Journal
CELL REPORTS
Volume 1, Issue 1, Pages 56-68Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2011.11.005
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Funding
- National Institutes of Health (NIH) [R01AG31797, R01DK090556, AR056296, HL49373, HL94525, 1 P20 RR02/1945]
- American Heart Association [09POST2250225]
- North Carolina Biotechnology Center grant [2007-IDG-1021]
- National Cancer Institute grant [5P30CA12197]
- NATIONAL CANCER INSTITUTE [P30CA012197] Funding Source: NIH RePORTER
- NATIONAL CENTER FOR RESEARCH RESOURCES [P20RR021945] Funding Source: NIH RePORTER
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [P01HL049373, R01HL094525] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF ARTHRITIS AND MUSCULOSKELETAL AND SKIN DISEASES [R01AR056296] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [R01DK090556, P30DK072476] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE ON AGING [R01AG031797] Funding Source: NIH RePORTER
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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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