Influenza A viruses limit NLRP3‐NEK7‐complex formation and pyroptosis in human macrophages

Boal-Carvalho, Inês; Mazel-Sanchez, Béryl; Silva, Filo; Garnier, Laure; Yildiz, Soner; Bonifacio, Joao P P; Niu, Chengyue; Williams, Nathalia; François, Patrice; Schwerk, Nicolaus; Schöning, Jennifer; Carlens, Julia; Viemann, Dorothee; Hugues, Stéphanie; Schmolke, Mirco

doi:10.15252/embr.202050421

Cited by 36 publications

(21 citation statements)

References 98 publications

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“…These differences in cellular compartmentalization could explain the opposite effects observed. Accordingly, the pro-apoptotic effects exerted by PB1-F2 on macrophages has recently been called into question [ 26 ]. Similarly, the pro-inflammatory activity of PB1-F2 is highly questioned, as it has also been described that PB1-F2 is able to inhibit the host response, especially through its inhibitory action on MAVS [ 27 , 28 ].…”

Section: Introductionmentioning

confidence: 99%

Study of the host specificity of PB1-F2-associated virulence

et al. 2021

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Influenza A viruses cause important diseases in both human and animal. The PB1-F2 protein is a virulence factor expressed by some influenza viruses. Its deleterious action for the infected host is mostly described in mammals, while the available information is scarce in avian hosts. In this work, we compared the effects of PB1-F2 in avian and mammalian hosts by taking advantage of the zoonotic capabilities of an avian H7N1 virus. In vitro, the H7N1 virus did not behave differently when PB1-F2 was deficient while a H3N2 virus devoid of PB1-F2 was clearly less inflammatory. Likewise, when performing in vivo challenges of either chickens or embryonated eggs, with the wild-type or the PB1-F2 deficient virus, no difference could be observed in terms of mortality, host response or tropism. PB1-F2 therefore does not appear to play a major role as a virulence factor in the avian host. However, when infecting NF-κB-luciferase reporter mice with the H7N1 viruses, a massive PB1-F2-dependent inflammation was quantified, highlighting the host specificity of PB1-F2 virulence. Surprisingly, a chimeric 7:1 H3N2 virus harboring an H7N1-origin segment 2 (i.e. expressing the avian PB1-F2) induced a milder inflammatory response than its PB1-F2-deficient counterpart. This result shows that the pro-inflammatory activity of PB1-F2 is governed by complex mechanisms involving components from both the virus and its infected host. Thus, a mere exchange of segment 2 between strains is not sufficient to transmit the deleterious character of PB1-F2.

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Section: Introductionmentioning

confidence: 99%

Study of the host specificity of PB1-F2-associated virulence

et al. 2021

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“…NIMA-related kinase 7 (NEK7) is widely expressed in the brain, which is related to the initiation of mitosis, cell cycle progression, and mitotic progression [ 28 ]. Studies have found that NEK7 regulated the activation of NLRP3, which played an important role in the inflammatory cascade of macrophages [ 29 ]. Here, we show that liquiritin (40 mg/kg) inhibited the protein expression of NLRP3 inflammasome components in the hippocampal region by western blot and IHC assay, accompanied by significantly lower levels of IL-1 β and IL-18 as well.…”

Section: Discussionmentioning

confidence: 99%

Liquiritin Alleviates Depression-Like Behavior in CUMS Mice by Inhibiting Oxidative Stress and NLRP3 Inflammasome in Hippocampus

