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. 2021 Oct 7;13(10):e14012.
doi: 10.15252/emmm.202114012. Epub 2021 Aug 27.

Inhibition of the NLRP3 inflammasome improves lifespan in animal murine model of Hutchinson-Gilford Progeria

Alvaro González-Dominguez  1 , Raúl Montañez  1 , Beatriz Castejón-Vega  2 , Jéssica Nuñez-Vasco  1 , Débora Lendines-Cordero  1 , Chun Wang  3 , Gabriel Mbalaviele  3 , José M Navarro-Pando  4 , Elísabet Alcocer-Gómez  5 , Mario D Cordero  1
Affiliations

Inhibition of the NLRP3 inflammasome improves lifespan in animal murine model of Hutchinson-Gilford Progeria

Alvaro González-Dominguez et al. EMBO Mol Med. .

Abstract

Inflammation is a hallmark of aging and accelerated aging syndromes such as Hutchinson-Gilford progeria syndrome (HGPS). In this study, we present evidence of increased expression of the components of the NLRP3 inflammasome pathway in HGPS skin fibroblasts, an outcome that was associated with morphological changes of the nuclei of the cells. Lymphoblasts from HGPS patients also showed increased basal levels of NLRP3 and caspase 1. Consistent with these results, the expression of caspase 1 and Nlrp3, but not of the other inflammasome receptors was higher in the heart and liver of Zmpste24-/- mice, which phenocopy the human disease. These data were further corroborated in LmnaG609G/G609G mice, another HGPS animal model. We also showed that pharmacological inhibition of the NLRP3 inflammasome by its selective inhibitor, MCC950, improved cellular phenotype, significantly extended the lifespan of progeroid animals, and reduced inflammasome-dependent inflammation. These findings suggest that inhibition of the NLRP3 inflammasome is a potential therapeutic approach for the treatment of HGPS.

Keywords: NLRP3 inflammasome; aging; progeria.

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Conflict of interest statement

The authors declare that they have no conflict of interest.

Figures

Figure 1
Figure 1. NLRP3 signaling is associated with HGPS

  1. Western blot analysis with representative blot including lamin A/C, NLRP3, caspase 1, and actin levels in skin fibroblasts from patients with HGPS, n = 2 controls and 2 patients. Positive control correspond to THP1 cells stimulated with LPS+ATP.

  2. Immunofluorescence (IF) visualization of NLRP3 (green) and nuclei (blue) in skin fibroblasts from a representative patient and control. Scale bar: 30 µm.

  3. Protein expression of NLRP3 and caspase 1 in lymphoblasts from control and one patient after stimulation with uric acid and cholesterol crystal.

  4. IL‐1β and IL‐18 medium release from lymphoblasts which were assessed after a 24‐h incubation with uric acid and cholesterol. ***P < 0.001, **P < 0.005, * treatment vs no treatment; aaa P < 0.001; aa P < 0.01 control cells vs patient cells.

  5. Western blot analysis with representative blot including NLRP3, caspase 1, IL‐1β and actin levels in heart and liver tissues from wild‐type and Zmpste24−/− mice.

  6. NLRP3 and caspase 1 transcript expression levels were determined in heart and liver tissues by real‐time quantitative RT–PCR. n = 5 for Zmpste24+/+ and n = 5 for Zmpste24−/− groups respectively. ***P < 0.001, **P < 0.005, wild‐type vs Zmpste24−/− mice. Data are showed means ± SD, n = 4 mice per group.

Data information: Results are presented as the mean ± SD of three independent experiments. One‐way ANOVA test was used for statistical analysis Source data are available online for this figure.
Figure EV1
Figure EV1. NLRP3 inflammasomes expression in lung and muscle from progeroid animals
Western blot analysis with representative blot including NLRP3, caspase 1, and actin levels in lung and muscle tissues from wild‐type and Zmpste24−/− mice. Densitometric analysis is shown as means ± SD, n = 5 mice per group. Data are shown as means ± SD. ***P < 0.001, wild‐type vs Zmpste24−/− mice. One‐way ANOVA test was used for statistical analysis. Source data are available online for this figure.
Figure EV2
Figure EV2. NLRP3 inflammasomes expression in heart and liver from LmnaG609G/G609G mice
Western blot analysis with representative blot including NLRP3, IL‐1β, and actin levels in cardiac and liver tissues from wild‐type and LmnaG609G/G609G mice. Densitometric analysis is shown as means ± SD, n = 4 mice per group. Data are shown as means ± SD. ***P < 0.001, **P < 0.005, *P < 0.05 wild‐type vs LmnaG609G/G609G mice. One‐way ANOVA test was used for statistical analysis. Source data are available online for this figure.
Figure 2
Figure 2. NLRP3 inhibition by MCC950 ameliorates skin fibroblasts and Zmpste24‐deficient mice progeroid phenotypes
  1. A

    Cell growth (lower subpanel left patient 1 and right patient 2) and morphological aspect (upper subpanel) with MCC950 determined in healthy and representative HGPS fibroblasts. **P < 0.01, *P < 0.05 patient cells no treatment vs treatment. Results are presented as the mean ± SD of three independent experiments.

  2. B

    Western blot analysis with representative blots including lamin A/C, NLRP3, IL‐1β, and actin levels in skin fibroblasts from control and HGPS patient after 48 h of vehicle and MCC950 treatment.

  3. C–E

    Representative fluorescence images of HGPS and control fibroblasts to evaluate the effect of the MCC950 in the nuclear morphology (D) and NLRP3 expression (E). Scale bar: 30 µm. Results are presented as the mean ± SD of three independent experiments. ***P < 0.01 patient vs control cells, aaa P < 0.01 patient cells no treatment vs treatment. One‐way ANOVA test was used for statistical analysis.

  4. F

    Kaplan–Meier graph showing a significant increase in the maximum lifespan in WT mice compared with Zmpste24−/− mice. N = 7 per group.

  5. G

    Body weights evolution of the groups over time. Data are showed means ± SD, n = 6 mice per group.

  6. H

    Analysis of serum concentrations of IL‐1β measured by ELISA. N = 6 per group. Data are shown as means ± SD. ***P < 0.001, wild‐type vs Zmpste24−/− mice; aaa P < 0.001; vehicle vs MCC950.

Source data are available online for this figure.
See this image and copyright information in PMC

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