IKKβ is an IRF5 kinase that instigates inflammation

Ren, Junyao; Chen, Xiang; Chen, Zhijian J.

doi:10.1073/pnas.1418516111

Cited by 88 publications

(101 citation statements)

References 33 publications

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“…Our finding on TLR8-induced signaling in human primary monocytes and MDMs is similar to this newly described TLR7-TAK1-IKKb-IRF5-IFN-b pathway in Gen2.2 cells. The function of IKKb as a kinase activating IRF5 was confirmed by another study (51). Our study using human primary monocytes and MDMs stimulated with live S. aureus captures a more physiological relevant function of this recently identified IKKb-IRF5 link.…”

Section: Discussionsupporting

confidence: 76%

TLR8 Senses Staphylococcus aureus RNA in Human Primary Monocytes and Macrophages and Induces IFN-β Production via a TAK1–IKKβ–IRF5 Signaling Pathway

Bergstrøm

Aune

Awuh

et al. 2015

The Journal of Immunology

122

162

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Staphylococcus aureus may cause serious infections and is one of the most lethal and common causes of sepsis. TLR2 has been described as the main pattern recognition receptor that senses S. aureus and elicits production of proinflammatory cytokines via MyD88–NF-κB signaling. S. aureus can also induce the production of IFN-β, a cytokine that requires IFN regulatory factors (IRFs) for its transcription, but the signaling mechanism for IFN-β induction by S. aureus are unclear. Surprisingly, we demonstrate that activation of TLR2 by lipoproteins does not contribute to IFN-β production but instead can suppress the induction of IFN-β in human primary monocytes and monocyte-derived macrophages. The production of IFN-β was induced by TLR8-mediated sensing of S. aureus RNA, which triggered IRF5 nuclear accumulation, and this could be antagonized by concomitant TLR2 signaling. The TLR8-mediated activation of IRF5 was dependent on TAK1 and IκB kinase (IKK)β, which thus reveals a physiological role of the recently described IRF5-activating function of IKKβ. TLR8–IRF5 signaling was necessary for induction of IFN-β and IL-12 by S. aureus, and it also contributed to the induction of TNF. In conclusion, our study demonstrates a physiological role of TLR8 in the sensing of entire S. aureus in human primary phagocytes, including the induction of IFN-β and IL-12 production via a TAK1–IKKβ–IRF5 pathway that can be inhibited by TLR2 signaling.

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Section: Discussionsupporting

confidence: 76%

TLR8 Senses Staphylococcus aureus RNA in Human Primary Monocytes and Macrophages and Induces IFN-β Production via a TAK1–IKKβ–IRF5 Signaling Pathway

Bergstrøm

Aune

Awuh

et al. 2015

The Journal of Immunology

122

162

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“…Chen and coworkers have independently identified IKKβ as an IRF5 kinase (35). The phosphorylation site Ser462 of human IRF5 isoform 2 in our paper is equivalent to Ser446 of human IRF5 isoform 1 in their paper.…”

Section: Methodssupporting

confidence: 48%

Protein kinase IKKβ-catalyzed phosphorylation of IRF5 at Ser462 induces its dimerization and nuclear translocation in myeloid cells

López-Peláez

Lamont

Peggie

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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The siRNA knockdown of IFN Regulatory Factor 5 (IRF5) in the human plasmacytoid dendritic cell line Gen2.2 prevented IFNβ production induced by compound CL097, a ligand for Toll-like receptor 7 (TLR7). CL097 also stimulated the phosphorylation of IRF5 at Ser462 and stimulated the nuclear translocation of wild-type IRF5, but not the IRF5[Ser462Ala] mutant. The CL097-stimulated phosphorylation of IRF5 at Ser462 and its nuclear translocation was prevented by the pharmacological inhibition of protein kinase IKKβ or the siRNA knockdown of IKKβ or its "upstream" activator, the protein kinase TAK1. Similar results were obtained in a murine macrophage cell line stimulated with the TLR7 agonist compound R848 or the nucleotide oligomerization domain 1 (NOD1) agonist KF-1B. IKKβ phosphorylated IRF5 at Ser462 in vitro and induced the dimerization of wild-type IRF5 but not the IRF5[S462A] mutant. These findings demonstrate that IKKβ activates two "master" transcription factors of the innate immune system, IRF5 and NF-κB.T he transcription factor IFN Regulatory Factor 5 (IRF5) has a critical role in the production of proinflammatory cytokines. The secretion of interleukin 12 (IL-12), IL-6, and TNFα by ligands that activate Toll-like receptor 3 (TLR3), TLR4, TLR5, and TLR9, is greatly impaired in macrophages, conventional dendritic cells (cDCs), and plasmacytoid dendritic cells (pDCs) of mice that do not express IRF5 (1). However, the role of IRF5 in type 1 IFN production in pDCs has been less clear. The TLR9-stimulated secretion of IFNα was initially reported to be similar in pDCs from IRF5-deficient and wild-type mice (1), but a later study found that the TLR7-or TLR9-stimulated production of IFNα was reduced in pDCs from IRF5-deficient mice (2). Subsequently, some IRF5-deficient mouse lines were shown to carry a second mutation in the gene encoding the guanine nucleotide exchange factor (dedicator of cytokinesis 2 (Dock2), and it was reported that TLR9-stimulated IFNα secretion was largely intact in pDCs from mice where this secondary mutation had been eliminated (3). A further study using pDCs from IRF5-deficient mice, carrying or not carrying the DOCK2 mutation, confirmed that IRF5 had little effect on TLR9-stimulated IFNα secretion, but indicated an important role for IRF5 in the secretion of IFNβ (4). IRF5 was also required for the TLR9-stimulated production of IFNβ in the human pDC line CAL-1 (5) and for the production of IFNβ induced by streptococcal RNA in cDCs (6) and by the fungal pathogen Candida albicans in a pathway dependent on the Dectin 1 and Dectin 2 receptors (7). IRF5 was also found to be needed for the production of IFNβ by a small subset of viruses (8, 9). Thus, IRF5 does appear to be a key regulator of IFNβ production by several pathogens.IRF5 is present in a latent form in the cell cytosol but accumulates in the nucleus to stimulate gene transcription following viral infection (10, 11) or stimulation with the TLR7/TLR8 agonist R848 (9). The nuclear export signal (NES) (12) of IRF5 therefore appears to ...

