The Synthetic Lignan Secoisolariciresinol Diglucoside Prevents Asbestos-Induced NLRP3 Inflammasome Activation in Murine Macrophages

Our plain-English summary of The Synthetic Lignan Secoisolariciresinol Diglucoside Prevents Asbestos-Induced NLRP3 Inflammasome Activation in Murine Macrophages, by R.A. Pietrofesa, P. Woodruff, W.T. Hwang, et al (Oxidative Medicine and Cellular Longevity, 2017).

The study

• Authors: R.A. Pietrofesa, P. Woodruff, W.T. Hwang, P. Patel, S. Chatterjee, S.M. Albelda, M. Christofidou-Solomidou
• Journal: Oxidative Medicine and Cellular Longevity
• Published: 2017;2017:7395238
• Cited by: 21 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Background: The interaction of asbestos with macrophages drives two key processes that are linked to malignancy: (1) the generation of reactive oxygen species (ROS)/reactive nitrogen species (RNS) and (2) the activation of an inflammation cascade that drives acute and chronic inflammation, with the NLRP3 inflammasome playing a key role. Synthetic secoisolariciresinol diglucoside (SDG), LGM2605, is a nontoxic lignan with anti-inflammatory and antioxidant properties and was evaluated for protection from asbestos in murine peritoneal macrophages (MF).

Methods: MFs were exposed to crocidolite asbestos ± LGM2605 given 4 hours prior to exposure and evaluated at various times for NLRP3 expression, secretion of inflammasome-activated cytokines (IL-1β and IL-18), proinflammatory cytokines (IL-6, TNFα, and HMGB1), NF-κB activation, and levels of total nitrates/nitrites.

Results: Asbestos induces a significant (p < 0.0001) increase in the NLRP3 subunit, release of proinflammatory cytokines, NLRP3-activated cytokines, NF-κB, and levels of nitrates/nitrites. LGM2605 significantly reduced NLRP3 ranging from 40 to 81%, IL-1β by 89-96%, and TNFα by 67-78%, as well as activated NF-κB by 48-49% while decreasing levels of nitrates/nitrites by 85-93%.

Conclusions: LGM2605 reduced asbestos-induced NLRP3 expression, proinflammatory cytokine release, NF-κB activation, and nitrosative stress in MFs supporting its possible use in preventing the asbestos-induced inflammatory cascade leading to malignancy.

