Blogs

Thie section will have blogs written on important updates in iron related research, clincial biochemistry and lab medicine

Duodenal lamina propria transferrin — a new player in the mucosal block of dietary iron absorption?

Iron is an essential trace element required for various biological functions in the body. It is absorbed from the diet in the duodenum, and it is transported across the basolateral aspect of the enterocyte into the blood through an iron efflux protein, ferroportin. Hepcidin, a hepatocyte -derived peptide hormone regulates this process, as it binds and causes subsequent degradation of ferroportin causing a mucosal block of iron absorption . Hence this hepcidin-regulated iron absorption is the major determinant of systemic iron levels in the body.

A recent work by Sukhbaatar et al., identified that macrophages of the lamina propria (LP) in the intestine can regulate intestinal iron absorption by modulating the levels of the iron-transporter protein transferrin. This finding shed new insights into the role of intestinal macrophages and transferrin (Tf) in iron homeostasis. They have used an engineered mice model, in which the tuberous sclerosis complex-2 (Tsc-2), a negative regulator of mammalian target of rapamycin complex -1 (mTORC1) is deleted specifically in the macrophages. These engineered mice with increased macrophage mTORC1 activity developed a defect in the erythropoiesis (depleted iron stores and reduced number of erythroid precursors in bone marrow, splenomegaly) and systemic iron deficiency (microcytic and hypochromic red blood cells, increased red cell width, reduced transferrin saturation, TfSat). However, the serum iron and ferritin levels were comparable with the control mice. These phenotypical changes observed in the engineered mice were corrected to a maximum extent by treating them with everolimus, a pharmacological inhibitor of mTORC1. The mice were given an oral gavage with radio-labelled iron to check for iron absorption, and it was found the iron was retained in the duodenal epithelial cells and there was reduced distribution of labelled iron to the bone marrow. This blockade in iron absorption occurred despite the increased ferroportin levels in the enterocytes and suppressed hepatic hepcidin expression, which are the physiological response seen towards anemia. These findings suggest the possibility of hepcidin independent mechanism to regulate iron absorption.

An important aspect of this study which was key to explaining this alternative mechanism is the immunofluorescence staining of the duodenal section of these mice. The expression of Tf was significantly reduced in the villous interstitium of LP, despite the total duodenal Tf comparable to the control mice. This reduced LP Tf expression was largely corrected by treating with everolimus, suggesting the role of mTORC1 signaling on transferrin expression and subsequent iron efflux from the enterocyte. The authors addressed the immunological role of LP macrophages by showing that the LP Tf expression was increased in wild type mice following an overnight starvation or infection with Citrobacter rodentium. The single-cell transcriptome analysis of the LP macrophages revealed the increased activity of the cathepsin-related proteases and enrichment of lysosome and phagosome-related pathways in the engineered mice. Hence the unrestricted activity of mTORC1 in LP macrophages and subsequent proteasomal degradation of Tf leads to defective iron absorption (iron retention in the enterocytes). This in turn causes reduced TfSat and subsequent Tf-iron flux to the bone marrow leading to anemia.

This study had shown novel findings on iron absorption, and it also leads to many interesting questions especially in disease conditions with dysregulated iron homeostasis.