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Immunity. 2012 Dec 14;37(6):1009-23. doi: 10.1016/j.immuni.2012.08.027. Epub 2012 Dec 6.

NLRP1 inflammasome activation induces pyroptosis of hematopoietic progenitor cells.

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1
The Walter and Eliza Hall Institute of Medical Research, Parkville 3052, Australia.

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.

Comment in

PMID:
23219391
PMCID:
PMC4275304
DOI:
10.1016/j.immuni.2012.08.027
[Indexed for MEDLINE]
Free PMC Article

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