Mechanisms of aggravation of cutaneous leishmaniasis by iron overload

Abstract text

Iron overload can cause increased susceptibility to certain intracellular infectious pathogens, but the exact underlying mechanisms remain poorly defined. Here, we investigated how iron loading affects the disease outcome in self-healing C57BL/6 mice infected with the intracellular protozoan parasite Leishmania (L.) major.

Iron-loaded L. major-infected C57BL/6 mice showed disease exacerbation with aggravated skin swelling at the site of infection and higher parasite loads in the lesion. This was paralleled by enhanced cell death in the infected tissue, increased influx of CD11b+Ly6G+Ly6C+ neutrophil-like cells lacking suppressor activity and decreased percentages of T-cells, eosinophils, macrophages and dendritic cells. Furthermore, iron overload increased the expression of IFN-gamma, TNF, IL-1ß, IL-4, IL-17A, TGF-beta and type 2 nitric oxide synthase (NOS2) mRNA in skin lesions, whereas NOS2 protein expression and NO production in vivo was suppressed compared to control mice. In vitro, iron partially rescued L. major from NO-dependent, but ferroportin-independent killing by macrophages and favored the differentiation of Th2 cells, which was due to an oxidant-dependent increased nuclear translocation of STAT6. Arginase (Arg) 1, which competes with NOS2 for the substrate L-arginine, was upregulated on mRNA and protein level. In C57BL/6 mice lacking Arg1 in hematopoietic and endothelial cells, the aggravated course of disease following iron loading was abolished and NO production in the skin lesions was partially restored. Similar effects were observed, when iron-loaded C57BL/6 mice were treated with anti-IL-4-antibodies, indicating that iron-driven Arg1 induction is mainly due to enhanced IL-4 levels.

Thus, iron overload differentially affects NOS2 and Arg1 expression. Disease exacerbation and impaired parasite control by iron excess in the infected tissues at least partially result from an oxidant-dependent expansion of Th2 cells and an IL-4-mediated Arg1 expression that decreases NO production in iron-loaded mice.