Iron overload in pyruvate kinase mutant mice affects the response of splenic macrophage to fungal infection
Date Issued
2010
Date
2010
Author(s)
Wenshane Fu, Catherine
Abstract
Iron is a critical element in host-pathogen interaction. It is both a modifier of cellular immune function and an essential nutrient for microbes. Here, I investigated immune cell functions in pyruvate kinase deficient mice following infection by Histoplasma capsulatum (HC). Pyruvate kinase (PK) deficiency is the most common enzyme abnormality of glycolysis causing chronic non-spherocytic haemolytic anemia and accumulation of iron in the liver and spleen. Whether pyruvate kinase deficiency affects immune cell functions has never been addressed. The availability of ENU-mutagenized mice P354 with point-mutated pklr gene presents an opportunity to study how pyruvate kinase deficiency affects immune response to infection.
In this study, cytometric analysis of the splenic cell populations revealed elevated numbers of TER119-positive erythroid precursor cells and lower percentages of T cells and B cells in P354 mutant mice compared to wild-type mice. However, the T cell populations in the thymus and lymph nodes of P354 mutant mice were comparable to that in wild-type mice. I demonstrated in this study that there was iron accumulation in the spleen and liver of P354 mutant mice and found that fungal burdens in the spleen and liver but not that in the lung of P354 mutant mice were higher than in wild-type mice at different time points after Histoplasma infection. Furthermore, the levels of cytokines (TNF-α, IL-6, IFN-γ, IL-4, IL-10, and IL-17) and the numbers of IFN-γ-producing T cells were lower in P354 mutant mice than in wild-type mice. Interestingly, while peritoneal macrophages from P354 mutant mice were functionally comparable to wild-type mice, splenic macrophages obtained from P354 mutant mice were less competent in phagocytosis of Histoplasma and production of TNF-α.
These results showed that mice with pyruvate kinase deficiency were inefficient to clear Histoplasma from the spleen and liver, coinciding with increased iron contents in these organs. Inefficiency to rid the spleen of fungus also correlated with lower cytokine production and impaired macrophage function. While the function of peritoneal macrophages from P354 mutant mice was comparable to that of wild-type mice, the addition of holo-transferrin to peritoneal macrophages from wild-type mice impaired their ability to produce TNF-α. Although the possibility of overcrowding effect has not been excluded, the results of my study suggest that iron overload as observed in the spleen and liver of mice with pyruvate kinase deficiency impairs the function of macrophages, thereby directly or indirectly, affects their ability to rid an intracellular pathogen.
Subjects
Histoplasma capsulatum(Hc)
Pyruvate kinase(PK)
N-ethyl-N-nitrosourea(ENU)
Pyruvate kinase, liver and RBC(PKLR)
Pedigree 354(P354)
Antigen-presenting cell (APC)
Wild-type(WT)
Type
thesis
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