The Nlrp3 inflammasome promotes age-related thymic demise and immunosenescence

Authors

Yun-Hee Youm, Immunobiology Laboratory, Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, LA 70808, USA.
Thirumala-Devi Kanneganti
Bolormaa Vandanmagsar
Xuewei Zhu
Anthony Ravussin
Ayinuer Adijiang
John S. Owen
Michael J. Thomas
Joseph Francis
John S. Parks
Vishwa Deep Dixit

Document Type

Article

Publication Date

1-26-2012

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.

Publication Source (Journal or Book title)

Cell reports

First Page

56

Last Page

68

Recommended Citation

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