Role for NLRP3 Inflammasome–mediated, IL-1β–Dependent Responses in Severe, Steroid-Resistant Asthma

Kim, Richard; Pinkerton, James; Essilfie, Ama-Tawiah; Robertson, Avril A. B.; Baines, Katherine J.; Brown, Alexandra C.; Mayall, Jemma; Ali, Khadem; Starkey, Malcolm R.; Hansbro, Philip M.; Hirota, Jeremy A.; Wood, Lisa G.; Simpson, Jodie L.; Knight, Darryl A.; Wark, Peter; Gibson, Peter G.; O’Neill, Luke A. J.; Cooper, Matthew A.; Horvat, Jay C.

doi:10.1164/rccm.201609-1830oc

Cited by 342 publications

(361 citation statements)

References 51 publications

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“…A549 cells were infected or transfected prior to cell lysis in KALB buffer (150 m m NaCl, 50 m m Tris–HCl pH 7.5, 1% (v/v) Triton X‐100, 1 m m ethylenediaminetetraacetic acid) containing protease inhibitors (complete cocktail tablets; Roche, Mannheim, Germany), 1 m m phenylmethylsulfonyl fluoride, 1 m m Na 3 VO 4 and 1 m m NaF. Lysates were then analyzed using gel electrophoresis and immunoblotting as previously described …”

Section: Methodsmentioning

confidence: 99%

RIPLET, and not TRIM25, is required for endogenous RIG‐I‐dependent antiviral responses

et al. 2019

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The innate immune system is our first line of defense against viral pathogens. Host cell pattern recognition receptors sense viral components and initiate immune signaling cascades that result in the production of an array of cytokines to combat infection. Retinoic acid–inducible gene‐I (RIG‐I) is a pattern recognition receptor that recognizes viral RNA and, when activated, results in the production of type I and III interferons (IFNs) and the upregulation of IFN‐stimulated genes. Ubiquitination of RIG‐I by the E3 ligases tripartite motif‐containing 25 (TRIM25) and Riplet is thought to be requisite for RIG‐I activation; however, recent studies have questioned the relative importance of these two enzymes for RIG‐I signaling. In this study, we show that deletion of Trim25 does not affect the IFN response to either influenza A virus (IAV), influenza B virus, Sendai virus or several RIG‐I agonists. This is in contrast to deletion of either Rig‐i or Riplet, which completely abrogated RIG‐I‐dependent IFN responses. This was consistent in both mouse and human cell lines, as well as in normal human bronchial cells. With most of the current TRIM25 literature based on exogenous expression, these findings provide critical evidence that Riplet, and not TRIM25, is required endogenously for the ubiquitination of RIG‐I. Despite this, loss of TRIM25 results in greater susceptibility to IAV infection in vivo, suggesting that it may have an alternative role in host antiviral defense. This study refines our understanding of RIG‐I signaling in viral infections and will inform future studies in the field.

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Section: Methodsmentioning

confidence: 99%

RIPLET, and not TRIM25, is required for endogenous RIG‐I‐dependent antiviral responses

et al. 2019

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“…Kim and colleagues demonstrate that infection of mice with either Chlamydia or Haemophilus after allergen sensitization and challenge resulted in steroid-resistant disease characterized by neutrophilic inflammation and an increase in expression and activation of the NLRP3/IL-1b pathway (4). Further analysis of clinical samples corroborated the notion that the NLRP3/IL-1b pathway was instrumental in SRA, with sputum NLRP3 and IL-1b expression correlating with neutrophilia, severity of disease, and steroid resistance.…”

mentioning

confidence: 91%

“…In this edition of the Journal, Kim and colleagues (pp. 283-297) use robust animal models and paired clinical studies to demonstrate the importance of nucleotide-binding domain and leucine-rich repeat-containing protein 3 (NLRP3) inflammasome-mediated IL-1b production in driving the pathology of SRA and highlight that intervention of this pathway offers clear therapeutic potential (4).…”

