The NLRP3 Inflammasome Promotes Age-Related Thymic Demise and Immunosenescence

SummaryThe 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.

Graphical AbstractFigure optionsDownload full-size imageDownload as PowerPoint slideHighlights► 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