L-arginine exacerbates experimental cerebral malaria by enhancing pro-inflammatory responses.
L-Arginine (L-Arg), the substrate for nitric oxide (NO) synthase, has been used to treat malaria to reverse endothelial dysfunction in adults. However, the safety and efficacy of L-Arg remains unknown in malaria patients under the age of five, who are at the greatest risk of developing cerebral malaria (CM), a severe malaria complication. Here, we tested effects of L-Arg treatment on the outcomes of CM using a mouse model. Experimental cerebral malaria (ECM) was induced in female C57BL/6 mice infected with Plasmodium berghei ANKA, and L-Arg was administrated either prophylactically or after parasite infection. Surprisingly, both types of L-Arg administration caused a decline in survival time and raised CM clinical scores. L-Arg treatment increased the population of CD4(+)T-bet(+)IFN-γ(+) Th1 cells and the activated macrophages (F4/80(+)CD36(+)) in the spleen. The levels of pro-inflammatory cytokines, IFN-γ and TNF-α, in splenocyte cultures were also increased by L-Arg treatment. The above changes were accompanied with a rise in the number of dendritic cells (DCs) and an increase in their maturation. However, L-Arg did not affect the population of regulatory T cells or the level of IL-10 in the spleen. Taken together, these data suggest that L-Arg may enhance the Th1 immune response, which is essential for a protective response in uncomplicated malaria but could be lethal in CM patients. Therefore, the prophylactic use of L-Arg to treat CM, based on the assumption that restoring the bioavailability of endothelial NO improves the outcome of CM, may need to be reconsidered especially for children.
Department of Immunology, College of Basic Medical Sciences, China Medical University.
Hongbin
H
Xu
Yonghui
Y
Feng
Guang
G
Chen
Xiaotong
X
Zhu
Wei
W
Pang
Yunting
Y
Du
Qinghui
Q
Wang
Zanmei
Z
Qi
Yaming
Y
Cao
D000818:Animals; D001120:Arginine / Q000009:adverse effects*; D049109:Cell Proliferation / Q000187:drug effects; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology; D018450:Disease Progression; D005260:Female; D007109:Immunity / Q000187:drug effects; D018836:Inflammation Mediators / Q000378:metabolism*; D016753:Interleukin-10 / Q000378:metabolism; D018655:Lymphocyte Count; D008262:Macrophage Activation / Q000187:drug effects; D016779:Malaria, Cerebral / Q000276:immunology / Q000469:parasitology / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018512:Parasitemia / Q000276:immunology; D010641:Phenotype; D010962:Plasmodium berghei / Q000187:drug effects / Q000276:immunology; D016019:Survival Analysis; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology; D018417:Th1 Cells / Q000187:drug effects / Q000276:immunology
D018836:Inflammation Mediators; D016753:Interleukin-10; D001120:Arginine