MyD88 Interacts with Interferon Regulatory Factor (IRF) 3 and IRF7 in Atlantic Salmon (Salmo salar)

Iliev, Dimitar B.; Sobhkhez, Mehrdad; Fremmerlid, Kjersti; Jørgensen, Jorunn B.

doi:10.1074/jbc.m111.293969

Cited by 49 publications

(17 citation statements)

References 69 publications

(71 reference statements)

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“…For example, IRF4 can negatively regulate of TLR signaling by targeting MyD88 (20) and IRF8 interacts with TRAF6 to participate in the MyD88dependent activation of NF-κB to induce pro-inflammatory cytokines in mammals (42). Interestingly, previous studies have reported that fish (Atlantic salmon) MyD88 interacted with IRF3 and was involved in the positive regulation of IRF-induced IFN response (43). IRF3 can positively regulate NF-κB pathway, according to our results.…”

Section: Discussionsupporting

confidence: 82%

IRF3 and IRF8 Regulate NF-κB Signaling by Targeting MyD88 in Teleost Fish

et al. 2020

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MyD88 is a conserved intracellular adaptor, which plays an important role in the innate immune system. MyD88 transmits signals for downstream of toll-like and IL-1 receptors to activate NF-κB signaling pathway, which is tightly controlled in the immune response to maintain immune intensity and immune homeostasis at different stages. NF-κB signaling pathway has been extensively studied in mammals, but regulatory molecular mechanism is still unclear in teleost fish. We determined that IRF3 and IRF8 can regulate MyD88-mediated NF-κB signaling pathway in fish. Interestingly, MyD88 is precisely regulated by IRF3 and IRF8 through the same mechanism but in completely opposite ways. IRF3 promotes MyD88-mediated NF-κB signaling pathway, whereas IRF8 inhibits the signaling pathway. MyD88 is regulated via ubiquitin-proteasome degradation, whereas IRF3 or IRF8 inhibited or promoted MyD88 degradation in this pathway. Specifically, in the early stage of lipopolysaccharide (LPS) stimulation or Vibrio infection, up-regulation of IRF3 and down-regulation of IRF8 eventually increased MyD88 expression to activate the NF-κB signaling pathway to trigger immune response. In the late stage of stimulation, down-regulated IRF3 and up-regulated IRF8 synergistically regulate the expression of MyD88 to a normal level, thus maintaining the immune balance of homeostasis and preventing serious damage from persistent over-immunization. This study presents information on Myd88-NF-κB signaling pathway in teleost fish and provides new insights into its regulatory mechanism in fish immune system.

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Section: Discussionsupporting

confidence: 82%

IRF3 and IRF8 Regulate NF-κB Signaling by Targeting MyD88 in Teleost Fish

et al. 2020

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“…A previous study in which the expression of surface MHCII was analyzed in salmon HK and spleen leukocytes identified a population of granular cells which expressed relatively high levels of surface MHCII but had a low capacity to endocytose dextran and Ova (Iliev et al, 2011; Lagos et al, 2012). In the current study, the morphology of sorted cells, examined using May Grünwald–Giemsa staining and TEM indicate that these cells are most likely polymorphonuclear granulocytes.…”

Section: Discussionmentioning

confidence: 99%

Homing of Antigen-Presenting Cells in Head Kidney and Spleen – Salmon Head Kidney Hosts Diverse APC Types

Iliev¹,

Thim²,

Lagos³

et al. 2013

Front. Immunol.

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Lymph nodes and spleen are major organs where mammalian antigen-presenting cells (APCs) initiate and orchestrate Ag-specific immune responses. Unlike mammals, teleosts lack lymph nodes and an interesting question is whether alternative organs may serve as sites for antigen presentation in teleosts. In the current study, fluorescent ovalbumin (Ova) and CpG oligonucleotides (ODNs) injected intra-abdominally were detected in significant numbers of salmon head kidney (HK) MHCII+ cells over a period of 2 weeks while in spleen the percentage of these was transient and declined from day 1 post injection. In vitro studies further shed light on the properties of the diverse MHCII+ cell types found in HK. The ultrastructure of a subpopulation of MHCII+ cells with a high capacity to endocytose and process Ova indicated that these were able to perform constitutive macropinocytosis. Upon stimulation with CpG ODNs these cells upregulated CD86 and gave very high levels of TNF mRNA indicating that these are professional APCs, related to macrophages and dendritic cells (DCs). A subpopulation of HK granulocytes expressed high levels of surface MHCII and upon CpG stimulation upregulated most of the tested APC marker genes. Although these granulocytes expressed TNF weakly, they had relatively high basal levels of IL-1β mRNA and the CpG stimulation upregulated IL-1β, along with its signaling and decoy receptors, to the highest levels as compared to other HK cell types. Interestingly, the high expression of IL-1β mRNA in the granulocytes correlated with a high autophagy flux as demonstrated by LC3-II conversion. Autophagy has recently been found to be implicated in IL-1β processing and secretion and the presented data suggests that granulocytes of salmon, and perhaps other teleost species, may serve as a valuable model to study the involvement of autophagy in regulation of the vertebrate immune response.