mentioning

confidence: 99%

“…Kim and colleagues demonstrate the therapeutic efficacy of targeting the NLRP3 inflammasome pathway at various levels, be it inhibition of caspase-1 or NLRP3 itself or IL-1b antagonism (4). As with all antiinflammatory strategies, there is always an inherent risk of compromising host defense, and yet adverse infectious events are seemingly rare in patients in whom IL-1b signaling has been perturbed (11).…”

mentioning

confidence: 99%

“…Nonetheless, given the specific involvement of the NLRP3 inflammasome in driving SRA, it may be prudent to assess the therapeutic potential of selective NLRP3 inhibitors, such as MCC950, in the clinic rather than strategies that will affect global IL-1b production from all inflammasome complexes. Regardless, these exciting studies by Kim and colleagues highlight a clear rationale to reduce IL-1b availability to ameliorate neutrophilic SRA (4). n…”

mentioning

confidence: 99%

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An NLRP3, IL-1β, Neutrophil Axis in the Respiratory Tract Leaves You Breathless

Snelgrove

Lloyd

2017

Am J Respir Crit Care Med

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Exposure to environmental black carbon exacerbates nasal epithelial inflammation via the reactive oxygen species (ROS)–nucleotide‐binding, oligomerization domain–like receptor family, pyrin domain containing 3 (NLRP3)–caspase‐1–interleukin 1β (IL‐1β) pathway

Ouyang

Jiao

et al. 2020

Int Forum Allergy Rhinol

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Background Allergic rhinitis AR is an increasing challenge to public health worldwide Exposure to environmental black carbon BC is associated with increased risk of allergic rhinitis but the molecular mechanisms underlying its toxicity have not been fully elucidated The aims of the present study were therefore to determine the effect of BC on the expression of interleukin β IL-β and to investigate the mechanism underlying BC-induced IL-β production in pollen-sensitized human nasal epithelial cells hNECs Methods Nasal mucosal samples collected from patients undergoing nasal surgery were used to isolate and culture epithelial cells as air-liquid interface ALI cultures Cultures exposed to BC ± pollen allergen for hours were assessed for the presence of IL-β the production of reactive oxygen species ROS and activation of the nucleotidebinding oligomerization domain-like receptor family pyrin domain containing NLRP inflammasome Furthermore the mechanisms underlying BC ± pollen allergen-induced IL-β in hNECs were evaluated Results Exposure to BC significantly increased the production of IL-β and ROS and the expression of NLRP in hNECs compared with control all of which were significantly increased further by exposure to a combination of BC and pollen Incubation of hNECs with N-acetyl-L-cysteine NAC significantly attenuated BC ± polleninduced expression of ROS NLRP and IL-β NLRP and Caspase-inhibitors MCC and YVAD significantly inhibited IL-β expression and NLRP activation but not NLRP expression following exposure to BC ± pollen Conclusion These findings suggest that exposure to BC and pollen can exaggerate oxidative stress and significantly increase the expression of IL-β in hNECs and that this may involve a pathway integrating ROS-NLRP-Caspase-IL-β signaling © 2020 ARS-AAOA, LLC.

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Role for NLRP3 Inflammasome–mediated, IL-1β–Dependent Responses in Severe, Steroid-Resistant Asthma

Abstract: NLRP3 inflammasome responses drive experimental severe, steroid-resistant asthma and are potential therapeutic targets in this disease.

Cited by 342 publications

References 51 publications

RIPLET, and not TRIM25, is required for endogenous RIG‐I‐dependent antiviral responses

RIPLET, and not TRIM25, is required for endogenous RIG‐I‐dependent antiviral responses

An NLRP3, IL-1β, Neutrophil Axis in the Respiratory Tract Leaves You Breathless

Exposure to environmental black carbon exacerbates nasal epithelial inflammation via the reactive oxygen species (ROS)–nucleotide‐binding, oligomerization domain–like receptor family, pyrin domain containing 3 (NLRP3)–caspase‐1–interleukin 1β (IL‐1β) pathway

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