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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

Departments of Microbiology and.
Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104.
Departments of Microbiology and


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.


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

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