Liu

Yuan

Zhang

et al. 2022

Evidence-Based Complementary and Alternative Medicine

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Objective. Central inflammation is generally accepted to be involved in the pathology of depression. We investigated whether liquiritin exerts antidepressant effects by inhibiting central NLRP3 inflammasomes. Results. The behavioral despair model and chronic unpredictable mild stress (CUMS) model in mice were established to evaluate the antidepressant action of liquiritin. In the despair model study, liquiritin (40 mg/kg) administration reduced immobility time in tail suspension test (TST) and forced swimming test (FST) without affecting locomotion activity. In CUMS model study, liquiritin (40 mg/kg, once daily for 4 weeks) significantly increased sucrose consumption and body weight of CUMS mice. The behavioral experiment results showed that liquiritin reduced the immobile time of CUMS mice in TST and FST, respectively, and increased the time spent and open arm entries in the elevated plus-maze (EPM) test. Further, the hippocampal superoxide dismutase (SOD) activity was increased in liquiritin-treated group, while malonaldehyde (MDA) decreased. Additionally, the hippocampal cytokines interleukin-18 (IL-18) and interleukin-1 beta (IL-1β) contents were reduced in the liquiritin-treated group. Further, liquiritin downregulated the expression of NLRP3 in the hippocampus of CUMS mice rather than TLR4. Besides, NLRP3 inflammasome-associated proteins caspase-1 and ASC were also downregulated. However, liquiritin did not alter the thermal stability of NLRP3 in the cellular thermal shift assay (CETSA), suggesting that its inhibition of NLPR3 was not by direct targeting of NLRP3 protein. Conclusions. Liquiritin attenuates depression-like behavior of CUMS mice and inhibited cytokines levels triggered by NLRP3 inflammasome, suggesting the antidepressant action is, at least partially, associated with antioxidant stress and inhibition of NLRP3 inflammasome activation.

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“…A study suggested that LRR domain is unnecessary for mouse NLRP3 inflammasome activation [37]. However, most of viruses use the viral proteins to interact with the LRR domain to activate/promote NLRP3 inflammasome, such as EV71 3D interacted with LRR domain of NLRP3 [28]; Zika virus NS5 protein binds NLRP3 by interacting with NACHT and LRR domains [29]; and PB1-F2 of Influenza A viruses binds to the PYD and LRR domain of NLRP3 [38], so we speculated that LRR domain may act as the NLRP3 receptor domain for ligands after viral infection. Without stimulator, NLRP3 protein is thought to be auto-repressed through interaction between the domains of NACHT and LRRs.…”

Section: Discussionmentioning

confidence: 99%

FMDV Leader Protein Interacts with the NACHT and LRR Domains of NLRP3 to Promote IL-1β Production

Choudhury

et al. 2021

Viruses

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Foot-and-mouth disease virus (FMDV) infection causes inflammatory clinical symptoms, such as high fever and vesicular lesions, even death of animals. Interleukin-1β (IL-1β) is an inflammatory cytokine that plays an essential role in inflammatory responses against viral infection. The viruses have developed multiple strategies to induce the inflammatory responses, including regulation of IL-1β production. However, the molecular mechanism underlying the induction of IL-1β by FMDV remains not fully understood. Here, we found that FMDV robustly induced IL-1β production in macrophages and pigs. Infection of Casp-1 inhibitor-treated cells and NOD-, LRR- and pyrin domain-containing 3 (NLRP3)-knockdown cells indicated that NLRP3 is essential for FMDV-induced IL-1β secretion. More importantly, we found that FMDV Lpro associates with the NACHT and LRR domains of NLRP3 to promote NLRP3 inflammasome assembly and IL-1β secretion. Moreover, FMDV Lpro induces calcium influx and potassium efflux, which trigger NLRP3 activation. Our data revealed the mechanism underlying the activation of the NLRP3 inflammasome after FMDV Lpro expression, thus providing insights for the control of FMDV infection-induced inflammation.

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Influenza A viruses limit NLRP3‐NEK7‐complex formation and pyroptosis in human macrophages

Cited by 36 publications

References 98 publications

Study of the host specificity of PB1-F2-associated virulence

Study of the host specificity of PB1-F2-associated virulence

Liquiritin Alleviates Depression-Like Behavior in CUMS Mice by Inhibiting Oxidative Stress and NLRP3 Inflammasome in Hippocampus

FMDV Leader Protein Interacts with the NACHT and LRR Domains of NLRP3 to Promote IL-1β Production

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