Inhibition of Neutrophil Apoptosis by Type 1 IFN Depends on Cross-Talk Between Phosphoinositol 3-Kinase, Protein Kinase C-δ, and NF-κB Signaling Pathways

Wang, KeQing; Scheel‐Toellner, Dagmar; Wong, See Heng; Craddock, Rachel; Caamaño, Jorge H.; Akbar, Arne N.; Salmon, Mike; Lord, Janet M.

doi:10.4049/jimmunol.171.2.1035

Cited by 82 publications

(77 citation statements)

References 53 publications

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“…Significantly, the TRIF-TRAM branch has cellsurvival potential through the activation of the IRF3-IFN-␤ pathway (33)(34)(35). In this context, we hypothesized that SRA engagement might somehow suppress this branch of the TLR4 pathway.…”

Section: Tlr4 Is Required For Sra-induced Apoptosis In Er-stressed Mamentioning

confidence: 99%

Combinatorial pattern recognition receptor signaling alters the balance of life and death in macrophages

Seimon

Obstfeld²,

Moore³

et al. 2006

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

166

194

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Macrophage pattern recognition receptors (PRRs) play key roles in innate immunity, but they also may contribute to disease processes under certain pathological conditions. We recently showed that engagement of the type A scavenger receptor (SRA), a PRR, triggers JNK-dependent apoptosis in endoplasmic reticulum (ER)-stressed macrophages. In advanced atherosclerotic lesions, the SRA, activated JNK, and ER stress are observed in macrophages, and macrophage death in advanced atheromata leads to plaque necrosis. Herein, we show that SRA ligands trigger apoptosis in ER-stressed macrophages by cooperating with another PRR, Tolllike receptor 4 (TLR4), to redirect TLR4 signaling from prosurvival to proapoptotic. Common SRA ligands activate both TLR4 signaling and engage the SRA. The TLR4 effect results in activation of the proapoptotic MyD88-JNK branch of TLR4, whereas the SRA effect silences the prosurvival IRF-3-IFN-␤ branch of TLR4. The normal cell-survival effect of LPS-induced TLR4 activation is converted into an apoptosis response by immunoneutralization of IFN-␤, and the apoptosis effect of SRA ligands is converted into a cell-survival response by reconstitution with IFN-␤. Thus, combinatorial signaling between two distinct PRRs results in a functional outcomemacrophage apoptosis that does not occur with either PRR alone. PRR-induced macrophage death may play important roles in advanced atherosclerosis and in other innate immunity-related processes in which the balance between macrophage survival and death is critical.apoptosis ͉ atherosclerosis ͉ scavenger receptor ͉ Toll-like receptor ͉ innate immunity

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Section: Tlr4 Is Required For Sra-induced Apoptosis In Er-stressed Mamentioning

confidence: 99%

Combinatorial pattern recognition receptor signaling alters the balance of life and death in macrophages

Seimon

Obstfeld²,

Moore³

et al. 2006

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

166

194

View full text Add to dashboard Cite

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“…Although IFN-␣ and -␤ are generally associated with autoimmune diseases and host responses to viral infection (28), both can also modulate neutrophil behavior. Notably, type I IFN can prolong neutrophil life span by inhibiting apoptosis via PI3K, protein kinase C-␦, NF-B, and STAT3 signaling pathways (29,30). IFN-␣ is also able to enhance the respiratory burst in the presence of other stimuli, such as fMLP, leukotriene B4, or influenza A virus (31,32).…”

Section: P Eripheral Blood Neutrophils (Pbn)mentioning

confidence: 99%

Periodontitis Associates with a Type 1 IFN Signature in Peripheral Blood Neutrophils

