Abstract
We earlier established that nitric oxide (NO) is protective against severe malaria and that arginine and NO levels are reduced in malaria patients. We now show that an M2-like blood monocyte phenotype is significantly associated with hypoargininemia, NO insufficiency, and disease severity in Tanzanian children with falciparum malaria. Compared to control children (n = 106), children with moderately severe (n = 77) and severe falciparum malaria (n = 129) had significantly higher mononuclear cell arginase 1 mRNA, protein, and enzyme activity; lower NOS2 mRNA; lower plasma arginine; and higher plasma IL-10, IL-13, and IL-4. In addition, monocyte CD206 and CD163 and plasma soluble CD163 were elevated. Multivariate logistic regression analysis revealed a significant correlation of risk of severe malaria with both plasma IL-10 and soluble CD163 levels. Monocyte M2 skewing likely contributes to NO bioinsufficiency in falciparum malaria in children. Treatments that reverse the M2 polarization may have potential as adjunctive treatment for malaria.
Highlights
Investigators have noted that monocytes and macrophages can be activated in vivo or in vitro in response to infection with microbes or cytokines to display different phenotypes
Our data demonstrate that there is an M2-like activation monocyte phenotype in children with falciparum malaria, with high monocyte counts and plasma arginase levels, low arginine levels, and low monocyte NOS2, forming an important basis of the low nitric oxide (NO) bioavailability observed in malaria
We reported that adults and children with falciparum malaria have low NO levels and decreased PBMC NOS2 mRNA and protein expression[3], low plasma arginine[4], NOS2 promoter polymorphisms modulating NO production[5], increased plasma arginase activity[3], increased levels of the endogenous NOS inhibitor asymmetric dimethylarginine[6,24], increased plasma levels of the NO-quencher hemoglobin[3], and low levels of the NOS cofactor tetrahydrobiopterin[7,8]
Summary
Investigators have noted that monocytes and macrophages can be activated in vivo or in vitro in response to infection with microbes or cytokines to display different phenotypes. Infection with Listeria monocytogenes or bacillus Calmette Guerin, or in vitro in treatment with cytokines such as IFN-γand TNF causes “classical” (M1) activation with cells displaying enzymatic mechanisms of microbicidal activities including high NOS2-produced NO and NADPH oxidase-produced superoxide[9,10,11,12]. Arginase 1 is typically elevated in alternatively activated (M2) monocytes and macrophages in vivo or in vitro by treatment with factors such as IL-4, IL-13, IL-10, and TGF-ß13–19. We note that Tanzanian children with falciparum malaria have markedly increased PBMC arginase 1 and IL-10, reduced PBMC NOS2 and plasma arginine, and monocytes expressing markers of alternative activation (M2-like monocytes). The data indicates that this monocyte M2 skewing likely underlies NO bioinsufficiency in falciparum malaria in children
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