The Nlrp3 inflammasome promotes age-related thymic demise and immunosenescence
Open accessAbstract
The collapse of thymic stromal cell microenvironment with age and resultant inability of the thymus to produce naive T cells contributes to lower immune-surveillance in the elderly. Here we show that age-related increase in 'lipotoxic danger signals' such as free cholesterol (FC) and ceramides, leads to thymic caspase-1 activation via the Nlrp3 inflammasome. Elimination of Nlrp3 and Asc, a critical adaptor required for inflammasome assembly, reduces age-related thymic atrophy and results in an increase in cortical thymic epithelial cells, T cell progenitors and maintenance of T cell repertoire diversity. Using a mouse model of irradiation and hematopoietic stem cell transplantation (HSCT), we show that deletion of the Nlrp3 inflammasome accelerates T cell reconstitution and immune recovery in middle-aged animals. Collectively, these data demonstrate that lowering inflammasome-dependent caspase-1 activation increases thymic lymphopoiesis and suggest that Nlrp3 inflammasome inhibitors may aid the re-establishment of a diverse T cell repertoire in middle-aged or elderly patients undergoing HSCT.
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Inhibition of NLRP3 suppressed T-cell senescence and atherosclerosis.
“Inhibition of the nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3 inflammasome (NLRP3) suppressed T-cell senescence57 and atherosclerosis.58”
From Senescence-induced inflammation: an important player and key therapeutic target in atherosclerosis (2020) · cites this paper as [57]
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References 50 · Cited by 172
- Authors
- Youm, Y.-H., Kanneganti, T.-D., Vandanmagsar, B., Zhu, X., Ravussin, A., Adijiang, A., Owen, J. S., Thomas, M. J., Francis, J., Parks, J. S., & Dixit, V. D.
- Affiliations
- Pennington Biomedical Research Center (US)
- St. Jude Children's Research Hospital (US)
- Wake Forest University Health Sciences (US)
- Louisiana State University System (US)
- Corresponding author
- Dixit, Vishwa Deep
- ORCID
- Venue
- Cell Reports
- Publisher
- Elsevier BV
- Published
- 2012-01
- Volume
- 1
- Issue
- 1
- Pages
- 56-68
- ISSN
- 2211-1247 (ISSN-L)
- PMC
- PMC3883512
- OpenAlex
- W2053527010
- Cited by
- 172
- References
- 50
- Citations by year
- 2026: 9 · 2025: 20 · 2024: 12 · 2023: 11 · 2022: 10 · 2021: 12 · 2020: 19 · 2019: 11 · 2018: 12 · 2017: 9 · 2016: 8 · 2015: 14 · 2014: 6 · 2013: 11 · 2012: 8
- FWCI
- 4.98
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cell Reports (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Civil War Book Review (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- American Heart Association
- North Carolina Biotechnology Center
- Wake Forest University
- National Institutes of Health
- Genentech
- School of Medicine, Duke University
- Wake Forest School of Medicine
- National Institute on Aging (R01AG031797)
- National Heart, Lung, and Blood Institute (R01HL094525, HL 49373, HL94525, P01HL049373)
- National Cancer Institute (P30CA012197)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK090556, P30DK072476)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01AR056296, AR-056296)
- National Center for Research Resources (P20RR021945)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Keywords
- NLRP3 inflammasome, thymic atrophy, immunosenescence, caspase-1, free cholesterol, ceramide, thymic epithelial cells, T cell reconstitution, hematopoietic stem cell transplantation, T cell repertoire diversity
- MeSH terms
- NLR Family, Pyrin Domain-Containing 3 Protein, Aging, Animals, Carrier Proteins, Ceramides, Cholesterol, Enzyme Activation, Epithelial Cells, Lipids, Organ Size, Stem Cells, T-Lymphocytes, Thymus Gland, Cellular Senescence, Apoptosis, Gene Deletion, Hematopoietic Stem Cell Transplantation, Caspase 1, Interleukin-18, Mice, Interleukin-1beta, Inflammasomes, Thymocytes, Cellular Microenvironment
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