The Nlrp3 inflammasome promotes age-related thymic demise and immunosenescence
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.
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Youm, Y., Kanneganti, T., Vandanmagsar, B., Zhu, X., Ravussin, A., Adijiang, A., Owen, J. S., Thomas, M. J., Francis, J., Parks, J. S., & Dixit, V. D. (2012). The Nlrp3 inflammasome promotes age-related thymic demise and immunosenescence. Cell reports, 1 (1), 56-68. https://doi.org/10.1016/j.celrep.2011.11.005