scholarly journals Deficiency of Interferon Regulatory Factor 5 in Myeloid Cells Prevents Necrotizing Enterocolitis by Inhibiting M1 Macrophage Polarization

2019 ◽  
Vol 33 (S1) ◽  
Author(s):  
Jia Wei ◽  
Yidong Wang ◽  
Zhejun Cai ◽  
Qiang Shu
Keyword(s):  
Necrotizing Enterocolitis ◽  
Macrophage Polarization ◽  
Myeloid Cells ◽  
Interferon Regulatory Factor ◽  
Regulatory Factor ◽  
Interferon Regulatory Factor 5 ◽  
M1 Macrophage

scholarly journals The COP9 Signalosome Interacts with and Regulates Interferon Regulatory Factor 5 Protein Stability

2012 ◽  
Vol 33 (6) ◽  
pp. 1124-1138 ◽  
Author(s):  
Justyna Korczeniewska ◽  
Betsy J. Barnes
Keyword(s):  
Protein Stability ◽  
Inflammatory Responses ◽  
Macrophage Polarization ◽  
Death Receptor ◽  
Interferon Regulatory Factor ◽  
Cop9 Signalosome ◽  
Small Interfering Rnas ◽  
Regulatory Factor ◽  
Interferon Regulatory Factor 5 ◽  
Enhanced Degradation

The transcription factor interferon regulatory factor 5 (IRF5) exerts crucial functions in the regulation of host immunity against extracellular pathogens, DNA damage-induced apoptosis, death receptor signaling, and macrophage polarization. Tight regulation of IRF5 is thus warranted for an efficient response toward extracellular stressors and for limiting autoimmune and inflammatory responses. Here we report that the COP9 signalosome (CSN), a general modulator of diverse cellular and developmental processes, associates constitutively with IRF5 and promotes its protein stability. The constitutive CSN/IRF5 interaction was identified using proteomics and confirmed by endogenous immunoprecipitations. The CSN/IRF5 interaction occurred on the carboxyl and amino termini of IRF5; a single internal deletion from amino acids 455 to 466 (Δ455-466) was found to significantly reduce IRF5 protein stability. CSN subunit 3 (CSN3) was identified as a direct interacting partner of IRF5, and knockdown of this subunit with small interfering RNAs resulted in enhanced degradation. Degradation was further augmented by knockdown of CSN1 and CSN3 together. The ubiquitin E1 inhibitor UBEI-41 or the proteasome inhibitor MG132 prevented IRF5 degradation, supporting the idea that its stability is regulated by the ubiquitin-proteasome system. Importantly, activation of IRF5 by the death receptor ligand tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) resulted in enhanced degradation via loss of the CSN/IRF5 interaction. This study defines CSN to be a new interacting partner of IRF5 that controls its stability.

scholarly journals Irf5 deficiency in myeloid cells prevents necrotizing enterocolitis by inhibiting M1 macrophage polarization

2019 ◽  
Vol 12 (4) ◽  
pp. 888-896 ◽  
Author(s):  
Jia Wei ◽  
Daxing Tang ◽  
Chengjie Lu ◽  
Jin Yang ◽  
Yulei Lu ◽  
...  
Keyword(s):  
Necrotizing Enterocolitis ◽  
Macrophage Polarization ◽  
Myeloid Cells ◽  
Intestinal Barrier ◽  
Intestinal Epithelial ◽  
Barrier Dysfunction ◽  
M1 Macrophages ◽  
M1 Macrophage ◽  
Epithelial Cell Apoptosis ◽  
Life Threatening

