Toll-like receptor 9 mediates innate immune activation by the malaria pigment hemozoin
By C. Coban, K. Ishii, Taro Kawai, H. Hemmi, Shintaro Sato, Satoshi Uematsu, Masahiro Yamamoto, O. Takeuchi, Sawako Itagaki, Nirbhay Kumar and 2 more. Journal of Experimental Medicine, 2005
684 citations recorded by the source corpus.
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.
Subfields: Immunology, Public Health, Environmental and Occupational Health
View Paper: https://www.semanticscholar.org/paper/819f2aa9cc2c177b43b37429d6da8164d5bd0fb6
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Citations in the corpus
- A Toll-like receptor–independent antiviral response induced by double-stranded B-form DNA (2006, methodology): “Mouse bone marrow DCs were generated by 7 d of culture of bone marrow cells with either granulocyte-monocyte colony-stimulating factor (GM-DCs) or Flt3 ligand (FL-DCs) as describe”
- Immunity to malaria: more questions than answers (2008, background): “58 ), and hemazoin or, more likely, contaminating DNA activates DCs through TLR9 (refs”
- Pathogen Recognition and Inflammatory Signaling in Innate Immune Defenses (2009, neutral): “degradation product, stimulates TLR9 (58).”
- Pattern recognition receptors and inflammation. (2010, background): “In addition to DNA, TLR9 also recognizes hemozoin, a crystalline metabolite of hemoglobin produced by the malaria parasite (Coban et al., 2005).”
- Negative regulation of Toll-like receptor-mediated immune responses (2005, background): “TLRs might also promote the pathogenesis of infections by hyperinduction of pro-inflammatory cytokine”
- Pathogen recognition and innate immunity. (2006, neutral): “Recently, hemozoin, a heme byproduct, was shown to be a TLR9 stimulant (Coban et al., 2005).”
- Toll-like receptors and their crosstalk with other innate receptors in infection and immunity. (2011, background): “Notably, TLR9 is involved in the recognition of the heatlabile non-DNA fractions and hemozoin derived from P. falciparum (Coban et al., 2005).”
- NF-κB and the immune response (2006, background): “Recently, TLR9 has been reported to recognize the malarial pigment hemozoin, a byproduct of heme metabolism in infected erythrocytes (Coban et al., 2005) whereas TLR11 recognizes a profilin-like protein that is conserved in apicomplexan parasites including Toxoplasma gondii (Yarovinsky et al.,…”
- TLR9 regulates Th1 responses and cooperates with TLR2 in mediating optimal resistance to Mycobacterium tuberculosis (2005, background): “A recently described precedent is the stimulation of TLR9 by hemozoin pigment from malaria (48).”