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bioRxiv · 10.1101/2020.09.09.288290

NLRP3 inflammasome inhibition rescues Hutchinson-Gilford Progeria cellular phenotype and extend longevity of an animal model

Alcocer-Gomez, E.·Castejon-Vega, B.·Nunez-Vasco, J.·Lendines-Cordero, D.·Navarro-Pando, J. M.·Cordero, M. D.
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Abstract

Inflammation is a hallmark of aging and accelerated aging syndromes. In this context, inflammation has been associated to the pathophysiology of Hutchinson-Gilford progeria syndrome (HGPS). In this study, we report that progeroid skin fibroblasts and animal models present an hyperactivation of the NLRP3-inflammasome complex. High expression of NLRP3 and caspase 1 was also observed in skin fibroblasts from HGPS associated to the nuclei morphology. Lymphoblast from HGPS also showed increased basal levels of NLRP3 and caspase 1 independent to the induction from metabolic factors. Consistent with these results, Zmpste24-/- showed high expression of Nlrp3 and caspase 1 in heart, liver and kidney and reduced levels of Nlrc3, however these changes were not observed in other inflammasomes. We also show that pharmacological inhibition of NLRP3 using a direct NLRP3 inhibitor, MCC950, improved cellular phenotype, significantly extends the lifespan of these progeroid animals and reduced inflammasome-dependent inflammation. These findings suggest the NLRP3-inflammasome comples as a therapeutic approach for patients with HGPS.

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Alcocer-Gomez, E., Castejon-Vega, B., Nunez-Vasco, J., Lendines-Cordero, D., Navarro-Pando, J. M., Cordero, M. D.. 2020-09-10. NLRP3 inflammasome inhibition rescues Hutchinson-Gilford Progeria cellular phenotype and extend longevity of an animal model. https://doi.org/10.1101/2020.09.09.288290

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