Dual engagement of the NLRP3 and AIM2 inflammasomes by plasmodium-derived hemozoin and DNA during malaria

Cell Rep. 2014 Jan 16;6(1):196-210. doi: 10.1016/j.celrep.2013.12.014. Epub 2014 Jan 2.


Hemozoin (Hz) is the crystalline detoxification product of hemoglobin in Plasmodium-infected erythrocytes. We previously proposed that Hz can carry plasmodial DNA into a subcellular compartment that is accessible to Toll-like receptor 9 (TLR9), inducing an inflammatory signal. Hz also activates the NLRP3 inflammasome in primed cells. We found that Hz appears to colocalize with DNA in infected erythrocytes, even before RBC rupture or phagolysosomal digestion. Using synthetic Hz coated in vitro with plasmodial genomic DNA (gDNA) or CpG oligodeoxynucleotides, we observed that DNA-complexed Hz induced TLR9 translocation, providing a priming and an activation signal for inflammasomes. After phagocytosis, Hz and DNA dissociate. Hz subsequently induces phagolysosomal destabilization, allowing phagolysosomal contents access to the cytosol, where DNA receptors become activated. Similar observations were made with Plasmodium-infected RBCs. Finally, infected erythrocytes activated both the NLRP3 and AIM2 inflammasomes. These observations suggest that Hz and DNA work together to induce systemic inflammation during malaria.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism*
  • Cells, Cultured
  • DNA, Protozoan / metabolism*
  • DNA, Protozoan / pharmacology
  • DNA-Binding Proteins
  • Erythrocytes / drug effects
  • Erythrocytes / metabolism
  • Erythrocytes / parasitology
  • Hemeproteins / metabolism*
  • Hemeproteins / pharmacology
  • Humans
  • Inflammasomes / genetics
  • Inflammasomes / metabolism*
  • Interleukin-1beta / genetics
  • Interleukin-1beta / metabolism
  • Malaria / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism*
  • Phagocytosis
  • Plasmodium / pathogenicity
  • Toll-Like Receptor 9 / metabolism


  • Aim2 protein, mouse
  • Carrier Proteins
  • DNA, Protozoan
  • DNA-Binding Proteins
  • Hemeproteins
  • Inflammasomes
  • Interleukin-1beta
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Nlrp3 protein, mouse
  • Nuclear Proteins
  • TLR9 protein, human
  • Toll-Like Receptor 9
  • hemozoin