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.
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville 3052, Australia.
authors.forename: Seth L
authors.initials: SL
authors.lastname: Masters
authors.forename: Motti
authors.initials: M
authors.lastname: Gerlic
authors.forename: Donald
authors.initials: D
authors.lastname: Metcalf
authors.forename: Simon
authors.initials: S
authors.lastname: Preston
authors.forename: Marc
authors.initials: M
authors.lastname: Pellegrini
authors.forename: Joanne A
authors.initials: JA
authors.lastname: O'Donnell
authors.forename: Kate
authors.initials: K
authors.lastname: McArthur
authors.forename: Tracey M
authors.initials: TM
authors.lastname: Baldwin
authors.forename: Stephane
authors.initials: S
authors.lastname: Chevrier
authors.forename: Cameron J
authors.initials: CJ
authors.lastname: Nowell
authors.forename: Louise H
authors.initials: LH
authors.lastname: Cengia
authors.forename: Katya J
authors.initials: KJ
authors.lastname: Henley
authors.forename: Janelle E
authors.initials: JE
authors.lastname: Collinge
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Kastner
authors.forename: Lionel
authors.initials: L
authors.lastname: Feigenbaum
authors.forename: Douglas J
authors.initials: DJ
authors.lastname: Hilton
authors.forename: Warren S
authors.initials: WS
authors.lastname: Alexander
authors.forename: Benjamin T
authors.initials: BT
authors.lastname: Kile
authors.forename: Ben A
authors.initials: BA
authors.lastname: Croker
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism*; D053468:CARD Signaling Adaptor Proteins; D020170:Caspase 1 / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism; D003872:Dermatitis / Q000276:immunology / Q000378:metabolism; D005472:Fluorouracil / Q000494:pharmacology; D006410:Hematopoiesis / Q000187:drug effects / Q000276:immunology; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000378:metabolism* / Q000821:virology; D058847:Inflammasomes / Q000378:metabolism*; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D007371:Interferon-gamma / Q000378:metabolism; D020382:Interleukin-18 / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D010198:Pancytopenia / Q000276:immunology / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; D053468:CARD Signaling Adaptor Proteins; D003598:Cytoskeletal Proteins; D058847:Inflammasomes; D020382:Interleukin-18; D053583:Interleukin-1beta; C529636:NALP1 protein, mouse; C498534:Pycard protein, mouse; D007371:Interferon-gamma; D020170:Caspase 1; D005472:Fluorouracil