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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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Systemic Inflammation is Augmented in FeD Mice.Concentration of IFNγ (a), TNFα (b), IL-10 (c), IL-1β (d) and IL-6 (e) in the serum on day 7 post-infection. n = 5 for the control, uninfected group mice and n = 6 for all other groups. Levels of TNFα are below the limit of detection in the uninfected groups. FeD = iron dextran, PBS = control. Statistically significant differences, shown by asterisks (* P < 0.05 and ** P < 0.01), were determined by unpaired Student’s t-test.
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pone.0118451.g003: Systemic Inflammation is Augmented in FeD Mice.Concentration of IFNγ (a), TNFα (b), IL-10 (c), IL-1β (d) and IL-6 (e) in the serum on day 7 post-infection. n = 5 for the control, uninfected group mice and n = 6 for all other groups. Levels of TNFα are below the limit of detection in the uninfected groups. FeD = iron dextran, PBS = control. Statistically significant differences, shown by asterisks (* P < 0.05 and ** P < 0.01), were determined by unpaired Student’s t-test.

Mentions: The activation of the inflammatory response by parasite antigens and immune cell adhesion has been shown to contribute to ECM pathology. Therefore, to discern the effect of parenteral iron supplementation on the systemic immune response, the concentrations of several cytokines in the serum were measured on day 7 post-infection. Overall, our data suggests that iron supplementation increased the proinflammatory response at late time points during P. berghei ANKA infection. Importantly, administration of iron dextran without infection did not appear to have a significant effect on most of the inflammatory mediators analyzed (Fig. 3A-E). Surprisingly, IFNγ, which has been established to be integral to the development of ECM pathology [13,14,28,29,34], was observed to be significantly increased in the FeD mice compared to the control mice (Fig. 3A). The FeD mice also had increased concentrations of TNFα (Fig. 3B) and IL-10 (Fig. 3C) after infection. TNFα and IL-10 have been shown to be associated with decreased tissue parasite accumulation during ECM [29,35], and this may account for the observed reduction in parasite burden in the FeD mice (Fig. 2A-C). Furthermore, the FeD mice exhibited an increased serum concentration of IL-1β (Fig. 3D) and IL-6 (Fig. 3E), indicating a strong inflammatory response, but neither cytokine has been shown to play a role in the development of ECM [36,37]. The levels of cytokines in the serum were also measured over the course of the infection. The serum concentration of IFNγ, TNFα, IL-10 and IL-6 only started to increase substantially on day 6 post-infection, and no apparent difference was observed in the serum levels of IL-1β (Figure C in S1 File). Interestingly, in contrast to the results obtained for the serum, the expression of inflammatory and immune response-related genes in the brain, spleen and liver of the FeD mice was predominately unchanged or reduced compared to the control mice (Table A-C in S1 File).


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)

Systemic Inflammation is Augmented in FeD Mice.Concentration of IFNγ (a), TNFα (b), IL-10 (c), IL-1β (d) and IL-6 (e) in the serum on day 7 post-infection. n = 5 for the control, uninfected group mice and n = 6 for all other groups. Levels of TNFα are below the limit of detection in the uninfected groups. FeD = iron dextran, PBS = control. Statistically significant differences, shown by asterisks (* P < 0.05 and ** P < 0.01), were determined by unpaired Student’s t-test.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0118451.g003: Systemic Inflammation is Augmented in FeD Mice.Concentration of IFNγ (a), TNFα (b), IL-10 (c), IL-1β (d) and IL-6 (e) in the serum on day 7 post-infection. n = 5 for the control, uninfected group mice and n = 6 for all other groups. Levels of TNFα are below the limit of detection in the uninfected groups. FeD = iron dextran, PBS = control. Statistically significant differences, shown by asterisks (* P < 0.05 and ** P < 0.01), were determined by unpaired Student’s t-test.
Mentions: The activation of the inflammatory response by parasite antigens and immune cell adhesion has been shown to contribute to ECM pathology. Therefore, to discern the effect of parenteral iron supplementation on the systemic immune response, the concentrations of several cytokines in the serum were measured on day 7 post-infection. Overall, our data suggests that iron supplementation increased the proinflammatory response at late time points during P. berghei ANKA infection. Importantly, administration of iron dextran without infection did not appear to have a significant effect on most of the inflammatory mediators analyzed (Fig. 3A-E). Surprisingly, IFNγ, which has been established to be integral to the development of ECM pathology [13,14,28,29,34], was observed to be significantly increased in the FeD mice compared to the control mice (Fig. 3A). The FeD mice also had increased concentrations of TNFα (Fig. 3B) and IL-10 (Fig. 3C) after infection. TNFα and IL-10 have been shown to be associated with decreased tissue parasite accumulation during ECM [29,35], and this may account for the observed reduction in parasite burden in the FeD mice (Fig. 2A-C). Furthermore, the FeD mice exhibited an increased serum concentration of IL-1β (Fig. 3D) and IL-6 (Fig. 3E), indicating a strong inflammatory response, but neither cytokine has been shown to play a role in the development of ECM [36,37]. The levels of cytokines in the serum were also measured over the course of the infection. The serum concentration of IFNγ, TNFα, IL-10 and IL-6 only started to increase substantially on day 6 post-infection, and no apparent difference was observed in the serum levels of IL-1β (Figure C in S1 File). Interestingly, in contrast to the results obtained for the serum, the expression of inflammatory and immune response-related genes in the brain, spleen and liver of the FeD mice was predominately unchanged or reduced compared to the control mice (Table A-C in S1 File).

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