Regulation of Reticuloendothelial Iron Transporter MTP1 (Slc11a3) by Inflammation

Abstract

Acute and chronic inflammation cause many changes in total body iron metabolism including the sequestration of iron in phagocytic cells of the reticuloendothelial system. This change in iron metabolism contributes to the development of the anemia of inflammation. MTP1, the duodenal enterocyte basolateral iron exporter, is also expressed in the cells of the reticuloendothelial system (RES) and is likely to be involved in iron recycling of these cells. In this study, we use a lipopolysaccharide model of the acute inflammation in the mouse and demonstrate that MTP1 expression in RES cells of the spleen, liver, and bone marrow is down-regulated by inflammation. The down-regulation of splenic expression of MTP1 by inflammation was also observed in a Leishmania donovani model of chronic infection. The response of MTP1 to lipopolysaccharide (LPS) requires signaling through the LPS receptor, Toll-like receptor 4 (TLR4). In mice lacking TLR4, MTP1 expression is not altered in response to LPS. In addition, mice lacking tumor necrosis factor-receptor 1a respond appropriately to LPS with down-regulation of MTP1, despite hyporesponsiveness to tumor necrosis factor-␣ signaling, suggesting that this cytokine may not be required for the LPS effect. We hypothesize that the iron sequestration in the RES system that accompanies inflammation is because of down-regulation of MTP1.Iron is an essential nutrient for growth and development of eucaryotes and most prokaryote species. A normal individual will absorb ϳ1 mg of elemental iron a day through the duodenum, to match an equivalent daily physiologic loss. The plasma turnover of iron is ϳ10 -20 mg a day and one source of this pool is iron released from the reticuloendothelial system (RES).

Differential regulation of iron homeostasis during human macrophage polarized activation

“…2D). In line with previous results obtained in mouse spleen macrophages [12], human monocytic cell lines [19] and human monocyte-derived macrophages [14], LPS/IFN-g stimulation of human macrophages led to much lower Fpn expression levels than in unpolarized M0 cells; however, M2 polarization repressed Fpn less, and thus there was a tenfold difference in Fpn mRNA expression between M1 and M2 macrophages (Fig. 3A).…”

“…However, we also found a considerable difference in Fpn mRNA level between M1 and M2 macrophages. Fpn expression is also subject to transcriptional control [4,42], and decreased Fpn mRNA levels have previously been found under conditions of LPS-induced inflammation [12,39]. As Fpn is also post-transcriptionally regulated by the IRE/IRP system (see [30] for recent review), our finding of a less marked difference in Fpn protein levels between M1 and M2 macrophages than the difference in the corresponding mRNA at all the time points examined indicates that the Fpn gene is actively transcribed in M2 macrophages and that the impaired translation of Fpn mRNA due to increased IRP2-binding activity is not sufficient to abolish the increase in protein levels.…”

“…Macrophage Fpn is also negatively regulated at transcriptional and post-transcriptional levels by inflammatory mediators [12][13][14]. It is still unknown whether the inflammatory response affects the feline leukemia virus, subgroup C, receptor that exports heme from macrophages [15] and whether the heme transporter HRG1 proteins play a role in macrophage iron metabolism [16].…”

“…Increased iron retention within inflammatory macrophages is due to increased iron uptake and decreased iron export [7], and is favoured by the induction of the iron storage protein ferritin (Ft) [8,9]. The blockade of macrophage iron release is mainly due to the interaction between the acute phase protein hepcidin and the iron exporter ferroportin (Fpn) [1][2][3], as the increase in circulating hepcidin triggered by inflammatory cytokines causes the internalization and degradation of Fpn [10], the exporter of non-heme iron [11], thus blocking iron release from macrophages.Macrophage Fpn is also negatively regulated at transcriptional and post-transcriptional levels by inflammatory mediators [12][13][14]. It is still unknown whether the inflammatory response affects the feline leukemia virus, subgroup C, receptor that exports heme from macrophages [15] and whether the heme transporter HRG1 proteins play a role in macrophage iron metabolism [16].…”

Kupffer cells and macrophages are not required for hepatic hepcidin activation during iron overload

“…This might be due to the fact that in inflamed GdCl 3 -treated animals, in spite of normalized hepcidin levels, inactivation depletion of Kupffer cells might deprive the circulatory iron pool of an important source of iron. In addition, during inflammation, the downregulation of ferroportin expression in macrophages, 26 the main iron exporter macrophages, likely persists even in the presence of GdCl 3 treatment.…”