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Publications

Journal Article Ppublish

PubMed: 42361162 DOI: 10.1126/sciadv.aec9499

NLRP3 haploinsufficiency unmasks a compensatory NLRP1-NLRP3 interaction that drives accelerated aging in mice.

Sci Adv 12(26):eaec9499

Authors: Inés Muela-Zarzuela, Elisabet Alcocer-Gómez, Juan M Suarez-Rivero, Evon Low, Abbas Ishaq, Mikel Azkargorta, Amparo Luque-Sierra, Franz Martin, Félix Elortza, Antonio Astorga-Gamaza, Rosa Antón, Sofía Bali, Joaquin Tamargo-Azpilicueta, Alejandra Guerra-Castellano, Irene Díaz-Moreno, Lukasz A Joachimiak, Javier Oroz, Jesús Ruiz-Cabello, Thomas von Zglinicki, Alberto Sanz, Mario D Cordero

Affiliations

  • Department of Molecular Biology and Biochemical Engineering, Universidad Pablo de Olavide, 41013 Seville, Spain.
  • Departamento de Psicología Experimental, Facultad de Psicología, Universidad de Sevilla, 41009 Seville, Spain.
  • Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK.
  • Proteomics Platform, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), CIBERehd, Derio, Spain.
  • Andalusian Center of Molecular Biology and Regenerative Medicine-CABIMER, University Pablo Olavide-University of Seville-CSIC, Seville, Spain.
  • CIBER de Diabetes y Enfermedades Metabólicas asociadas (CIBERDEM), Instituto de Salud Carlos III, Madrid, Spain.
  • Instituto de Química Física Blas Cabrera (IQF), CSIC, E-28006 Madrid, Spain.
  • Molecular Biophysics Graduate Program, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
  • Center for Alzheimer's and Neurodegenerative Diseases, Peter O'Donnell Jr. Brain Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
  • Institute for Chemical Research, cicCartuja, University of Seville-CSIC, Seville, Spain.
  • Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
  • CIC biomaGUNE, Basque Research and Technology Alliance (BRTA), Paseo de Miramon 182, 20014 Donostia San Sebastián, Spain.
  • Ikerbasque, Basque Foundation for Science, Plaza Euskadi 5, 48009 Bilbao, Spain.
  • Ciber Enfermedades Respiratorias (Ciberes), 28029 Madrid, Spain.
  • NMR and Imaging in Biomedicine Group, Department of Chemistry in Pharmaceutical Sciences, Pharmacy School, University Complutense Madrid, 28040 Madrid, Spain.
  • School of Molecular Biosciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, G12 8QQ Glasgow, UK.

Abstract

The NLRP3 inflammasome has been implicated in a wide range of human diseases, including cardiovascular, metabolic, neurodegenerative (such as Alzheimer's disease), and other age-related conditions. This has positioned NLRP3 as a promising pharmacological target. Numerous studies have shown that complete NLRP3 ablation can prevent or mitigate these diseases. However, total elimination of NLRP3 is not a feasible therapeutic strategy for the millions of patients affected by these degenerative disorders. Consequently, drug development efforts have focused on partial inhibition of NLRP3 using compounds that reduce its expression or activity. Paradoxically, although many studies have used Nlrp3 knockout mouse models, Nlrp3 haploinsufficient mice-more representative of the effects of pharmacological inhibition-are rarely included and remain poorly characterized. Here, we report the long-term effects of Nlrp3 haploinsufficiency during aging. Although no overt differences were observed in early life, by 16 months of age, Nlrp3 heterozygous mice exhibited signs of accelerated inflammatory aging, driven by compensatory overexpression of NLRP1. Mechanistic studies provide evidence of a previously unidentified interaction between NLRP1 and NLRP3, forming a hybrid inflammasome that drives NLRP1-mediated inflammatory overactivation when NLRP3 expression is reduced. Accordingly, anti-inflammatory treatment provided notable but moderate improvement of the inflammatory phenotype, whereas genetic inhibition of Nlrp1 more consistently reduced inflammation and extended health span. Our findings reveal a previously unidentified compensatory interaction between NLRP1 and NLRP3 and suggest that multiinflammasome inhibition may offer a more effective strategy for treating aging and age-related diseases.

MeSH

Biological Science Disciplines, Aging, Inflammasomes, Haploinsufficiency, Therapeutics