AbstractNecrotizing enterocolitis (NEC) is a life-threatening inflammatory disease in newborns, but the mechanisms remain unclear. Interferon regulatory factor 5 (IRF5) is a master regulator of macrophage function and is essential for proinflammatory M1 macrophage polarization. Our previous data indicated that M1 macrophages promote NEC injury. Here, we investigated whether IRF5 is involved in the pathogenesis of NEC. First, we found that IRF5 was upregulated in infiltrated macrophages in human neonates with NEC compared to controls. We further confirmed IRF5 upregulation in macrophages in experimental murine NEC and that the infiltrated macrophages were predominantly polarized into the M1 but not the M2 phenotype. Myeloid-specific deficiency of Irf5, which was associated with reduced M1 macrophage polarization and systematic inflammation, dramatically prevented experimental NEC. Moreover, we found that the ablation of Irf5 in myeloid cells markedly suppressed intestinal epithelial cell apoptosis and further prevented intestinal barrier dysfunction in experimental NEC. Bioinformatic and chromatin immunoprecipitation analysis further showed that IRF5 binds to the promoters of the M1 macrophage-associated genes Ccl4, Ccl5, Tnf, and Il12b. Overall, our study provides evidence that IRF5 participates in the pathogenesis of NEC, while the deletion of Irf5 in myeloid cells prevents NEC via inhibiting M1 macrophage polarization.

scholarly journals Polysaccharides from Citrus grandis associate with luteolin relieves chronic pharyngitis by anti-inflammatory via suppressing NF-κB pathway and the polarization of M1 macrophages

2018 ◽  
Vol 32 ◽  
pp. 205873841878059 ◽  
Author(s):  
Xiumei Chen ◽  
Yongfeng Lai ◽  
Xicheng Song ◽  
Jinying Wu ◽  
Li Wang ◽  
...  
Keyword(s):  
Disease Severity ◽  
Macrophage Polarization ◽  
Mannose Receptor ◽  
Interferon Regulatory Factor ◽  
Protective Effects ◽  
Regulatory Factor ◽  
Necrosis Factor Alpha ◽  
Ear Edema ◽  
M1 Macrophage ◽  
Anti Inflammatory

Chronic pharyngitis is characterized as a common inflammation of the pharyngeal mucosa, and anti-inflammatory medications are the common treatment to relieve it. Polysacharides of Citrus grandis L. Osbeck (PCG) and luteolin have been reported to have anti-inflammatory activities. In this study, the protective effects of PCG and luteolin on chronic pharyngitis are evaluated and the underlying mechanisms are explored. PCG and luteolin are administrated to animal models with granuloma, ear edema and chronic pharyngitis and the effects of PCG and luteolin on disease severity are evaluated. We also evaluate the effects of PCG and luteolin on inflammatory cytokine production in macrophages stimulated with lipopolysaccharides (LPS)/interferon-gamma (IFN-γ) and detect the effects of PCG and luteolin on macrophage polarization. Finally, we evaluate the effects of PCG and luteolin on activations of LPS-induced downstream signaling pathways. PCG and luteolin alleviate the disease severity of granuloma, ear edema and chronic pharyngitis. PCG and luteolin suppress the productions of pro-inflammatory cytokines interlukin-6 (IL-6), interlukin-12 (IL-12) and tumor necrosis factor alpha (TNF-α) in macrophages. Luteolin promotes macrophage M2 polarization by enhancing expressions of arginase (Arg1) and mannose receptor C type 1 (Mrc1). PCG and luteolin suppress nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) activation and interferon regulatory factor 1 (IRF1), interferon regulatory factor 5 (IRF5) expression. PCG together with luteolin relieves chronic pharyngitis by anti-inflammatory via suppressing NF-κB pathway and the polarization of M1 macrophage.

scholarly journals Increased Adipose Tissue Expression of Interferon Regulatory Factor (IRF)-5 in Obesity: Association with Metabolic Inflammation

Cells ◽  
2019 ◽  
Vol 8 (11) ◽  
pp. 1418 ◽  
Author(s):  
Sardar Sindhu ◽  
Reeby Thomas ◽  
Shihab Kochumon ◽  
Ajit Wilson ◽  
Mohamed Abu-Farha ◽  
...  
Keyword(s):  
Gene Expression ◽  
Adipose Tissue ◽  
Protein Expression ◽  
Macrophage Polarization ◽  
Interferon Regulatory Factor ◽  
Regulatory Factor ◽  
Metabolic Inflammation ◽  
M1 Macrophage ◽  
Gene And Protein Expression ◽  
Local Expression

