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

doi:10.1016/j.immuni.2012.08.027

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

Research output: Contribution to journal › Article › peer-review

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 language	English
Pages (from-to)	1009-1023
Number of pages	15
Journal	Immunity
Volume	37
Issue number	6
DOIs	https://doi.org/10.1016/j.immuni.2012.08.027
State	Published - 14 Dec 2012
Externally published	Yes

All Science Journal Classification (ASJC) codes

Immunology and Allergy
Immunology
Infectious Diseases

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.immuni.2012.08.027

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Masters, S. L., Gerlic, M., Metcalf, D., Preston, S., Pellegrini, M., O'Donnell, J. A., McArthur, K., Baldwin, T. M., Chevrier, S., Nowell, C. J., Cengia, L. H., Henley, K. J., Collinge, J. E., Kastner, D. L., Feigenbaum, L., Hilton, D. J., Alexander, W. S., Kile, B. T., & 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

@article{d9d05b6e79db4b7f97d8d056e3fb5ce9,

title = "NLRP1 Inflammasome Activation Induces Pyroptosis of Hematopoietic Progenitor Cells",

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.",

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

note = "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.",

year = "2012",

month = dec,

day = "14",

doi = "10.1016/j.immuni.2012.08.027",

language = "الإنجليزيّة",

volume = "37",

pages = "1009--1023",

journal = "Immunity",

issn = "1074-7613",

publisher = "Cell Press",

number = "6",

}

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

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 - http://www.scopus.com/inward/record.url?scp=84870950668&partnerID=8YFLogxK

U2 - 10.1016/j.immuni.2012.08.027

DO - 10.1016/j.immuni.2012.08.027

M3 - مقالة

SN - 1074-7613

VL - 37

SP - 1009

EP - 1023

JO - Immunity

JF - Immunity

IS - 6

ER -

NLRP1 Inflammasome Activation Induces Pyroptosis of Hematopoietic Progenitor Cells

Abstract

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