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“…These indicate that IRF5 is involved in the development of systemic inflammatory responses. There are some experimental clues to support IRF5 as a central regulator in the TLR signaling pathway: (1) When IRF5 is deficient, TLRs (TLR7/9, TLR4, TLR5) are not able to mediate inflammatory responses (4); (2) IRF5-deficient mice resist lethal shock induced by CpG ODN (TLR9 agonist) or lipopolysaccharide (LPS) (TLR4 agonist) (4); (3) individuals with IRF5 dysregulation may develop autoinflammatory diseases (10); (4) in CAL-1 cells, plasmacytoid-like dendritic cell (pDC) line cells, inhibiting IRF5 expression, significantly reduce mRNA expression of IFN-α and IL-6 (7); and (5) IRF5-/-mice have a significantly reduced number of neutrophils recruited into the lung post LPS challenge and reduced acute lung injury (11). These studies demonstrate that blockade of IRF5 might be an effective method for downregulating production of inflammatory cytokines and therefore ameliorating acute inflammation.…”

mentioning

confidence: 99%

An Oligodeoxynucleotide with AAAG Repeats Significantly Attenuates Burn-induced Systemic inflammatory Responses by inhibiting interferon Regulatory Factor 5 Pathway

Xiao

et al. 2017

Mol Med

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Previously, we showed that an oligodeoxynucleotide (ODN) with AAAG repeats (AAAG ODN) rescued mice from fatal acute lung injury (ALI) induced by influenza virus and inhibited production of tumor necrosis factor-α (TNF-α) in the injured lungs. However, its underlying mechanisms remain to be elucidated. Upon the bioinformatic analysis revealing that the sequence of AAAG ODN is in consensus with the interferon regulatory factor 5 (IRF5) binding site in the cis-regulatory elements of proinflammatory cytokines, we tried to explore whether AAAG ODN could attenuate burn injury-induced systemic inflammatory responses by inhibiting the IRF5 pathway. Using a mouse model with sterile systemic inflammation induced by burn injury, we found that AAAG ODN prolonged the lifespan of the mice, decreased the expression of IRF5 in the injured skin, reduced the production of TNF-α and IL-6 in the blood and injured skin, and attenuated the ALI. These effects were correlated with AAAG ODN-mediated inhibition of nuclear translocation of IRF5. The data suggest that AAAG ODN could act as a cytoplasmic decoy capable of interfering the function of IRF5 and be developed as a drug candidate for the treatment of inflammatory diseases. online address: http://www.molmed.org

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IKKβ is an IRF5 kinase that instigates inflammation

Cited by 88 publications

References 33 publications

TLR8 Senses Staphylococcus aureus RNA in Human Primary Monocytes and Macrophages and Induces IFN-β Production via a TAK1–IKKβ–IRF5 Signaling Pathway

TLR8 Senses Staphylococcus aureus RNA in Human Primary Monocytes and Macrophages and Induces IFN-β Production via a TAK1–IKKβ–IRF5 Signaling Pathway

Protein kinase IKKβ-catalyzed phosphorylation of IRF5 at Ser462 induces its dimerization and nuclear translocation in myeloid cells

An Oligodeoxynucleotide with AAAG Repeats Significantly Attenuates Burn-induced Systemic inflammatory Responses by inhibiting interferon Regulatory Factor 5 Pathway

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