TY - JOUR
T1 - Dual engagement of the NLRP3 and AIM2 inflammasomes by plasmodium-derived hemozoin and DNA during Malaria
AU - Kalantari, Parisa
AU - DeOliveira, Rosane B.
AU - Chan, Jennie
AU - Corbett, Yolanda
AU - Rathinam, Vijay
AU - Stutz, Andrea
AU - Latz, Eicke
AU - Gazzinelli, Ricardo T.
AU - Golenbock, Douglas T.
AU - Fitzgerald, Katherine A.
N1 - Funding Information:
The authors thank Anna Cerny for animal husbandry, and Drs. Shizuo Akira, Bruce Beutler, and Hidde Pleogh (Massachusetts Institutes of Technology, Boston) for transgenic mice. This work was supported by NIH grants AI067497 (to K.A.F.), AI079293 (to K.A.F. and D.T.G.), and R21AI80907 (to R.T.G.).
PY - 2014
Y1 - 2014
N2 - 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 invitro 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.
AB - 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 invitro 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.
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U2 - 10.1016/j.celrep.2013.12.014
DO - 10.1016/j.celrep.2013.12.014
M3 - Article
C2 - 24388751
AN - SCOPUS:84892552656
SN - 2211-1247
VL - 6
SP - 196
EP - 210
JO - Cell Reports
JF - Cell Reports
IS - 1
ER -