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

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.

Mitochondrial dysfunction in cell senescence and aging

“…mtDNA has the capacity to activate multiple immune response pathways, including the NLRP3 inflammasome (120,121) and the cyclic GMP-AMP synthase (cGAS)/stimulator of interferon genes (STING) pathway (122). These innate immune responses are activated not only in aging (121,123,124), but also in cell senescence. The NLRP3 inflammasome was activated via a ROS/thioredoxin-interacting protein pathway in senescent vascular epithelial cells (125) and contributed to senescence maintenance via an NLRP3/IL-1β positive-feedback loop (126).…”

The Impact of Inflammatory Stimuli on Xylosyltransferase-I Regulation in Primary Human Dermal Fibroblasts

“…Whole sequence analysis identified four modifier genes in PXE that belong to the IL1B and inflammasome signaling pathway [ 29 ]. Furthermore, PXE has several similarities with the prominent premature aging disorder Hutchinson–Gilford progeria syndrome, which has also been shown previously to involve the aberrant regulation of inflammasome pathway components [ 30 ]. In addition, there is growing evidence indicating a correlation between ABCC6 dysfunction and dyslipidemia.…”

Podocyte-specific Nlrp3 inflammasome activation promotes diabetic kidney disease

“…Targeting NLRP3 may have an effect in addition to inhibiting inflammasome or inflammasome signaling (e.g., by blocking IL-1 receptor). The efficacy, feasibility, and safety of NLRP3 inflammasome inhibition in patients with DKD, potentially using small-molecule compounds, 51,52 remain to be evaluated. DISCLOSURE PRM reports honoraria from Roche, Novarits, Amgen, Genzyme, Boehringer Ingelheim, and BMS; patents and inventions including p18 protein as a marker of inflammatory disease; Midkine as marker of cardiovascular disease; and scientific advisor or membership with Clinical Nephrology.…”