In plain English

This was a laboratory study of mouse cells, not people. The authors exposed macrophages (immune cells) taken from the abdominal cavity of mice to crocidolite asbestos fibers in culture dishes, with or without LGM2605, a synthetic form of a flaxseed compound, given 4 hours beforehand. Over 24 hours, asbestos raised the cells' levels of NLRP3, a protein that triggers inflammation. It also raised their release of inflammatory signaling proteins (IL-1β, IL-18, IL-6, TNFα, HMGB1) and of nitrates/nitrites, a marker of nitrogen-based chemical stress. In cells pretreated with LGM2605, NLRP3 was 40–81% lower, IL-1β 89–96% lower, IL-18 84–95% lower, IL-6 and TNFα 62% and 66% lower, early HMGB1 73–75% lower, nitrates/nitrites 85–93% lower, and activation of NF-κB, a controller of inflammatory genes, about 48% lower. The authors concluded that LGM2605 may impede the asbestos-induced inflammatory cascade on the way to malignancy, and that it may be useful in longer-term animal models of asbestos-induced mesothelioma. They noted that how it blocks NF-κB is not clear.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory (in vitro) experiment on mouse cells grown in culture dishes
• Who was studied: Elicited peritoneal (abdominal-cavity) macrophages collected from mice aged 13 weeks at the University of Pennsylvania. The number of mice is not stated. Results come from three separate experiments.
• Exposure: Sterile UICC crocidolite asbestos fibers at 20 μg/cm2, with or without 50 μM LGM2605 (synthetic secoisolariciresinol diglucoside) given 4 hours before the asbestos. Measurements were taken at time points up to 24 hours after exposure.
• Main results:
  • In imaging, LGM2605 pretreatment reduced asbestos-induced NLRP3 expression by 40–81%, to levels comparable to untreated cells.
  • By Western blot, NLRP3 in asbestos-exposed cells rose to 1.63 ± 0.06-fold over control at 24 hours. In cells given asbestos plus LGM2605 it was 1.11 ± 0.09-fold over control.
  • In asbestos-exposed cells, IL-1β rose from 4.04 ± 0.13 pg/ml at baseline to 586.13 ± 4.61 pg/ml within 6 hours. IL-18 rose from 1.65 ± 0.10 to 424.62 ± 8.80 pg/ml by 24 hours. LGM2605 pretreatment reduced IL-1β by 89–96% and IL-18 by 84–95%.
  • In asbestos-exposed cells, IL-6 and TNFα peaked at 24 hours at 455.99 ± 3.03 and 695.34 ± 5.80 pg/ml. With LGM2605 they were reduced by 62% and 66%, to 172.98 ± 2.76 and 227.89 ± 3.30 pg/ml.
  • In asbestos-exposed cells, HMGB1 peaked at 30 minutes (39.85 ± 1.12 ng/ml). LGM2605 reduced this early rise by 73 to 75%.
  • In asbestos-exposed cells, nitrates/nitrites reached 465.99 ± 4.20 μM at 24 hours. With LGM2605 they were reduced by 85–93%, to 34.87 ± 0.55 μM.
  • iNOS mRNA in asbestos-exposed cells was 5.41- and 8.78-fold above untreated cells at 8 and 24 hours, compared with 1.84- and 2.20-fold with LGM2605. iNOS protein was not detectable in asbestos-exposed cells treated with LGM2605.
  • Asbestos increased active NF-κB in cell nuclei, peaking 2 hours after exposure. LGM2605 reduced asbestos-induced NF-κB activation and expression by about 48%.
• The authors' conclusion: The authors concluded that LGM2605 reduced proinflammatory cytokine release and markers of oxidative and nitrosative stress in mouse peritoneal macrophages. In their view, it may impede the asbestos-induced inflammatory cascade on the way to malignancy, and it is potentially useful in chronic in vivo models of asbestos-induced mesothelioma.
• Limitations the authors state:
  • The authors state that the mechanism by which LGM2605 inhibits NF-κB activation is not clear.

Topics

Medical terms in this study, explained in our Lexicon: Macrophage, Reactive Oxygen Species (ROS), Reactive Nitrogen Species (RNS), Inflammation, Chronic Inflammation, Crocidolite, Cytokine, High Mobility Group Box 1 (HMGB1).

Related studies

• Asbestos Induces Oxidative Stress and Activation of Nrf2 Signaling in Murine Macrophages: Chemopreventive Role of the Synthetic Lignan Secoisolariciresinol Diglucoside (LGM2605) — R.A. Pietrofesa, A. Velalopoulou, et al. (2016)
• Flaxseed lignans enriched in secoisolariciresinol diglucoside prevent acute asbestos-induced peritoneal inflammation in mice — R.A. Pietrofesa, A. Velalopoulou, et al. (2016)
• Synthetic secoisolariciresinol diglucoside (LGM2605) inhibits Libby amphibole fiber-induced acute inflammation in mice — M. Christofidou-Solomidou, R.A. Pietrofesa, et al. (2019)
• Synthetic Secoisolariciresinol Diglucoside (LGM2605) Prevents Asbestos-Induced Inflammation and Genotoxic Cell Damage in Human Mesothelial Cells — R.A. Pietrofesa, S. Chatterjee, et al. (2022)
• Late Inflammation Induced by Asbestiform Fibers in Mice Is Ameliorated by a Small Molecule Synthetic Lignan — R. Badger, K. Park, et al. (2021)
• Synthetic Lignan Secoisolariciresinol Diglucoside (LGM2605) Reduces Asbestos-Induced Cytotoxicity in an Nrf2-Dependent and -Independent Manner — R.A. Pietrofesa, S. Chatterjee, et al. (2018)

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