NLRP1 inflammasome activation induces pyroptosis of hematopoietic progenitor cells

Seth L. Masters, Motti Gerlic, Donald Metcalf, Simon Preston, Marc Pellegrini, Joanne A O'Donnell, Kate McArthur, Tracey M Baldwin, Stephane Chevrier, Cameron J. Nowell, Louise H Cengia, Katya J Henley, Janelle E Collinge, Daniel L Kastner, Lionel Feigenbaum, Douglas J. Hilton, Warren S. Alexander, Benjamin T. Kile, Ben A. Croker

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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-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.

Original languageEnglish
Pages (from-to)1009-1023
Number of pages15
JournalImmunity
Volume37
Issue number6
DOIs
Publication statusPublished - 14 Dec 2012
Externally publishedYes

Cite this

Masters, S. L., Gerlic, M., Metcalf, D., Preston, S., Pellegrini, M., O'Donnell, J. A., ... Croker, B. A. (2012). NLRP1 inflammasome activation induces pyroptosis of hematopoietic progenitor cells. Immunity, 37(6), 1009-1023. https://doi.org/10.1016/j.immuni.2012.08.027
Masters, Seth L. ; Gerlic, Motti ; Metcalf, Donald ; Preston, Simon ; Pellegrini, Marc ; O'Donnell, Joanne A ; McArthur, Kate ; Baldwin, Tracey M ; Chevrier, Stephane ; Nowell, Cameron J. ; Cengia, Louise H ; Henley, Katya J ; Collinge, Janelle E ; Kastner, Daniel L ; Feigenbaum, Lionel ; Hilton, Douglas J. ; Alexander, Warren S. ; Kile, Benjamin T. ; Croker, Ben A. / NLRP1 inflammasome activation induces pyroptosis of hematopoietic progenitor cells. In: Immunity. 2012 ; Vol. 37, No. 6. pp. 1009-1023.
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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-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.",
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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 2012, 'NLRP1 inflammasome activation induces pyroptosis of hematopoietic progenitor cells', Immunity, vol. 37, no. 6, pp. 1009-1023. https://doi.org/10.1016/j.immuni.2012.08.027

NLRP1 inflammasome activation induces pyroptosis of hematopoietic progenitor cells. / Masters, Seth L.; Gerlic, Motti; Metcalf, Donald; Preston, Simon; Pellegrini, Marc; O'Donnell, Joanne A; McArthur, Kate; Baldwin, Tracey M; Chevrier, Stephane ; Nowell, Cameron J.; Cengia, Louise H; Henley, Katya J; Collinge, Janelle E; Kastner, Daniel L; Feigenbaum, Lionel ; Hilton, Douglas J.; Alexander, Warren S. ; Kile, Benjamin T.; Croker, Ben A.

In: Immunity, Vol. 37, No. 6, 14.12.2012, p. 1009-1023.

Research output: Contribution to journalArticleResearchpeer-review

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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.

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.

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