Regulatory Factor 5 Mediates Lipopolysaccharide-Induced Neuroinflammation

2020 ◽  
Vol 11 ◽  
Author(s):  
Ziqi Fan ◽  
Shuai Zhao ◽  
Yueli Zhu ◽  
Zheyu Li ◽  
Zhirong Liu ◽  
...  
Keyword(s):  
Inflammatory Cytokines ◽  
Inflammatory Responses ◽  
Interferon Regulatory Factor ◽  
Microglial Cells ◽  
Regulatory Factor ◽  
Down Regulation ◽  
Interferon Regulatory Factor 5 ◽  
Bv2 Microglial Cells ◽  
Lps Treatment ◽  
Pro Inflammatory Cytokines

BackgroundActivated microglia play a vital role in neuroinflammation in the central nervous system (CNS), which is associated with the pathogenesis and the progression of neurological diseases. Interferon regulatory factor 5 (IRF5) has been well established participating in inflammatory responses and is highly expressed in M1 macrophage in the periphery, the role of which in the CNS remains elusive.MethodsLipopolysaccharide (LPS) was employed to induce neuroinflammation. Down-regulation of IRF5 in C57/BL6 mice and BV2 microglial cells were achieved by IRF5 siRNA transfection. The levels of pro-inflammatory cytokines were evaluated by ELISA and quantitative real-time PCR. The expression levels of IRF5 were examined by immunofluorescence and Western blot.ResultsLPS induced significantly elevated expression of IRF5 in mouse brain, which co-localized with CD11b-positive microglia. Down-regulation of IRF5 quenched the pro-inflammatory responses. The levels of pro-inflammatory cytokines TNF-α, IL-1β, and IL-6 were up-regulated at 4 h after LPS treatment, which were significantly down-regulated with the knockdown of IRF5. LPS-induced pro-inflammatory responses were transient, which were comparable to control group at 24 h after LPS treatment. However, LPS did not up-regulate the expression of IRF5 in BV2 microglial cells, indicating that LPS-induced inflammation in BV2 cells does not involve IRF5 signaling.ConclusionsIRF5 mediates the inflammatory responses in the CNS, which might serve as a therapeutic target for CNS inflammatory diseases. LPS-induced inflammation does not involve IRF5 signaling in BV2 microglia.

Sign in / Sign up

Export Citation Format

Share Document