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

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


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Caspase 1 / immunology
  • Caspases, Initiator / immunology*
  • Cell Death
  • Cells, Cultured
  • Gram-Negative Bacteria / immunology*
  • Gram-Negative Bacteria / pathogenicity*
  • Humans
  • Inflammasomes / immunology*
  • Interleukin-1alpha / metabolism
  • Interleukin-1beta / metabolism
  • Legionella pneumophila / immunology
  • Legionella pneumophila / pathogenicity
  • Lipopolysaccharides / toxicity
  • Macrophages / enzymology
  • Macrophages / immunology
  • Macrophages / microbiology
  • Mice
  • Salmonella typhimurium / immunology
  • Salmonella typhimurium / pathogenicity
  • Yersinia pseudotuberculosis / immunology
  • Yersinia pseudotuberculosis / pathogenicity


  • Inflammasomes
  • Interleukin-1alpha
  • Interleukin-1beta
  • Lipopolysaccharides
  • CASP4 protein, human
  • Caspases, Initiator
  • Caspase 1