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

Cevayir Coban, Ken J. Ishii, Taro Kawai, Hiroaki Hemmi, Shintaro Sato, Satoshi Uematsu, Masahiro Yamamoto, Osamu Takeuchi, Sawako Itagaki, Nirbhay Kumar, Toshihiro Horii, Shizuo Akira

Research output: Contribution to journalArticlepeer-review

Abstract

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 β-/- 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.

Original languageEnglish (US)
Pages (from-to)19-25
Number of pages7
JournalJournal of Experimental Medicine
Volume201
Issue number1
DOIs
StatePublished - Jan 3 2005

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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