The Nlrp3 inflammasome promotes age-related thymic demise and immunosenescence. Cell Rep 2012 Jan 26;1(1):56-68
Date
07/27/2012Pubmed ID
22832107Pubmed Central ID
PMC3883512DOI
10.1016/j.celrep.2011.11.005Scopus ID
2-s2.0-84861164794 (requires institutional sign-in at Scopus site) 111 CitationsAbstract
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.
Author List
Youm YH, Kanneganti TD, Vandanmagsar B, Zhu X, Ravussin A, Adijiang A, Owen JS, Thomas MJ, Francis J, Parks JS, Dixit VDAuthor
Michael J. Thomas PhD Professor in the Pharmacology and Toxicology department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AgingAnimals
Apoptosis
Carrier Proteins
Caspase 1
Cellular Microenvironment
Cellular Senescence
Ceramides
Cholesterol
Enzyme Activation
Epithelial Cells
Gene Deletion
Hematopoietic Stem Cell Transplantation
Inflammasomes
Interleukin-18
Interleukin-1beta
Lipids
Mice
NLR Family, Pyrin Domain-Containing 3 Protein
Organ Size
Stem Cells
T-Lymphocytes
Thymocytes
Thymus Gland
