title: Toll-like receptor 9 mediates innate immune activation by the malaria pigment hemozoin.
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 beta-/- 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.
authors.affiliation: Exploratory Research for Advanced Technology (ERATO), Japan Science and Technology Agency (JST), Osaka, Japan.
authors.forename: Cevayir
authors.initials: C
authors.lastname: Coban
authors.forename: Ken J
authors.initials: KJ
authors.lastname: Ishii
authors.forename: Taro
authors.initials: T
authors.lastname: Kawai
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Hemmi
authors.forename: Shintaro
authors.initials: S
authors.lastname: Sato
authors.forename: Satoshi
authors.initials: S
authors.lastname: Uematsu
authors.forename: Masahiro
authors.initials: M
authors.lastname: Yamamoto
authors.forename: Osamu
authors.initials: O
authors.lastname: Takeuchi
authors.forename: Sawako
authors.initials: S
authors.lastname: Itagaki
authors.forename: Nirbhay
authors.initials: N
authors.lastname: Kumar
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Horii
authors.forename: Shizuo
authors.initials: S
authors.lastname: Akira
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D000943:Antigens, Differentiation / Q000378:metabolism; D002478:Cells, Cultured; D018925:Chemokines / Q000096:biosynthesis; D002738:Chloroquine / Q000378:metabolism; D016207:Cytokines / Q000096:biosynthesis; D004268:DNA-Binding Proteins / Q000276:immunology* / Q000378:metabolism; D003713:Dendritic Cells / Q000187:drug effects / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D006420:Hemeproteins / Q000276:immunology* / Q000378:metabolism / Q000494:pharmacology*; D006790:Host-Parasite Interactions; D007113:Immunity, Innate / Q000187:drug effects / Q000276:immunology*; D008024:Ligands; D051379:Mice; D008817:Mice, Mutant Strains; D053594:Myeloid Differentiation Factor 88; D010963:Plasmodium falciparum / Q000737:chemistry* / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000276:immunology* / Q000378:metabolism; D011971:Receptors, Immunologic / Q000378:metabolism; D013154:Spleen / Q000187:drug effects / Q000378:metabolism; D051217:Toll-Like Receptor 9
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000943:Antigens, Differentiation; D018925:Chemokines; D016207:Cytokines; D004268:DNA-Binding Proteins; D006420:Hemeproteins; D008024:Ligands; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D011956:Receptors, Cell Surface; D011971:Receptors, Immunologic; C495370:Tlr9 protein, mouse; D051217:Toll-Like Receptor 9; C020753:hemozoin; D002738:Chloroquine