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Iron prevents the development of experimental cerebral malaria by attenuating CXCR3-mediated T cell chemotaxis.

Van Den Ham KM, Shio MT, Rainone A, Fournier S, Krawczyk CM, Olivier M - PLoS ONE (2015)

Bottom Line: Protection was concomitant with a significant decrease in the sequestration of CD4+ and CD8+ T cells within the brain.CD4+ T cells demonstrated markedly decreased CXCR3 expression and had reduced IFNγ-responsiveness, as indicated by mitigated expression of IFNγR2 and T-bet.Additional analysis of the splenic cell populations indicated that parenteral iron supplementation was also associated with a decrease in NK cells and increase in regulatory T cells.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology and Immunology, McGill University, Montréal, Québec, Canada; McGill International TB Centre, Research Institute of the McGill University Health Centre, Montréal, Québec, Canada.

ABSTRACT
Cerebral malaria is a severe neurological complication of Plasmodium falciparum infection. Previous studies have suggested that iron overload can suppress the generation of a cytotoxic immune response; however, the effect of iron on experimental cerebral malaria (ECM) is yet unknown. Here we determined that the incidence of ECM was markedly reduced in mice treated with iron dextran. Protection was concomitant with a significant decrease in the sequestration of CD4+ and CD8+ T cells within the brain. CD4+ T cells demonstrated markedly decreased CXCR3 expression and had reduced IFNγ-responsiveness, as indicated by mitigated expression of IFNγR2 and T-bet. Additional analysis of the splenic cell populations indicated that parenteral iron supplementation was also associated with a decrease in NK cells and increase in regulatory T cells. Altogether, these results suggest that iron is able to inhibit ECM pathology by attenuating the capacity of T cells to migrate to the brain.

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The Expression of Genes Involved in T Cell Chemotaxis are Attenuated by Parenteral Iron Supplementation.The expression of genes involved in T cell chemotaxis is shown for the brain (a) and the spleen (b) on day 7 post-infection. mRNA levels were normalized to Gusb. 2 samples pooled from 6 mice (3 mice per sample) were used for each group. UI = uninfected, I = infected, FeD = iron dextran, PBS = control.
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pone.0118451.g004: The Expression of Genes Involved in T Cell Chemotaxis are Attenuated by Parenteral Iron Supplementation.The expression of genes involved in T cell chemotaxis is shown for the brain (a) and the spleen (b) on day 7 post-infection. mRNA levels were normalized to Gusb. 2 samples pooled from 6 mice (3 mice per sample) were used for each group. UI = uninfected, I = infected, FeD = iron dextran, PBS = control.

Mentions: The expression of genes involved in the immune response was further profiled in the brain and the spleen on day 7 post-infection to develop a more comprehensive understanding of how parenteral iron supplementation may have been facilitating protection during ECM. Numerous studies have demonstrated that CD8+ T cell accumulation within the brain is necessary for the clinical onset of ECM [8–14,19,28–32,38]. In the brain, it was observed that multiple genes involved in T cell trafficking were downregulated (Fig. 4A). The mRNA expression of chemokines (CXCL10 and CCL5) and chemokine receptors (CXCR3 and CCR5) that have previously been determined to play a role in T cell trafficking and ECM pathogenesis were decreased [11,12,39]. IFNγ production by CD4+ T cells has been shown to contribute to the accumulation of CD8+ T cells in the brain by inducing the expression of chemokines [13,14]. Expression of IFNγ in the brain was also observed to be reduced in the FeD mice. Since T cell priming during ECM occurs in the spleen [8,15], we also analyzed the expression of genes involved in T cell trafficking in this organ (Fig. 4B). In the spleen, a large increase in the expression of CXCL10 and a decrease in the expression of CXCR3 were detected in FeD mice; whereas the expression of CCL5 and CCR5 were unchanged by iron supplementation. Additionally, the expression of IFNγ in the spleen was unchanged. This data suggests that CD4+ and CD8+ T cells in the FeD mice have an impaired ability to traffick to the brain during P. berghei ANKA infection.


