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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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Iron Dextran Mitigates the Upregulation of IFNγR2 and T-bet on CD4+ T Cells in the Spleen.Representative flow cytometric dot plots for IFNγR2+ CD4+ T cells (a) and the percentage of IFNγR2+ cells (b) after gating on CD4+ T cells on day 3 and day 7 post-infection. Representative flow cytometric dot plots for T-bet+ CD4+ T cells (c) and the percentage of T-bet+ cells (d) after gating on CD4+ T cells on day 3 and 7 post-infection. The numbers shown on the dot plots indicate the mean percentage of cells inside the gate ± S.E.M. On day 3 post-infection, n = 6 for control mice and n = 5 for FeD mice. On day 7 post-infection, n = 6 for control mice and n = 6 for FeD mice. FeD = iron dextran, PBS = control. Statistically significant differences, shown by asterisks (*** P < 0.001), were determined by unpaired Student’s t-test.
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pone.0118451.g007: Iron Dextran Mitigates the Upregulation of IFNγR2 and T-bet on CD4+ T Cells in the Spleen.Representative flow cytometric dot plots for IFNγR2+ CD4+ T cells (a) and the percentage of IFNγR2+ cells (b) after gating on CD4+ T cells on day 3 and day 7 post-infection. Representative flow cytometric dot plots for T-bet+ CD4+ T cells (c) and the percentage of T-bet+ cells (d) after gating on CD4+ T cells on day 3 and 7 post-infection. The numbers shown on the dot plots indicate the mean percentage of cells inside the gate ± S.E.M. On day 3 post-infection, n = 6 for control mice and n = 5 for FeD mice. On day 7 post-infection, n = 6 for control mice and n = 6 for FeD mice. FeD = iron dextran, PBS = control. Statistically significant differences, shown by asterisks (*** P < 0.001), were determined by unpaired Student’s t-test.

Mentions: On day 3 post-infection, IFNγR2 was expressed on a low percentage of CD4+ T cells and the percentage of IFNγR2+ CD4+ T cells was not significantly different in the FeD mice compared to the control mice (Fig. 7A,B). The percentage of T-bet+ CD4+ T cells on day 3 post-infection was increased in the FeD mice (Fig. 7C,D), concurring with the increased percentage of CXCR3+ CD4+ T cells observed on this day (Figure G.C,D in S1 File). The percentages of IFNγR2- and T-bet-expressing CD4+ T cells were increased in both groups on day 7 post-infection compared to day 3 post-infection; however, the percentages of IFNγR2+ and T-bet+ CD4+ T cells were markedly reduced in the FeD mice on day 7 post-infection (Fig. 7A-D). This result agrees with the decreased expression of CXCR3 measured on CD4+ T cells in the FeD mice on day 7 post-infection (Fig. 6A-D). No differences were observed in the expression of IFNγR2 or T-bet on CD8+ T cells on day 3 post-infection, but the expression of both IFNγR2 and T-bet were significantly decreased in the FeD mice on day 7 post-infection (Figure H.A-D in S1 File). However, this did not culminate in a decrease in CXCR3 expression (Fig. 6A-D). IFNγ stimulation induces T-bet through the activation of STAT1 [40]; therefore, the phosphorylation of STAT1 was examined to verify that iron supplementation was inhibiting IFNγ signalling in CD4+ T cells. The phosphorylation of STAT1 was notably reduced in CD4+ T cells in the FeD mice on day 7 post-infection (Figure I in S1 File). Thus, these results suggest that the attenuated expression of CXCR3 on splenic CD4+ T cells is dependent on the iron-mediated decrease in the IFNγ-responsiveness of CD4+ T cells.


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)

Iron Dextran Mitigates the Upregulation of IFNγR2 and T-bet on CD4+ T Cells in the Spleen.Representative flow cytometric dot plots for IFNγR2+ CD4+ T cells (a) and the percentage of IFNγR2+ cells (b) after gating on CD4+ T cells on day 3 and day 7 post-infection. Representative flow cytometric dot plots for T-bet+ CD4+ T cells (c) and the percentage of T-bet+ cells (d) after gating on CD4+ T cells on day 3 and 7 post-infection. The numbers shown on the dot plots indicate the mean percentage of cells inside the gate ± S.E.M. On day 3 post-infection, n = 6 for control mice and n = 5 for FeD mice. On day 7 post-infection, n = 6 for control mice and n = 6 for FeD mice. FeD = iron dextran, PBS = control. Statistically significant differences, shown by asterisks (*** P < 0.001), 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.g007: Iron Dextran Mitigates the Upregulation of IFNγR2 and T-bet on CD4+ T Cells in the Spleen.Representative flow cytometric dot plots for IFNγR2+ CD4+ T cells (a) and the percentage of IFNγR2+ cells (b) after gating on CD4+ T cells on day 3 and day 7 post-infection. Representative flow cytometric dot plots for T-bet+ CD4+ T cells (c) and the percentage of T-bet+ cells (d) after gating on CD4+ T cells on day 3 and 7 post-infection. The numbers shown on the dot plots indicate the mean percentage of cells inside the gate ± S.E.M. On day 3 post-infection, n = 6 for control mice and n = 5 for FeD mice. On day 7 post-infection, n = 6 for control mice and n = 6 for FeD mice. FeD = iron dextran, PBS = control. Statistically significant differences, shown by asterisks (*** P < 0.001), were determined by unpaired Student’s t-test.
Mentions: On day 3 post-infection, IFNγR2 was expressed on a low percentage of CD4+ T cells and the percentage of IFNγR2+ CD4+ T cells was not significantly different in the FeD mice compared to the control mice (Fig. 7A,B). The percentage of T-bet+ CD4+ T cells on day 3 post-infection was increased in the FeD mice (Fig. 7C,D), concurring with the increased percentage of CXCR3+ CD4+ T cells observed on this day (Figure G.C,D in S1 File). The percentages of IFNγR2- and T-bet-expressing CD4+ T cells were increased in both groups on day 7 post-infection compared to day 3 post-infection; however, the percentages of IFNγR2+ and T-bet+ CD4+ T cells were markedly reduced in the FeD mice on day 7 post-infection (Fig. 7A-D). This result agrees with the decreased expression of CXCR3 measured on CD4+ T cells in the FeD mice on day 7 post-infection (Fig. 6A-D). No differences were observed in the expression of IFNγR2 or T-bet on CD8+ T cells on day 3 post-infection, but the expression of both IFNγR2 and T-bet were significantly decreased in the FeD mice on day 7 post-infection (Figure H.A-D in S1 File). However, this did not culminate in a decrease in CXCR3 expression (Fig. 6A-D). IFNγ stimulation induces T-bet through the activation of STAT1 [40]; therefore, the phosphorylation of STAT1 was examined to verify that iron supplementation was inhibiting IFNγ signalling in CD4+ T cells. The phosphorylation of STAT1 was notably reduced in CD4+ T cells in the FeD mice on day 7 post-infection (Figure I in S1 File). Thus, these results suggest that the attenuated expression of CXCR3 on splenic CD4+ T cells is dependent on the iron-mediated decrease in the IFNγ-responsiveness of CD4+ T cells.

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