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Proc Natl Acad Sci U S A. 2015 May 26;112(21):6688-93. doi: 10.1073/pnas.1421699112. Epub 2015 May 11.

Human caspase-4 mediates noncanonical inflammasome activation against gram-negative bacterial pathogens.

Author information

1
Departments of Microbiology and.
2
Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104.
3
Departments of Microbiology and sunshin@mail.med.upenn.edu.

Abstract

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-1β secretion requires the caspase-1 inflammasome, whereas IL-1α release and cell death are caspase-1-independent. Instead, caspase-4 mediates IL-1α 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.

KEYWORDS:

caspase-4; gram-negative bacteria; inflammasome; innate immunity; primary macrophages

PMID:
25964352
PMCID:
PMC4450384
DOI:
10.1073/pnas.1421699112
[Indexed for MEDLINE]
Free PMC Article

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