Wright

Matthews

Chapple

et al. 2008

The Journal of Immunology

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Peripheral blood neutrophils from periodontitis patients exhibit a hyperreactive and hyperactive phenotype (collectively termed hyperresponsivity) in terms of production of reactive oxygen species (ROS). The molecular basis for this phenomenon, however, has yet to be determined. Our objectives were to identify genes differentially expressed in hyperresponsive peripheral blood neutrophils from chronic periodontitis patients relative to periodontally healthy controls and use these data to identify potential contributory pathways to the hyperresponsive neutrophil phenotype. Using microarray technology we demonstrated differential expression of 163 genes (149 increased, 14 decreased) representing a range of ontological classes. There was increased expression of a significant number of IFN-stimulated genes (ISG). RT-PCR analysis of ISG transcripts in individual and pooled samples further corroborated these data, and indicated that levels decreased to near those of controls following successful therapy. Significantly enhanced FcγR-stimulated ROS production was subsequently achieved by priming control neutrophils with IFN-α/-β/-γ, but not LPS, and gene expression analysis indicated that exposure to the type I IFN (in particular IFN-α) better replicated the mRNA profile observed in vivo. Further studies demonstrated that plasma levels of IFN-α were significantly higher in samples from patients relative to unaffected controls. Following successful periodontitis treatment, plasma IFN-α levels, neutrophil ISG expression, and FcγR-stimulated neutrophil ROS output of patients, all decreased to levels comparable with those of controls. In conclusion, although chronic periodontitis is a complex disease, raised IFN-α may be one determinant of the distinct molecular phenotype and hyperresponsivity exhibited by patients’ peripheral blood neutrophils.

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“…TLRs may activate many other signaling pathways, a number of which have already been implicated in the regulation of PMN life span, including MAPKs (24, 25), PI3K (26,27), and tyrosine kinases (28).…”

Section: Pi3k/akt Dependence Of Tlr Agonist Action On Pmn Apoptosismentioning

confidence: 99%

Inhibition of Neutrophil Apoptosis by TLR Agonists in Whole Blood: Involvement of the Phosphoinositide 3-Kinase/Akt and NF-κB Signaling Pathways, Leading to Increased Levels of Mcl-1, A1, and Phosphorylated Bad

François

Benna

Dang

et al. 2005

The Journal of Immunology

208

223

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Using flow cytometry, we investigated the effect of TLR agonists on human polymorphonuclear neutrophil (PMN) apoptosis in whole blood. LPS (TLR4), peptidoglycan (TLR2), R-848 (TLR7/8), and CpG-DNA (TLR9) were equally effective at delaying spontaneous apoptosis of PMN, while PamCSK4 (TLR1/2), macrophage-activating lipopeptide-2 (TLR2/6), flagellin (TLR5), and loxoribine (TLR7) were less effective or inactive. TLR agonists found to delay apoptosis also extended the functional life span of PMN. Analysis of signaling pathways revealed that the antiapoptotic effect of TLR agonists required NF-κB and PI3K activation. Furthermore, analysis of intact cells by flow cytometry showed that TLR agonists delaying PMN apoptosis increased phosphorylation of Akt, a major target of PI3K. This effect was associated with a PI3K-dependent increase in heat shock protein 27 phosphorylation, which has been reported to play a key role in PMN survival. Finally, the TLR-induced delay in PMN apoptosis was associated with increased levels of Mcl-1 and A1, which are antiapoptotic members of the Bcl-2 family. These effects were reversed by PI3K and NF-κB inhibitors, respectively. TLR activation also led to PI3K-dependent phosphorylation of the proapoptotic protein Bad. Taken together, our results strongly suggest a role of NF-κB and PI3K in TLR-induced PMN survival, leading to modulation of Bcl-2 family molecules.

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Inhibition of Neutrophil Apoptosis by Type 1 IFN Depends on Cross-Talk Between Phosphoinositol 3-Kinase, Protein Kinase C-δ, and NF-κB Signaling Pathways

Cited by 82 publications

References 53 publications

Combinatorial pattern recognition receptor signaling alters the balance of life and death in macrophages

Combinatorial pattern recognition receptor signaling alters the balance of life and death in macrophages

Periodontitis Associates with a Type 1 IFN Signature in Peripheral Blood Neutrophils

Inhibition of Neutrophil Apoptosis by TLR Agonists in Whole Blood: Involvement of the Phosphoinositide 3-Kinase/Akt and NF-κB Signaling Pathways, Leading to Increased Levels of Mcl-1, A1, and Phosphorylated Bad

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