期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 112, 期 21, 页码 6688-6693出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1421699112
关键词
inflammasome; caspase-4; innate immunity; primary macrophages; gram-negative bacteria
资金
- NIH [K99/R00AI087963, T32GM007229]
- American Lung Association [RG-268528-N]
- University of Pennsylvania University Research Foundation
- American Heart Association [13BGIA14780070]
- University of Pennsylvania Institute for Immunology Pilot Grant
- National Science Foundation [DGE-0822]
Inflammasomes are critical for host defense against bacterial pathogens. In murine macrophages infected by gram-negative bacteria, the canonical inflammasome activates caspase-1 to mediate pyroptotic cell death and release of IL-1 family cytokines. Additionally, a noncanonical inflammasome controlled by caspase-11 induces cell death and IL-1 release. However, humans do not encode caspase-11. Instead, humans encode two putative orthologs: caspase-4 and caspase-5. Whether either ortholog functions similar to caspase-11 is poorly defined. Therefore, we sought to define the inflammatory caspases in primary human macrophages that regulate inflammasome responses to gram-negative bacteria. We find that human macrophages activate inflammasomes specifically in response to diverse gram-negative bacterial pathogens that introduce bacterial products into the host cytosol using specialized secretion systems. In primary human macrophages, IL-1 beta secretion requires the caspase-1 inflammasome, whereas IL-1 alpha release and cell death are caspase-1-independent. Instead, caspase-4 mediates IL-1 alpha release and cell death. Our findings implicate human caspase-4 as a critical regulator of noncanonical inflammasome activation that initiates defense against bacterial pathogens in primary human macrophages.
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