Tohoku J. Exp. Med., 2015 May, 236(1)

L-Arginine Exacerbates Experimental Cerebral Malaria by Enhancing Pro-Inflammatory Responses

HONGBIN XU,¹ YONGHUI FENG,² GUANG CHEN,³ XIAOTONG ZHU,¹ WEI PANG,¹ YUNTING DU,¹ QINGHUI WANG,¹ ZANMEI QI¹ and YAMING CAO¹

¹Department of Immunology, College of Basic Medical Sciences, China Medical University, Shenyang, Liaoning, P.R. China
²Department of Laboratory Medicine, The First Hospital of China Medical University, Shenyang, Liaoning, P.R. China
³Department of Parasitology, College of Basic Medical Sciences, Jamusi University, Jamusi, Heilongjiang, P.R. China

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.

keywords —— dendritic cells; L-Arginine; malaria; regulatory T cell; Th1 immune responses

© 2015 Tohoku University Medical Press

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Tohoku J. Exp. Med., 2015, 236, 21-31

Correspondence: Yaming Cao, Department of Immunology, College of Basic Medical Sciences, China Medical University, No. 77 Pu He Road, Shen Bei Xin District, Shenyang, Liaoning 1100122, P.R. China.

e-mail: ymcao@mail.cmu.edu.cn