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

PLoS One. 2015 Mar 13;10(3):e0118451. doi: 10.1371/journal.pone.0118451. eCollection 2015.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain / drug effects
  • Brain / immunology
  • Brain / metabolism
  • CD4-Positive T-Lymphocytes / drug effects*
  • CD4-Positive T-Lymphocytes / immunology
  • CD4-Positive T-Lymphocytes / metabolism
  • CD8-Positive T-Lymphocytes / drug effects*
  • CD8-Positive T-Lymphocytes / immunology
  • CD8-Positive T-Lymphocytes / metabolism
  • Chemotaxis, Leukocyte / drug effects*
  • Chemotaxis, Leukocyte / immunology
  • Disease Models, Animal
  • Female
  • Interferon-gamma / immunology
  • Interferon-gamma / metabolism
  • Iron / immunology
  • Iron / pharmacology*
  • Killer Cells, Natural / drug effects
  • Killer Cells, Natural / immunology
  • Killer Cells, Natural / metabolism
  • Malaria, Cerebral / etiology
  • Malaria, Cerebral / immunology
  • Malaria, Cerebral / metabolism
  • Malaria, Cerebral / prevention & control*
  • Malaria, Falciparum / complications
  • Malaria, Falciparum / immunology
  • Malaria, Falciparum / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Plasmodium falciparum / immunology
  • Receptors, CXCR3 / immunology
  • Receptors, CXCR3 / metabolism*
  • T-Box Domain Proteins / immunology
  • T-Box Domain Proteins / metabolism
  • T-Lymphocytes, Regulatory / drug effects*
  • T-Lymphocytes, Regulatory / immunology
  • T-Lymphocytes, Regulatory / metabolism

Substances

  • Cxcr3 protein, mouse
  • Receptors, CXCR3
  • T-Box Domain Proteins
  • T-box transcription factor TBX21
  • Interferon-gamma
  • Iron