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, 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
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.
Figures
References
- Miller, L.H., and S.L. Hoffman. 1998. Research toward vaccines against malaria. Nat. Med. 4:520–524.
- Stevenson, M.M., and E.M. Riley. 2004. Innate immunity to malaria. Nat. Rev. Immunol. 4:169–180.
- Kwiatkowski, D., C.A. Bate, I.G. Scragg, P. Beattie, I. Udalova, and J.C. Knight. 1997. The malarial fever response–pathogenesis, polymorphism and prospects for intervention. Ann. Trop. Med. Parasitol. 91:533–542.
- Janeway, C.A., Jr., and R. Medzhitov. 2002. Innate immune recognition. Annu. Rev. Immunol. 20:197–216.
- Akira, S., and K. Takeda. 2004. Toll-like receptor signalling. Nat. Rev. Immunol. 4:499–511.
- Adachi, K., H. Tsutsui, S. Kashiwamura, E. Seki, H. Nakano, O. Takeuchi, K. Takeda, K. Okumura, L. Van Kaer, H. Okamura, et al. 2001. Plasmodium berghei infection in mice induces liver injury by an IL-12- and toll-like receptor/myeloid differentiation factor 88-dependent mechanism. J. Immunol. 167:5928–5934.
- Pichyangkul, S., K. Yongvanitchit, U. Kum-arb, H. Hemmi, S. Akira, A.M. Krieg, D.G. Heppner, V.A. Stewart, H. Hasegawa, S. Looareesuwan, et al. 2004. Malaria blood stage parasites activate human plasmacytoid dendritic cells and murine dendritic cells through a Toll-like receptor 9-dependent pathway. J. Immunol. 172:4926–4933.
- Sullivan, D.J. 2002. Theories on malarial pigment formation and quinoline action. Int. J. Parasitol. 32:1645–1653.
- Arese, P., and E. Schwarzer. 1997. Malarial pigment (haemozoin): a very active ‘inert’ substance. Ann. Trop. Med. Parasitol. 91:501–516.
- Sherry, B.A., G. Alava, K.J. Tracey, J. Martiney, A. Cerami, and A.F. Slater. 1995. Malaria-specific metabolite hemozoin mediates the release of several potent endogenous pyrogens (TNF, MIP-1 alpha, and MIP-1 beta) in vitro, and altered thermoregulation in vivo. J. Inflamm. 45:85–96.
- Coban, C., K.J. Ishii, D.J. Sullivan, and N. Kumar. 2002. Purified malaria pigment (hemozoin) enhances dendritic cell maturation and modulates the isotype of antibodies induced by a DNA vaccine. Infect. Immun. 70:3939–3943.
- Klinman, D.M. 2004. Immunotherapeutic uses of CpG oligodeoxynucleotides. Nat. Rev. Immunol. 4:249–258.
- Slater, A.F., W.J. Swiggard, B.R. Orton, W.D. Flitter, D.E. Goldberg, A. Cerami, and G.B. Henderson. 1991. An iron-carboxylate bond links the heme units of malaria pigment. Proc. Natl. Acad. Sci. USA. 88:325–329.
- Sullivan, D.J., Jr., I.Y. Gluzman, D.G. Russell, and D.E. Goldberg. 1996. On the molecular mechanism of chloroquine's antimalarial action. Proc. Natl. Acad. Sci. USA. 93:11865–11870.
- Koski, G.K., K. Kariko, S. Xu, D. Weissman, P.A. Cohen, and B.J. Czerniecki. 2004. Cutting edge: innate immune system discriminates between RNA containing bacterial versus eukaryotic structural features that prime for high-level IL-12 secretion by dendritic cells. J. Immunol. 172:3989–3993.
- Fitch, C.D. 2004. Ferriprotoporphyrin IX, phospholipids, and the antimalarial actions of quinoline drugs. Life Sci. 74:1957–1972.
- Macfarlane, D.E., and L. Manzel. 1998. Antagonism of immunostimulatory CpG-oligodeoxynucleotides by quinacrine, chloroquine, and structurally related compounds. J. Immunol. 160:1122–1131.
- Wagner, H. 2004. The immunobiology of the TLR9 subfamily. Trends Immunol. 25:381–386.
- Krieg, A.M. 2002. CpG motifs in bacterial DNA and their immune effects. Annu. Rev. Immunol. 20:709–760.
- Latz, E., A. Schoenemeyer, A. Visintin, K.A. Fitzgerald, B.G. Monks, C.F. Knetter, E. Lien, N.J. Nilsen, T. Espevik, and D.T. Golenbock. 2004. TLR9 signals after translocating from the ER to CpG DNA in the lysosome. Nat. Immunol. 5:190–198.
- Ishii, K.J., F. Takeshita, I. Gursel, M. Gursel, J. Conover, A. Nussenzweig, and D.M. Klinman. 2002. Potential role of phosphatidylinositol 3 kinase, rather than DNA-dependent protein kinase, in CpG DNA-induced immune activation. J. Exp. Med. 196:269–274.
- Seong, S.Y., and P. Matzinger. 2004. Hydrophobicity: an ancient damage-associated molecular pattern that initiates innate immune responses. Nat. Rev. Immunol. 4:469–478.
- Adachi, O., T. Kawai, K. Takeda, M. Matsumoto, H. Tsutsui, M. Sakagami, K. Nakanishi, and S. Akira. 1999. Targeted disruption of the MyD88 gene results in loss of IL-1- and IL-18-mediated function. Immunity. 9:143–150.
- Takeuchi, O., K. Hoshino, T. Kawai, H. Sanjo, H. Takada, T. Ogawa, K. Takeda, and S. Akira. 1999. Differential roles of TLR2 and TLR4 in recognition of gram-negative and gram-positive bacterial cell wall components. Immunity. 11:443–451.
- Hemmi, H., O. Takeuchi, T. Kawai, T. Kaisho, S. Sato, H. Sanjo, M. Matsumoto, K. Hoshino, H. Wagner, K. Takeda, and S. Akira. 2000. A Toll-like receptor recognizes bacterial DNA. Nature. 408:740–745.
- Hemmi, H., T. Kaisho, O. Takeuchi, S. Sato, H. Sanjo, K. Hoshino, T. Horiuchi, H. Tomizawa, K. Takeda, and S. Akira. 2002. Small anti-viral compounds activate immune cells via the TLR7 MyD88-dependent signaling pathway. Nat. Immunol. 3:196–200.
- Yamamoto, M., S. Sato, H. Hemmi, K. Hoshino, T. Kaisho, H. Sanjo, O. Takeuchi, M. Sugiyama, M. Okabe, K. Takeda, and S. Akira. 2003. Role of adaptor TRIF in the MyD88-independent Toll-like receptor signaling pathway. Science. 301:640–643.
- Jaramillo, M., I. Plante, N. Ouellet, K. Vandal, P.A. Tessier, and M. Olivier. 2004. Hemozoin-inducible proinflammatory events in vivo: potential role in malaria infection. J. Immunol. 172:3101–3110.
- Gursel, M., D. Verthelyi, I. Gursel, K.J. Ishii, and D.M. Klinman. 2002. Differential and competitive activation of human immune cells by distinct classes of CpG oligodeoxynucleotide. J. Leukoc. Biol. 71:813–820.
- Ishii, K.J., K. Suzuki, C. Coban, F. Takeshita, Y. Itoh, H. Matoba, L.D. Kohn, and D.M. Klinman. 2001. Genomic DNA released by dying cells induces the maturation of APCs. J. Immunol. 167:2602–2607.
Source: PubMed