The NLRP3 Inflammasome Promotes Age-Related Thymic Demise and Immunosenescence

• Published in: Cell reports (Cambridge) Vol. 1; no. 1; pp. 56 - 68
• Main Authors: Youm, Yun-Hee, Kanneganti, Thirumala-Devi, Vandanmagsar, Bolormaa, Zhu, Xuewei, Ravussin, Anthony, Adijiang, Ayinuer, Owen, John S., Thomas, Michael J., Francis, Joseph, Parks, John S., Dixit, Vishwa Deep
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 26.01.2012; Elsevier
• Subjects: Aging - drug effects; Aging - immunology; Animals; Apoptosis - drug effects; Apoptosis - immunology; Carrier Proteins - metabolism; Caspase 1 - metabolism; Cellular Microenvironment; Cellular Senescence - drug effects; Cellular Senescence - immunology; Ceramides - metabolism; Cholesterol - metabolism; Enzyme Activation - drug effects; Epithelial Cells - drug effects; Epithelial Cells - immunology; Epithelial Cells - pathology; Gene Deletion; Hematopoietic Stem Cell Transplantation; Inflammasomes - metabolism; Interleukin-18 - metabolism; Interleukin-1beta - metabolism; Lipids - toxicity; Mice; NLR Family, Pyrin Domain-Containing 3 Protein; Organ Size - drug effects; Stem Cells - drug effects; Stem Cells - pathology; T-Lymphocytes - drug effects; T-Lymphocytes - pathology; Thymocytes - drug effects; Thymocytes - immunology; Thymocytes - pathology; Thymus Gland - enzymology; Thymus Gland - growth & development; Thymus Gland - immunology; Thymus Gland - pathology
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2011.11.005

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. [Display omitted] ► Nlrp3 inflammasome senses age-related increase in thymic ceramides and free cholesterol ► Age-related intrathymic caspase-1 activation is mediated partly by Nlrp3 inflammasome ► Reduced Nlrp3 inflammasome activation slows thymic aging and T cell senescence ► Nlrp3 loss enhances T cell reconstitution after radiation and bone marrow transplantation Age-related thymic atrophy and the resultant loss of naive T cell production leads to reduced immune protection in the elderly. Youm et al show that the Nlrp3 inflammasome is activated by an age-related increase in “danger signals,” such as ceramides and free cholesterol, leading to thymic dysfunction. Their data show that dampening the Nlrp3 inflammasome activation delays the aging of the thymus and maintains a youthful T cell repertoire in mice.