title: The Nlrp3 inflammasome promotes age-related thymic demise and immunosenescence.
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.
authors: Immunobiology Laboratory, Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, LA 70808, USA.
authors: Yun-Hee
authors: YH
authors: Youm
authors: Thirumala-Devi
authors: TD
authors: Kanneganti
authors: Bolormaa
authors: B
authors: Vandanmagsar
authors: Xuewei
authors: X
authors: Zhu
authors: Anthony
authors: A
authors: Ravussin
authors: Ayinuer
authors: A
authors: Adijiang
authors: John S
authors: JS
authors: Owen
authors: Michael J
authors: MJ
authors: Thomas
authors: Joseph
authors: J
authors: Francis
authors: John S
authors: JS
authors: Parks
authors: Vishwa Deep
authors: VD
authors: Dixit
mesh_terms: D000375:Aging / Q000187:drug effects / Q000276:immunology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology; D002352:Carrier Proteins / Q000378:metabolism*; D020170:Caspase 1 / Q000378:metabolism; D060833:Cellular Microenvironment; D016922:Cellular Senescence / Q000187:drug effects / Q000276:immunology; D002518:Ceramides / Q000378:metabolism; D002784:Cholesterol / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D004847:Epithelial Cells / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D017353:Gene Deletion; D018380:Hematopoietic Stem Cell Transplantation; D058847:Inflammasomes / Q000378:metabolism*; D020382:Interleukin-18 / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D008055:Lipids / Q000633:toxicity; D051379:Mice; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D009929:Organ Size / Q000187:drug effects; D013234:Stem Cells / Q000187:drug effects / Q000473:pathology; D013601:T-Lymphocytes / Q000187:drug effects / Q000473:pathology; D060168:Thymocytes / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D013950:Thymus Gland / Q000201:enzymology / Q000254:growth & development* / Q000276:immunology* / Q000473:pathology
chemical_list: D002352:Carrier Proteins; D002518:Ceramides; D058847:Inflammasomes; D020382:Interleukin-18; D053583:Interleukin-1beta; D008055:Lipids; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D002784:Cholesterol; D020170:Caspase 1