Abstract
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.
Copyright © 2012 The Authors. Published by Elsevier Inc. All rights reserved.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Aging / drug effects
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Aging / immunology*
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Animals
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Apoptosis / drug effects
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Apoptosis / immunology
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Carrier Proteins / metabolism*
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Caspase 1 / metabolism
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Cellular Microenvironment
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Cellular Senescence / drug effects
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Cellular Senescence / immunology
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Ceramides / metabolism
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Cholesterol / metabolism
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Enzyme Activation / drug effects
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Epithelial Cells / drug effects
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Epithelial Cells / immunology
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Epithelial Cells / pathology
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Gene Deletion
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Hematopoietic Stem Cell Transplantation
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Inflammasomes / metabolism*
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Interleukin-18 / metabolism
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Interleukin-1beta / metabolism
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Lipids / toxicity
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Mice
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NLR Family, Pyrin Domain-Containing 3 Protein
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Organ Size / drug effects
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Stem Cells / drug effects
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Stem Cells / pathology
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T-Lymphocytes / drug effects
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T-Lymphocytes / pathology
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Thymocytes / drug effects
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Thymocytes / immunology
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Thymocytes / pathology
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Thymus Gland / enzymology
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Thymus Gland / growth & development*
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Thymus Gland / immunology*
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Thymus Gland / pathology
Substances
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Carrier Proteins
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Ceramides
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Inflammasomes
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Interleukin-18
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Interleukin-1beta
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Lipids
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NLR Family, Pyrin Domain-Containing 3 Protein
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Nlrp3 protein, mouse
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Cholesterol
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Caspase 1