Activation of TAK1 by Chemotactic and Growth Factors, and Its Impact on Human Neutrophil Signaling and Functional Responses

Sylvain-Prévost, Stéphanie; Ear, Thornin; Simard, François; Fortin, Carl; Dubois, Claire M.; Flamand, Nicolas; McDonald, Patrick P.

doi:10.4049/jimmunol.1402752

Cited by 16 publications

(21 citation statements)

References 51 publications

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“…By contrast, inhibition of Src tyrosine kinases consistently failed to interfere with NETosis. For physiological stimuli such as TNFα, fMLP, or GM-CSF, our data are consistent with our previous findings, which showed that they can all signal through the TAK1-MEK or TAK1-p38 axes in neutrophils ( 43 , 44 ). Conversely, PMA does not activate TAK1 in these cells (our unpublished data), and accordingly, TAK1 inhibition had no significant effect on PMA-elicited NETosis.…”

Section: Discussionsupporting

confidence: 92%

Physiological Stimuli Induce PAD4-Dependent, ROS-Independent NETosis, With Early and Late Events Controlled by Discrete Signaling Pathways

2018

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Neutrophils are known to extrude decondensed chromatin, thus forming NETs (neutrophil extracellular traps). These structures immobilize pathogens, thereby preventing their spreading, and are also adorned with antimicrobial molecules. NETs can also influence pathogenesis in chronic inflammation, autoimmunity, and cancer. Despite the importance of NETs, the molecular mechanisms underlying their formation, as well as the upstream signaling pathways involved, are only partially understood. Likewise, current methodological approaches to quantify NETs suffer from significant drawbacks, not the least being the inclusion of a significant non-specific signal. In this study, we used novel, fluorescent polymers that only bind extruded chromatin, allowing a specific and standardized quantification of NETosis. This allowed us to reliably rank the relative potency of various physiologic NET inducers. In neutrophils activated with such stimuli, inhibition of the Syk or PI3K pathways blocked NETosis by acting upon late events in NET formation. Inhibition of the TAK1, p38 MAPK, or MEK pathways also hindered NETosis, but by acting on early events. By contrast, inhibiting PKC, Src family kinases, or JNK failed to prevent NETosis; cycloheximide or actinomycin D were also ineffective. Expectedly, NET formation was deeply compromised following inhibition of the NADPH oxidase in PMA-activated neutrophils, but was found to be ROS-independent in response to physiological agonists. Conversely, we show for the first time in human neutrophils that selective inhibition of PAD4 potently prevents NETosis by all stimuli tested. Our data substantially extends current knowledge of the signaling pathways controlling NETosis, and reveals how they affect early or late stages of the phenomenon. In view of the involvement of NETs in several pathologies, our findings also identify molecular targets that could be exploited for therapeutic intervention.

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Section: Discussionsupporting

confidence: 92%

Physiological Stimuli Induce PAD4-Dependent, ROS-Independent NETosis, With Early and Late Events Controlled by Discrete Signaling Pathways

2018

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“…We have shown previously that the p38 MAPK, MEK/ERK, and PI3K/Akt cascades are controlled by the MAP3K, TAK1, in human neutrophils exposed to various physiological stimuli (24,25,32,33). We therefore verified whether this is also the case in response to MSU crystals.…”

Section: Signaling Cascades That Are Rapidly Elicited By Msusupporting

confidence: 64%

“…By comparison, our data represents the first demonstration that ERK and Akt Ser473 can also be activated by MSU. Thus, the kinases activated by MSU are essentially the same as those mobilized by several physiological neutrophil agonists (23,25,26,33,39,40). Morevoer, we found that the MSU-elicited phosphorylation of p38 MAPK, ERK, and Akt occurs downstream of TAK1 and Syk, much like it does in response to several classical neutrophil stimuli (24,33).…”

Section: Discussionsupporting

confidence: 52%

“…Thus, the kinases activated by MSU are essentially the same as those mobilized by several physiological neutrophil agonists (23,25,26,33,39,40). Morevoer, we found that the MSU-elicited phosphorylation of p38 MAPK, ERK, and Akt occurs downstream of TAK1 and Syk, much like it does in response to several classical neutrophil stimuli (24,33). Thus, the undetectable synthesis of several proteins despite strongly induced corresponding genes in MSU-treated cells, cannot be attributed to a general defect in signaling.…”