Interferon regulatory factor (IRF)-5 is known to be involved in M1 macrophage polarization, however, changes in the adipose expression of IRF5 in obesity and their relationship with the local expression of proinflammatory cytokines/chemokines are unknown. Therefore, IRF5 gene expression was determined in the subcutaneous adipose tissue samples from 53 non-diabetic individuals (6 lean, 18 overweight, and 29 obese), using real-time RT-PCR. IRF5 protein expression was also assessed using immunohistochemistry and/or confocal microscopy. Adipose gene expression of signature immune metabolic markers was also determined and compared with adipose IRF5 gene expression. Systemic levels of C-reactive protein and adiponectin were measured by ELISA. The data show that adipose IRF5 gene (P = 0.008) and protein (P = 0.004) expression was upregulated in obese compared with lean individuals. IRF5 expression changes correlated positively with body mass index (BMI; r = 0.37/P = 0.008) and body fat percentage (r = 0.51/P = 0.0004). In obese, IRF5 changes associated positively with HbA1c (r = 0.41/P = 0.02). A good agreement was found between gene and protein expression of IRF5 in obese subjects (r = 0.65/P = 0.001). IRF5 gene expression associated positively with adipose inflammatory signatures including local expression of TNF-α, IL-6, CXCL8, CCL-2/5, IL-1β, IL-18, CXCL-9/10, CCL7, CCR-1/2/5, TLR-2/7/8/9, IRF3, MyD88, IRAK-1, and inflammatory macrophage markers (P < 0.05). Interestingly, IRF5 gene expression correlated positively with CRP (r = 0.37, P = 0.03) and negatively with adiponectin levels (r = −0.43, P = 0.009). In conclusion, elevated adipose IRF5 expression in obesity concurs with the typical inflammatory signatures, locally and systemically. Hence, the IRF5 upregulation may represent a novel adipose tissue marker for metabolic inflammation.

scholarly journals Corrected and Republished from: The COP9 Signalosome Interacts with and Regulates Interferon Regulatory Factor 5 Protein Stability

2018 ◽  
Vol 38 (3) ◽  
Author(s):  
Justyna Korczeniewska ◽  
Betsy J. Barnes
Keyword(s):  
Protein Stability ◽  
Inflammatory Responses ◽  
Macrophage Polarization ◽  
Death Receptor ◽  
Interferon Regulatory Factor ◽  
Cop9 Signalosome ◽  
Small Interfering Rnas ◽  
Regulatory Factor ◽  
Interferon Regulatory Factor 5 ◽  
Enhanced Degradation

ABSTRACT The transcription factor interferon regulatory factor 5 (IRF5) exerts crucial functions in the regulation of host immunity against extracellular pathogens, DNA damage-induced apoptosis, death receptor signaling, and macrophage polarization. Tight regulation of IRF5 is thus warranted for an efficient response to extracellular stressors and for limiting autoimmune and inflammatory responses. Here we report that the COP9 signalosome (CSN), a general modulator of diverse cellular and developmental processes, associates constitutively with IRF5 and promotes its protein stability. The constitutive CSN/IRF5 interaction was identified using proteomics and confirmed by endogenous immunoprecipitations. The CSN/IRF5 interaction occurred on the carboxyl and amino termini of IRF5; a single internal deletion (Δ455-466) was found to significantly reduce IRF5 protein stability. CSN3 was identified as a direct interacting partner of IRF5, and knockdown of this subunit with small interfering RNAs (siRNAs) resulted in enhanced degradation. Degradation was further augmented by knockdown of CSN1 and CSN3 together. The ubiquitin E1 inhibitor UBEI-41 or the proteasome inhibitor MG132 prevented IRF5 degradation, supporting that its stability is regulated by the ubiquitin-proteasome system. Importantly, activation of IRF5 by the death receptor ligand tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) resulted in enhanced degradation via loss of the CSN/IRF5 interaction. This study defines the CSN as a new interacting partner of IRF5 that controls its stability.

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.

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.

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