Format

Send to

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

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

Author information

1
Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
2
Dipartimento di Scienze Farmacologiche e Biomolecolari, Università Degli Studi di Milano, Via Pascal 36, Milano 20133, Italy.
3
Institute of Innate Immunity, Biomedical Center, 1G008, University Hospitals, University of Bonn, Sigmund-Freud-Strasse 25, Bonn 53127, Germany.
4
Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, MA 01605, USA; Institute of Innate Immunity, Biomedical Center, 1G008, University Hospitals, University of Bonn, Sigmund-Freud-Strasse 25, Bonn 53127, Germany.
5
Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, MA 01605, USA; Department of Parasitology and Department of Biochemistry and Immunology, Biological Sciences Institute, Federal University of Minas Gerais, Avenida Antonio Carlos 6627, Belo Horizonte, MG 31270, Brazil.
6
Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, MA 01605, USA. Electronic address: kate.fitzgerald@umassmed.edu.

Abstract

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.

PMID:
24388751
PMCID:
PMC4105362
DOI:
10.1016/j.celrep.2013.12.014
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Elsevier Science Icon for PubMed Central
Loading ...
Support Center