Targeting Toll-like receptors by chloroquine protects mice from experimental cerebral malaria.
Excessive production of proinflammatory cytokines, elicited mostly by Th1 cells, is an important cause of cerebral malaria (CM). Dendritic cells (DCs), a critical link between innate and adaptive immune responses, rely heavily on Toll-like receptor (TLR) signaling. Using C57BL/6 mice infected with Plasmodium berghei ANKA (PbA) as an experimental CM model, we first confirmed that inhibition of TLR9 by suppressive oligodeoxynucleotides protected mice from CM. In addition to being a well-known antimalarial, chloroquine (CQ) has been used as an immunomodulator of endocytic TLRs because it inhibits endosomal acidification. We found that immediately before and shortly after infection by PbA, treatment with a single dose of 50 mg/kg of CQ protected mice from experimental CM. Both CQ treatments significantly inhibited expression of TLR9 and MHC-II on DCs, and reduced the number of myeloid and plasmatocytoid DCs at 3 and 5 days after infection. Consequently, activation of CD4+ T cells, especially the expansion of the Th1 subsets, was dramatically inhibited in CQ treated groups, which was accompanied by a remarkable decline in the production of Th1 type proinflammatory mediators IFN-γ, TNF-α, and nitric oxide. Taken together, these results corroborated the involvement of TLR9 in CM pathogenesis and suggest that interference with the activation of this receptor is a promising strategy to prevent deleterious inflammatory response mediating pathogenesis and severity of malaria.
Department of Immunology, College of Basic Medical Sciences, China Medical University, Shenyang, Liaoning, China.
Xiaotong
X
Zhu
Yanyan
Y
Pan
Ying
Y
Li
Yongjun
Y
Jiang
Hong
H
Shang
D Channe
DC
Gowda
Liwang
L
Cui
Yaming
Y
Cao
D000818:Animals; D000962:Antimalarials / Q000008:administration & dosage* / Q000009:adverse effects; D002478:Cells, Cultured; D002738:Chloroquine / Q000008:administration & dosage* / Q000009:adverse effects; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000187:drug effects* / Q000276:immunology / Q000469:parasitology; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000276:immunology; D000949:Histocompatibility Antigens Class II / Q000235:genetics / Q000378:metabolism; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D016779:Malaria, Cerebral / Q000517:prevention & control*; D051379:Mice; D008810:Mice, Inbred C57BL; D058990:Molecular Targeted Therapy; D020320:Oligoribonucleotides, Antisense / Q000235:genetics; D010962:Plasmodium berghei / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology; D051217:Toll-Like Receptor 9 / Q000235:genetics / Q000378:metabolism*
D000962:Antimalarials; D016207:Cytokines; D000949:Histocompatibility Antigens Class II; D018836:Inflammation Mediators; D020320:Oligoribonucleotides, Antisense; D051217:Toll-Like Receptor 9; D002738:Chloroquine