Section: Discussionmentioning

confidence: 58%

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Cytokine Production and NET Formation by Monosodium Urate-Activated Human Neutrophils Involves Early and Late Events, and Requires Upstream TAK1 and Syk

et al. 2020

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Gout is a prevalent and incapacitating disease triggered by the deposition of monosodium urate (MSU) crystals in joints, which are also massively infiltrated by neutrophils. The interaction of the latter with MSU crystals triggers several responses, including the generation of inflammatory mediators and of neutrophil extracellular traps (NETs). Though some of the signaling events mobilized by MSU in neutrophils have been described (e.g., Src family kinases, Syk, PKC, PI3K), the picture remains fragmentary. Likewise, the impact of these signaling events on cellular responses is incompletely understood. In this study, we examined transcriptomic changes triggered by MSU in neutrophils and their impact on the corresponding proteins, as well as the role of various signaling pathways in prominent functional responses. We report for the first time that neutrophils can secrete the monocyte chemoattractant, CCL4, in response to MSU. Accordingly, we found that transcription factors NF-κB, CREB, and C/EBP are belatedly activated by MSU crystals, and at least the former is involved in chemokine generation. Moreover, we show that MAPKs and Akt are activated by MSU in neutrophils, that they are under the control of TAK1 and Syk, and that they participate in cytokine generation and NETosis. In the latter instance, we found the phenomenon to be independent of endogenous ROS, but under the control of PAD4. We finally provide evidence that endogenous factors contribute to the belated phosphorylation of kinases and transcription factors in response to MSU. Collectively, our findings unveil potentially important therapeutic targets for gouty arthritis.

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“…More recently, we also found that FcγRIIIb induced a robust activation of ERK and also of the transcription factor Elk-1 ( 17 ), but we could not identify the molecule responsible for ERK activation. Similarly, others have reported that, in human neutrophils, TAK1 acted upstream of MEK (ERK kinase) and ERK signaling pathway ( 18 , 19 ). Thus, in this report, we explored the possibility that TAK1 is functionally coupled to FcγRIIIb leading to NETosis via ERK activation.…”

Section: Introductionmentioning

confidence: 75%

Transforming Growth Factor-β-Activated Kinase 1 Is Required for Human FcγRIIIb-Induced Neutrophil Extracellular Trap Formation

et al. 2016

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Neutrophils (PMNs) are the most abundant leukocytes in the blood. PMN migrates from the circulation to sites of infection where they are responsible for antimicrobial functions. PMN uses phagocytosis, degranulation, and formation of neutrophil extracellular traps (NETs) to kill microbes. Several stimuli, including bacteria, fungi, and parasites, and some pharmacological compounds, such as Phorbol 12-myristate 13-acetate (PMA), are efficient inducers of NETs. Antigen–antibody complexes are also capable of inducing NET formation. Recently, it was reported that FcγRIIIb cross-linking induced NET formation similarly to PMA stimulation. Direct cross-linking of FcγRIIA or integrins did not promote NET formation. FcγRIIIb-induced NET formation presented different kinetics from PMA-induced NET formation, suggesting differences in signaling. Because FcγRIIIb also induces a strong activation of extracellular signal-regulated kinase (ERK) and nuclear factor Elk-1, and the transforming growth factor-β-activated kinase 1 (TAK1) has recently been implicated in ERK signaling, in the present report, we explored the role of TAK1 in the signaling pathway activated by FcγRIIIb leading to NET formation. FcγRIIIb was stimulated by specific monoclonal antibodies, and NET formation was evaluated in the presence or absence of pharmacological inhibitors. The antibiotic LL Z1640-2, a selective inhibitor of TAK1 prevented FcγRIIIb-induced, but not PMA-induced NET formation. Both PMA and FcγRIIIb cross-linking induced phosphorylation of ERK. But, LL Z1640-2 only inhibited the FcγRIIIb-mediated activation of ERK. Also, only FcγRIIIb, similarly to transforming growth factor-β-induced TAK1 phosphorylation. A MEK (ERK kinase)-specific inhibitor was able to prevent ERK phosphorylation induced by both PMA and FcγRIIIb. These data show for the first time that FcγRIIIb cross-linking activates TAK1, and that this kinase is required for triggering the MEK/ERK signaling pathway to NETosis.

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Activation of TAK1 by Chemotactic and Growth Factors, and Its Impact on Human Neutrophil Signaling and Functional Responses

Cited by 16 publications

References 51 publications

Physiological Stimuli Induce PAD4-Dependent, ROS-Independent NETosis, With Early and Late Events Controlled by Discrete Signaling Pathways

Physiological Stimuli Induce PAD4-Dependent, ROS-Independent NETosis, With Early and Late Events Controlled by Discrete Signaling Pathways

Cytokine Production and NET Formation by Monosodium Urate-Activated Human Neutrophils Involves Early and Late Events, and Requires Upstream TAK1 and Syk

Transforming Growth Factor-β-Activated Kinase 1 Is Required for Human FcγRIIIb-Induced Neutrophil Extracellular Trap Formation

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