The Journal of Experimental Medicine
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Published 3 January 2005. doi:10.1084/jem.20041836
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 201, Number 1, 19-25
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BRIEF DEFINITIVE REPORT

 Toll-like receptor 9 mediates innate immune activation by the malaria pigment hemozoin

Cevayir Coban1,2,3, Ken J. Ishii1,2, Taro Kawai1,2, Hiroaki Hemmi2, Shintaro Sato1,2, Satoshi Uematsu2, Masahiro Yamamoto2, Osamu Takeuchi1,2, Sawako Itagaki4, Nirbhay Kumar5, Toshihiro Horii3,4, and Shizuo Akira1,2,3

1 Exploratory Research for Advanced Technology (ERATO), Japan Science and Technology Agency (JST)
2 Department of Host Defense, Combined Program on Microbiology and Immunology
3 The 21st Century COE, Combined Program on Microbiology and Immunology
4 Department of Molecular Protozoology, Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan
5 Department of Molecular Microbiology and Immunology, Malaria Research Institute, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD 21205

CORRESPONDENCE Shizuo Akira: sakira{at}biken.osaka-u.ac.jp

Malaria parasites within red blood cells digest host hemoglobin into a hydrophobic heme polymer, known as hemozoin (HZ), which is subsequently released into the blood stream and then captured by and concentrated in the reticulo-endothelial system. Accumulating evidence suggests that HZ is immunologically active, but the molecular mechanism(s) through which HZ modulates the innate immune system has not been elucidated. This work demonstrates that HZ purified from Plasmodium falciparum is a novel non-DNA ligand for Toll-like receptor (TLR)9. HZ activated innate immune responses in vivo and in vitro, resulting in the production of cytokines, chemokines, and up-regulation of costimulatory molecules. Such responses were severely impaired in TLR9–/– and myeloid differentiation factor 88 (MyD88)–/–, but not in TLR2, TLR4, TLR7, or Toll/interleukin 1 receptor domain–containing adaptor-inducing interferon ß–/– mice. Synthetic HZ, which is free of the other contaminants, also activated innate immune responses in vivo in a TLR9-dependent manner. Chloroquine (CQ), an antimalarial drug, abrogated HZ-induced cytokine production. These data suggest that TLR9-mediated, MyD88-dependent, and CQ-sensitive innate immune activation by HZ may play an important role in malaria parasite–host interactions.

C. Coban and K.J. Ishii contributed equally to this work.


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