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“…The protein samples prepared in LDS buffer were analysed as previously described [35] using NuPAGE Novex Bis-Tris 4–12% gels (Life Technologies). The SsTLR9 antibody has been previously characterized [15] and was used at 1:1000-fold dilution.…”

Section: Methodsmentioning

confidence: 99%

“…To visualise endolysosomes in live cells, CHSE cells grown in Lab-Tek™ Chambered Coverglass slides (Nunc) were incubated with 1 μM LysoSensor™ Green DND-189 (Life technologies) for 30 min, washed and subjected directly or following the indicated stimulations with CpG-B-Cy5 (Eurogenetech) to confocal microscopy. The transfections of CHSE and TO cells were performed using FuGeneHD (Roche) as previously described [35], The expression constructs include pDEST12.2 (Invitrogen), pDESTEGFP C1 [35] and pDEST12.2-SsTLR9 [39]. SYTOX ® Green and 7-aminoactinomycin D (7-AAD), which were used to stain cell nuclei, were purchased from Life Technologies.…”

Section: Methodsmentioning

confidence: 99%

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CpG oligonucleotides bind TLR9 and RRM-Containing proteins in Atlantic Salmon (Salmo salar)

2013

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BackgroundBacterial DNA is well-known for its potent immunostimulatory properties which have been attributed to the abundance of CpG dinucleotides within the genomes of prokaryotes. Research has found that mammalian TLR9 is a receptor which mediates the immune response to CpG DNA; however, its functional properties in non-mammalian vertebrates are still poorly characterized. Leukocytes isolated from lower vertebrates, including teleosts, respond to CpG DNA and TLR9 has been identified in many fish species; however, the ligand-binding properties of fish TLR9 have, so far, not been studied. The fact that some vertebrates, like chicken, lack TLR9 and use an alternative molecule (TLR21) as a receptor for CpGs has questioned the functional conservation of TLR9 within vertebrates.ResultsIn the current study, TLR9 from Atlantic salmon (SsTLR9) has been found to interact with synthetic oligonucleotides via a CpG-independent but a pH-dependent mechanism. The endogenous receptor, expressed by primary mononuclear phagocytes colocalizes with CpG oligonucleotides (ODNs) in vesicles that appear to be endosomes. When overexpressed in salmonid cell lines, SsTLR9 spontaneously activates ISRE-containing promoters of genes involved in the IFN response; however, the transgenic receptor fails to translocate to CpG-containing endosomes. This indicates that only specific immune cell types have the ability to relocate the receptor to the appropriate cellular compartments where it may become activated by its ligand. In addition, through co-precipitation and mass spectrometry, two salmon proteins - hnRNPA0 and NCOA5, which both contain RNA-binding domains (RRM), were found to bind CpG ODNs, suggesting they may be involved in the CpG response in salmon leukocytes.ConclusionThe presented data are the first to demonstrate that the DNA-binding properties of TLR9 are conserved between teleosts and mammals. The current study also identifies additional molecules which may function as mediators of the immunostimulatory properties of foreign DNA.

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MyD88 Interacts with Interferon Regulatory Factor (IRF) 3 and IRF7 in Atlantic Salmon (Salmo salar)

Cited by 49 publications

References 69 publications

IRF3 and IRF8 Regulate NF-κB Signaling by Targeting MyD88 in Teleost Fish

IRF3 and IRF8 Regulate NF-κB Signaling by Targeting MyD88 in Teleost Fish

Homing of Antigen-Presenting Cells in Head Kidney and Spleen – Salmon Head Kidney Hosts Diverse APC Types

CpG oligonucleotides bind TLR9 and RRM-Containing proteins in Atlantic Salmon (Salmo salar)

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