Year: 2012
Type: article
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.
Source: Cell Reports
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $5,620
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, National Heart, Lung, and Blood Institute, National Cancer Institute, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Center for Research Resources
Awards: G1375865199, Role of IL-1alpha signaling in inflammatory diseases and host defense, G2050705626, G3103832212, Macrophage, ABCA1, Inflammation, and Atherosclerosis, G3768947720, G3778236494, G3789341260, G424083508, Mentoring Obesity and Diabetes Research in Louisiana, G6937600811, G787533720, G799249705, Impact of Obesity and Weight-Loss Interventions on Immune-Surveillance Mechanisms, Lipoprotein Metabolism in Atherosclerosis, Pennington/Louisiana NORC
OpenAlex ID: W2053527010