Affiliation:
1. Section of Microbial Pathogenesis, Yale University School of Medicine, New Haven, Connecticut 06536
Abstract
ABSTRACT
Caspase-1 activation is a key feature of the innate immune response of macrophages elicited by pathogens and a variety of toxins. Here, we determined the requirement for different adapter proteins involved in regulating host processes mediated by caspase-1 after macrophage infection by
Legionella pneumophila
. The adapter protein Asc was found to be important for caspase-1 activation during
L. pneumophila
infection. Activation of caspase-1 through Asc did not require the flagellin-sensing pathway involving the host nucleotide-binding domain and leucine-rich repeat-containing protein Ipaf (NLRC4). Asc-dependent caspase-1 activation was inhibited by high extracellular potassium levels, whereas Ipaf-dependent activation was unaffected by potassium treatment. Activation of caspase-1 in macrophages occurred independently of Nalp3 and proteasome activity, suggesting that a previously uncharacterized mechanism for caspase-1 activation through Asc may be triggered by
L. pneumophila
. Rapid pore formation and pyroptosis induced by
L. pneumophila
required caspase-1, Ipaf, and bacterial flagellin but occurred independently of Asc. Equivalent levels of active interleukin-18 (IL-18) were detected in the lungs of mice infected with a flagellin-deficient strain of
L. pneumophila
and Asc-deficient mice infected with wild-type
L. pneumophila
. Active IL-18 was undetectable in the lungs of Asc-deficient mice infected with an
L. pneumophila
flagellin mutant, indicating independent roles for Ipaf and Asc in caspase-1-mediated processing and release of IL-18 in vivo. Ipaf-dependent activation of caspase-1 restricted bacterial replication in vivo, whereas Asc was dispensable for restriction of
L. pneumophila
replication in mice. Thus,
L. pneumophila-
mediated caspase-1 activation involves the coordinate activities of inflammasomes differentially regulated by Ipaf and Asc.
Publisher
American Society for Microbiology
Subject
Infectious Diseases,Immunology,Microbiology,Parasitology
Cited by
161 articles.
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