Iron prevents the development of experimental cerebral malaria by attenuating CXCR3-mediated T cell chemotaxis.

Van Den Ham KM, Shio MT, Rainone A, Fournier S, Krawczyk CM, Olivier M - PLoS ONE (2015)

The Expression of Genes Involved in T Cell Chemotaxis are Attenuated by Parenteral Iron Supplementation.The expression of genes involved in T cell chemotaxis is shown for the brain (a) and the spleen (b) on day 7 post-infection. mRNA levels were normalized to Gusb. 2 samples pooled from 6 mice (3 mice per sample) were used for each group. UI = uninfected, I = infected, FeD = iron dextran, PBS = control.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4359107&req=5

pone.0118451.g004: The Expression of Genes Involved in T Cell Chemotaxis are Attenuated by Parenteral Iron Supplementation.The expression of genes involved in T cell chemotaxis is shown for the brain (a) and the spleen (b) on day 7 post-infection. mRNA levels were normalized to Gusb. 2 samples pooled from 6 mice (3 mice per sample) were used for each group. UI = uninfected, I = infected, FeD = iron dextran, PBS = control.
Mentions: The expression of genes involved in the immune response was further profiled in the brain and the spleen on day 7 post-infection to develop a more comprehensive understanding of how parenteral iron supplementation may have been facilitating protection during ECM. Numerous studies have demonstrated that CD8+ T cell accumulation within the brain is necessary for the clinical onset of ECM [8–14,19,28–32,38]. In the brain, it was observed that multiple genes involved in T cell trafficking were downregulated (Fig. 4A). The mRNA expression of chemokines (CXCL10 and CCL5) and chemokine receptors (CXCR3 and CCR5) that have previously been determined to play a role in T cell trafficking and ECM pathogenesis were decreased [11,12,39]. IFNγ production by CD4+ T cells has been shown to contribute to the accumulation of CD8+ T cells in the brain by inducing the expression of chemokines [13,14]. Expression of IFNγ in the brain was also observed to be reduced in the FeD mice. Since T cell priming during ECM occurs in the spleen [8,15], we also analyzed the expression of genes involved in T cell trafficking in this organ (Fig. 4B). In the spleen, a large increase in the expression of CXCL10 and a decrease in the expression of CXCR3 were detected in FeD mice; whereas the expression of CCL5 and CCR5 were unchanged by iron supplementation. Additionally, the expression of IFNγ in the spleen was unchanged. This data suggests that CD4+ and CD8+ T cells in the FeD mice have an impaired ability to traffick to the brain during P. berghei ANKA infection.

Bottom Line: Protection was concomitant with a significant decrease in the sequestration of CD4+ and CD8+ T cells within the brain.CD4+ T cells demonstrated markedly decreased CXCR3 expression and had reduced IFNγ-responsiveness, as indicated by mitigated expression of IFNγR2 and T-bet.Additional analysis of the splenic cell populations indicated that parenteral iron supplementation was also associated with a decrease in NK cells and increase in regulatory T cells.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology and Immunology, McGill University, Montréal, Québec, Canada; McGill International TB Centre, Research Institute of the McGill University Health Centre, Montréal, Québec, Canada.

ABSTRACT
Cerebral malaria is a severe neurological complication of Plasmodium falciparum infection. Previous studies have suggested that iron overload can suppress the generation of a cytotoxic immune response; however, the effect of iron on experimental cerebral malaria (ECM) is yet unknown. Here we determined that the incidence of ECM was markedly reduced in mice treated with iron dextran. Protection was concomitant with a significant decrease in the sequestration of CD4+ and CD8+ T cells within the brain. CD4+ T cells demonstrated markedly decreased CXCR3 expression and had reduced IFNγ-responsiveness, as indicated by mitigated expression of IFNγR2 and T-bet. Additional analysis of the splenic cell populations indicated that parenteral iron supplementation was also associated with a decrease in NK cells and increase in regulatory T cells. Altogether, these results suggest that iron is able to inhibit ECM pathology by attenuating the capacity of T cells to migrate to the brain.

Show MeSH
Related in: MedlinePlus