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Am J Physiol Lung Cell Mol Physiol. 2015 Oct 15;309(8):L902-13. doi: 10.1152/ajplung.00228.2015. Epub 2015 Aug 21.

Differential ASC requirements reveal a key role for neutrophils and a noncanonical IL-1β response to Pseudomonas aeruginosa.

Author information

1
Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire.
2
Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire berwin@dartmouth.edu.

Abstract

The NLRC4 inflammasome is responsible for IL-1β processing by macrophages in response to Pseudomonas aeruginosa infection. We therefore hypothesized that mice that lack ASC, an NLRC4 inflammasome adaptor protein necessary for in vitro IL-1β production by macrophages, would be preferentially protected from a hyperinflammatory lethal challenge that is dependent on bacterial type three secretion system (T3SS) activity. We report herein that lack of ASC does not confer preferential protection in response to P. aeruginosa acute infection and that ASC(-/-) mice are capable of producing robust amounts of IL-1β comparable with C57BL/6 mice. We now identify that neutrophils represent the ASC-independent source of IL-1β production during the acute phases of infection both in models of acute pneumonia and peritonitis. Consequently, depletion of neutrophils in ASC(-/-) mice leads to a marked deficit in IL-1β production in vivo. The pulmonary neutrophil IL-1β response is predominantly dependent on caspase-1, which contrasts with data derived from ocular infection. These studies therefore identify a noncanonical mechanism of IL-1β production by neutrophils independent of ASC and demonstrate the first physiological contribution of neutrophils as an important source of IL-1β in response to acute P. aeruginosa infection during acute pneumonia and peritonitis.

KEYWORDS:

ASC; Pseudomonas aeruginosa; inflammation; interleukin-1β; neutrophils

PMID:
26472815
PMCID:
PMC4609944
DOI:
10.1152/ajplung.00228.2015
[Indexed for MEDLINE]
Free PMC Article

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