TAK1 restricts spontaneous NLRP3 activation and cell death to control myeloid proliferation

Malireddi, R. K. Subbarao; Gurung, Prajwal; Mavuluri, Jayadev; Tk, Dasari; Jm, Klco; H, Chi; Kanneganti, Thirumala‐Devi

doi:10.1084/jem.20171922

Cited by 189 publications

(216 citation statements)

References 68 publications

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“…In this issue, Malireddi and colleagues used a myeloid-specific TAK1 KO mouse to shed new light on a novel, antiinflammatory function of TAK1 in macrophages that may explain, at first sight, the paradoxical inflammatory findings. As previously demonstrated in other cell models, they found that TAK1 deletion or inhibition resulted in spontaneous death of the TAK1-deficient macrophages, mediated by enhanced RIP1 and RIP3 signaling (Malireddi et al, 2018). Strikingly, however, these cells also underwent spontaneous NLRP3 inflammasome activation in the absence of any exogenous signals.…”

Section: Tak1ng Control: Tak1 Restrains Nlrp3 Activationsupporting

confidence: 68%

TAK1ng control: TAK1 restrains NLRP3 activation

Mangan

Latz

2018

Journal of Experimental Medicine

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Section: Tak1ng Control: Tak1 Restrains Nlrp3 Activationsupporting

confidence: 68%

TAK1ng control: TAK1 restrains NLRP3 activation

Mangan

Latz

2018

Journal of Experimental Medicine

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“…TAK1 has been shown to be crucial for mediating inflammation through NF-kB activation in many cell types (21). Recent published studies have demonstrated that TAK1 is also essential to prevent cell death in macrophages, cancer cells, and ECs (27,28,32). In our studies, under basal conditions we did not observe endothelial cell death either in TAK1 knockdown ECs or in TAK1-null ECs.…”

Section: Discussionsupporting

confidence: 47%

“…In B cells, TAK1 is required for B cell development and activation of NF-κB and MAPK signaling in response to TLR ligands, and BCR stimuli (23)(24)(25); whereas TAK1 in neutrophils negatively regulates NF-κB and p38MAP kinase activation (26). A study using myeloid-specific TAK1 knockout mice showed that TAK1 restricts spontaneous NLRP3 inflammasome activation and thereby prevents cell death in macrophages (27). TAK1 also suppresses RIPK1-dependent melanoma cell death (28) and RIPK3-dependent endothelial necroptosis (29).…”

Section: Introductionmentioning

confidence: 99%

TAK1 Regulates Endothelial Integrity Through Stabilization of Junctions via GSK3β and FoxO1

Soni

Wang

et al. 2019

Preprint

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TLR4 signaling in endothelial cells (ECs) induces vascular injury by disrupting the endothelial junctional barrier. However, it is not known whether TLR4 signaling can also promote endothelial barrier repair after vascular injury. Here we addressed the role of TAK1 activation downstream of TLR4 in the mechanism of vascular integrity. In inducible EC-restricted TAK1 knockout (TAK1 i∆EC ) mice, the endothelial barrier was compromised. Blocking TAK1 activity caused spontaneous loss of the endothelial barrier. Importantly, TAK1 inactivated GSK3β via AKT to prevent β-catenin downregulation. We observed in ECs of GSK3β i∆EC mice an increase in β-catenin transfer to the nucleus to form a complex with transcription factor FoxO1, thus repressing the expression of the tight junction protein claudin-5 and causing vascular leak.Strikingly, in TAK1 i∆EC mice, FoxO1 expression was dramatically increased while expression of AKT was suppressed, and in vivo inhibition of FoxO1 prevented sepsis-induced lung vascular leak in GSK3β i∆EC and TAK1 i∆EC mice. Further, EC-restricted deletion of FoxO1 in mice suppressed sepsis-induced lung vascular leak and mortality. Our findings point to the potential of targeting the TAK1-AKT-GSK3b-FoxO1 axis as a therapeutic approach to treat uncontrolled lung vascular leak in sepsis.

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“…Intriguingly, a previous study exploring kinase inhibitors in the context of inflammasome signaling had also identified TAK1 kinase activity as an important facilitator of NLRP3 inflammasome activation (Gong et al, 2010). While these data would argue for TAK1 kinase activity as a potential drug target in the NLRP3 inflammasome pathway, it has to be noted that prolonged inhibition of TAK1 can result in the induction of lytic cell death in the context of pro-inflammatory signals (Malireddi et al, 2018). This, in turn, can lead to secondary activation of the NLRP3 inflammasome due to the perturbation of membrane integrity and associated K + efflux.…”

Section: Discussionmentioning

confidence: 99%

Priming enables a NEK7-independent route of NLRP3 activation

Gaidt

Szymanska

et al. 2019

Preprint

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The NLRP3 inflammasome plays a central role in antimicrobial defense, as well as in sterile inflammatory conditions. NLRP3 activity is governed by two independent signals. The first signal primes NLRP3, allowing it to respond to its activation signal. In the murine system, the mitotic spindle kinase NEK7 has been identified as a crucial factor in relaying the activation signal to NLRP3. Here we show that the requirement for NEK7 can be bypassed by TAK1-dependent post-translational priming. Under pro-inflammatory conditions that activate TAK1, NEK7 was dispensable for NLRP3 inflammasome formation in human and murine cells. Intriguingly, dissecting the NEK7 requirement in iPSC-derived primary human macrophages revealed that this NEK7-independent mechanism constitutes the predominant NLRP3 priming pathway in these cells. In summary, our results suggest that NEK7 functions as an NLRP3 primingrather than activationfactor that can work in synergy or redundancy with other priming pathways to accelerate inflammasome activation.

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TAK1 restricts spontaneous NLRP3 activation and cell death to control myeloid proliferation

Cited by 189 publications

References 68 publications

TAK1ng control: TAK1 restrains NLRP3 activation

TAK1ng control: TAK1 restrains NLRP3 activation

TAK1 Regulates Endothelial Integrity Through Stabilization of Junctions via GSK3β and FoxO1

Priming enables a NEK7-independent route of NLRP3 activation

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