TY - JOUR
T1 - NLRP1 Inflammasome Activation Induces Pyroptosis of Hematopoietic Progenitor Cells
AU - Masters, Seth L.
AU - Gerlic, Motti
AU - Metcalf, Donald
AU - Preston, Simon
AU - Pellegrini, Marc
AU - O'Donnell, Joanne A.
AU - McArthur, Kate
AU - Baldwin, Tracey M.
AU - Chevrier, Stephane
AU - Nowell, Cameron J.
AU - Cengia, Louise H.
AU - Henley, Katya J.
AU - Collinge, Janelle E.
AU - Kastner, Daniel L.
AU - Feigenbaum, Lionel
AU - Hilton, Douglas J.
AU - Alexander, Warren S.
AU - Kile, Benjamin T.
AU - Croker, Ben A.
N1 - Funding Information: We thank S. Mifsud, L. DiRago, and J. Corbin for excellent technical assistance and E. Lanera, S. Ross, S. Guzzardi, S. Brown, E. Salt, and M. Salzone for outstanding animal husbandry. We thank V. Dixit for Caspase-11-deficient mice. This work was supported by Project Grants (637367, 1002426), a Program Grant (461219), Fellowships (B.A.C., D.J.H., W.S.A., S.L.M., B.T.K.), and an Independent Research Institutes Infrastructure Support Scheme Grant (361646) from the Australian National Health and Medical Research Council (NHMRC); Fellowships from the Australian Research Council (B.A.C., B.T.K.), the Sylvia and Charles Viertel Foundation (B.T.K.), and the Cancer Council of Victoria (D.M.); the Australian Cancer Research Fund; the Australian Phenomics Network; and a Victorian State Government Operational Infrastructure Support Grant.
PY - 2012/12/14
Y1 - 2012/12/14
N2 - 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-1β but was independent of apoptosis-associated speck-like protein containing a CARD (ASC) and ameliorated by IL-18. Surprisingly, in the absence of IL-1β-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 NLRP1a 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.
AB - 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-1β but was independent of apoptosis-associated speck-like protein containing a CARD (ASC) and ameliorated by IL-18. Surprisingly, in the absence of IL-1β-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 NLRP1a 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.
UR - https://www.scopus.com/pages/publications/84870950668
U2 - 10.1016/j.immuni.2012.08.027
DO - 10.1016/j.immuni.2012.08.027
M3 - Article
SN - 1074-7613
VL - 37
SP - 1009
EP - 1023
JO - Immunity
JF - Immunity
IS - 6
ER -