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Published on: January 2, 2013
Iron prevents the development of experimental cerebral malaria by attenuating CXCR3-mediated T cell chemotaxis
Kristin M Van Den Ham1, Marina Tiemi Shio1, Anthony Rainone2
1Department 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.
Insights
Iron supplementation reduced experimental cerebral malaria (ECM) incidence in mice. This protection involved decreased T cell brain infiltration and reduced T cell responses, suggesting iron can mitigate ECM pathology.
Area of Science:
- Immunology
- Neuroscience
- Infectious Diseases
Background:
- Cerebral malaria (CM) is a severe neurological complication of Plasmodium falciparum infection.
- Iron overload's impact on cytotoxic immune responses is known, but its role in experimental cerebral malaria (ECM) remains unclear.
Purpose of the Study:
- To investigate the effect of iron supplementation on the development of experimental cerebral malaria (ECM).
- To elucidate the immunological mechanisms underlying iron's influence on ECM pathology.
Main Methods:
- Mice were treated with iron dextran to induce iron overload.
- Incidence of ECM was monitored.
- T cell populations (CD4+, CD8+), their brain sequestration, CXCR3 expression, IFNγ-responsiveness (IFNγR2, T-bet), NK cells, and regulatory T cells were analyzed.
Main Results:
- Iron dextran treatment significantly reduced the incidence of ECM.
- A marked decrease in CD4+ and CD8+ T cell sequestration in the brain was observed.
- T cells showed reduced CXCR3 expression and diminished IFNγ-responsiveness, with decreased IFNγR2 and T-bet expression.
- Splenic analysis revealed decreased NK cells and increased regulatory T cells.
Conclusions:
- Iron supplementation can inhibit experimental cerebral malaria (ECM) pathology.
- Protection is mediated by attenuating T cell migration to the brain and dampening their inflammatory responses.
- Iron influences multiple immune cell populations, impacting the overall immune landscape during ECM.
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