Oral 1731-1 - The role of alternatively activated (M2) monocytes in limiting NO bioavailability in falciparum malaria
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Date
2014
Journal Title
Journal ISSN
Volume Title
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Weinberg, J.B., Volkheimer, A.D., Chen, Y., Rubach, M.P., Mwaikambo, E.D., Mukemba, J., Florence, S., Yeo, T.W., Granger, D.L. and Anstey, N.M., 2014. The role of alternatively activated (M2) monocytes in limiting NO bioavailability in falciparum malaria. Nitric Oxide, (42), p.101.
Abstract
Background: We established earlier that NO has potent anti-malaria disease activity in humans.
We have discovered a variety of mechanisms by which host NO bioavailability is decreased in
children and adults with falciparum malaria (Weinberg et al., Curr. Opin. Infect. Dis. 21 (2008)
468–475, for review). The underlying process(es) causing changes in these factors with resultant
low NO in malaria is not known. Monocytes-macrophages can be activated through the classical
pathway (“M1”) with cytokines such as IFN-g and TNF, or through the alternative pathway (“M2”)
with cytokines such asIL-4, IL-10, and IL-13. M1 cells are characterized by increased NOS2, NO,
and superoxide production, while M2 cells have de-creased NOS2 and NO production, increased
arginase 1expression, and increased expression of the scavenger receptor CD163 and the mannose
receptor CD206 by monocytes.
Hypothesis: Monocytes in falciparum malaria patients are alternatively activated, and this
activation contributes to the low NO bioavailability in malaria.
Objective: Determine the status of monocyte activation in Tanzanian children with falciparum
malaria.
Methods: We studied the categories healthy control (HC, n=62), moderately severe malaria (MSM,
n=54), and severe malaria (SM, n=50) (total n=166). We used real-time RT-PCR to measure
PBMC mRNA for arginase1& 2, NOS2, and GTP cyclohydrolase 1; flow cytometry for monocyte
surface CD163& CD206; ELISA for plasma soluble CD163; and ELISA for plasmacytokine
levels.
Results: Compared to HC subjects, patients with malaria had significantly higher PBMC arginase
1 mRNA, lower NOS2 mRNA, slightly higher GTPCH-1 mRNA, and unchanged arginase
2mRNA; higher PBMC arginase 1 protein by immunoblot; higher plasma arginase enzyme activity
and soluble CD163; higher monocyte surface CD206 and CD163; and higher plasma IL-10, IL-4,
and IL-13. Overall, this pattern of changes we see in malaria patients is characteristic of
alternatively activated (M2) monocytes.
Conclusions: Our results indicate presence of alternatively activated (M2) monocytes in children
with falciparum malaria. We speculate that the M2 status of mononuclear phagocytes is a major
factor underlying certain causes of low NO bioavailability in malaria. Preventing M2 development
or reversing M2 status to either no activation or M1 activation status will likely be useful in
preventing and treating malaria.
Description
Keywords
Malaria, Monocyte, Alternative activation
Citation
Weinberg, J.B., Volkheimer, A.D., Chen, Y., Rubach, M.P., Mwaikambo, E.D., Mukemba, J., Florence, S., Yeo, T.W., Granger, D.L. and Anstey, N.M., 2014. The role of alternatively activated (M2) monocytes in limiting NO bioavailability in falciparum malaria. Nitric Oxide, (42), p.101.