Caspase-12 dampens the immune response to malaria independently of the inflammasome by targeting NF-kappaB signaling

J Immunol. 2010 Nov 1;185(9):5495-502. doi: 10.4049/jimmunol.1002517. Epub 2010 Sep 27.


Pathogen sensing by the inflammasome activates inflammatory caspases that mediate inflammation and cell death. Caspase-12 antagonizes the inflammasome and NF-κB and is associated with susceptibility to bacterial sepsis. A single-nucleotide polymorphism (T(125)C) in human Casp12 restricts its expression to Africa, Southeast Asia, and South America. Here, we investigated the role of caspase-12 in the control of parasite replication and pathogenesis in malaria and report that caspase-12 dampened parasite clearance in blood-stage malaria and modulated susceptibility to cerebral malaria. This response was independent of the caspase-1 inflammasome, as casp1(-/-) mice were indistinguishable from wild-type animals in response to malaria, but dependent on enhanced NF-κB activation. Mechanistically, caspase-12 competed with NEMO for association with IκB kinase-α/β, effectively preventing the formation of the IκB kinase complex and inhibiting downstream transcriptional activation by NF-κB. Systemic inhibition of NF-κB or Ab neutralization of IFN-γ reversed the increased resistance of casp12(-/-) mice to blood-stage malaria infection.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Caspase 12 / genetics
  • Caspase 12 / immunology*
  • Cytokines / biosynthesis
  • Cytokines / immunology
  • Enzyme Activation / immunology
  • Enzyme-Linked Immunosorbent Assay
  • Female
  • Genetic Predisposition to Disease
  • Humans
  • Inflammation / genetics
  • Inflammation / immunology*
  • Malaria / genetics
  • Malaria / immunology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • NF-kappa B / immunology*
  • NF-kappa B / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction / genetics
  • Signal Transduction / immunology*


  • Cytokines
  • NF-kappa B
  • Casp12 protein, mouse
  • Caspase 12