NLRP1 Inflammasome Activation Induces Pyroptosis of Hematopoietic Progenitor Cells
- Author(s)
- Masters, SL; Gerlic, M; Metcalf, D; Preston, S; Pellegrini, M; O'Donnell, JA; McArthur, K; Baldwin, TM; Chevrier, S; Nowell, CJ; Cengia, LH; Henley, KJ; Collinge, JE; Kastner, DL; Feigenbaum, L; Hilton, DJ; Alexander, WS; Kile, BT; Croker, BA;
- Details
- Publication Year 2012-12-14,Volume 37,Issue #6,Page 1009-1023
- Journal Title
- IMMUNITY
- Publication Type
- Journal Article
- Abstract
- Cytopenias are key prognostic indicators of life-threatening infection, contributing to immunosuppression and mortality. Here we define a role for Caspase-1 -dependent death, known as pyroptosis, in infection-induced cytopenias by studying inflammasome activation in hematopoietic progenitor cells. The NLRP1a inflammasome is expressed in hematopoietic progenitor cells and its activation triggers their pyroptotic death. Active NLRP1a induced a lethal systemic inflammatory disease that was driven by Caspase-1 and IL-1 beta but was independent of apoptosis-associated speck-like protein containing a CARD (ASC) and ameliorated by IL-18. Surprisingly, in the absence of IL-1 beta-driven inflammation, active NLRP1a triggered pyroptosis of hematopoietic progenitor cells resulting in leukopenia at steady state. During periods of hematopoietic stress induced by chemotherapy or lymphocytic choriomeningitis virus (LCMV) infection, active NLRP1 a caused prolonged cytopenia, bone marrow hypoplasia, and immunosuppression. Conversely, NLRP1-deficient mice showed enhanced recovery from chemotherapy and LCMV infection, demonstrating that NLRP1 acts as a cellular sentinel to alert Caspase-1 to hematopoietic and infectious stress.
- Publisher
- CELL PRESS
- Keywords
- LYMPHOCYTIC CHORIOMENINGITIS VIRUS; CASPASE-1 ACTIVATION; BINDING-PROTEIN; LETHAL TOXIN; IN-VIVO; DISEASE; DEATH; INFECTION; NALP1; IL-18
- Research Division(s)
- Cancer And Haematology; Molecular Medicine; Inflammation; Infection And Immunity
- Publisher's Version
- https://doi.org/10.1016/j.immuni.2012.08.027
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Creation Date: 2012-12-14 12:00:00