Achievements of science (2022). DOI: 10.1126/sciadv.abq4469″ width=”800″ height=”529″/>

Acute ablation of IRP in adulthood causes erythropenia and myelopenia. P1/2-CTR and P1/2-KO littermates received tamoxifen on days 1 and 3 to induce IRP ablation. Mice were analyzed on the 10th day. (A) Genome-wide polymerase chain reaction (PCR) analysis of Irp1 (Aco1) and Irp2 (Ireb2) alleles in tissues from P1/2-KO mice. The floxed (flox) and truncated (Δ) alleles are indicated. (B) RBC parameters (P1/2-CTR, n = 16; P1/2-KO, n = 18). HGB, hemoglobin; MCV, mean corpuscular volume; MCHC, mean corpuscular hemoglobin concentration. (C) Iron levels in liver and spleen (n = 11). (D) Serum iron parameters (n = 10). (E) Markers of erythrocyte breakdown (n = 10). (F) Serum levels of EPO (P1/2-CTR, n = 18; P1/2-KO, n = 17) and hepcidin (P1/2-CTR, n = 18; P1/2-KO, n = 16) ). (G) Splenic index = √[(100 × spleen weight in milligrams per body weight in grams)] (n = 7), and frequency of reticulocytes in peripheral blood (PB) (P1/2-CTR, n = 7; P1/2-KO, n = 9). OS, conditional units. (H) White blood cell (WBC) and platelet counts in PB (P1/2-CTR, n = 16; P1/2-KO, n = 18). (I) Analysis of major leukocyte populations in PB by flow cytometry (FCM). The gating strategy is shown in the contour plots to the left. Histograms represent cell counts for 3 × 105 recorded events (n = 8). (B to I) Results are presented as box plots (minimum to maximum values). Unpaired, two-tailed t-test between P1/2-CTR and P1/2-KO. *P Advances in Science (2022). DOI: 10.1126/sciadv.abq4469

The two proteins ensure that cells can take up iron when needed. When both control proteins are disabled in mice, the animals develop severe anemia, as expected. At the same time, surprisingly, a type of innate immune defense cell, neutrophils, also declines dramatically, as scientists from the German Cancer Research Center have now shown for the first time. Iron deficiency, a known defense mechanism against infectious pathogens, is a double-edged sword as it simultaneously suppresses the defensive power of an important part of the innate immune system.

Balanced iron Metabolism is an important prerequisite for our health. Medicines aimed at iron deficiency or iron overload are among the most widely prescribed treatments worldwide. The fact that iron is an indispensable component of blood, almost common knowledge: The metal is an important component of the blood pigment hemoglobin, which is responsible for carrying oxygen to erythrocytes.

Iron supply to cells is controlled by two proteins IRP-1 and IRP-2. When a cell lacks iron, IRP-1 and IRP-2 activate the production of various iron transport proteins that take iron into the cell. IRP-1 and IRP-2 also ensure that an equally dangerous excess of iron does not occur.

IRP-1 and IRP-2 are essential for survival: mice lacking both control proteins during embryonic development die in utero. But what happens when IRP-1 and IRP-2 fail in adult mice? A team led by Bruno Galli from the DKFZ has now investigated this in mice, in which the production of IRP can be stopped by injecting a drug.

As the researchers expected, the most striking change after disabling IRP was a marked decrease in red blood cells. Due to the lack of hemoglobin, these erythrocytes reached only minimal sizes.

However, the researchers were surprised to see this leukocytes also decreased tremendously. A closer look revealed that this decline was largely due to shortages neutrophils. These immune cells make up to two-thirds of leukocytes in humans and are an important component of the innate immune system.

This decrease is not caused by the mass death of neutrophils, but by the blockade of the development of the hematopoietic system: progenitor cells in bone marrow no longer turn into mature neutrophils, as this differentiation process appears to be iron-dependent. Other leukocyte types, such as monocytes, are not affected by the IRP-dependent developmental block.

Iron limitations are a double-edged sword

“This strong dependence of neutrophils on iron was previously unknown. Perhaps it affects the immune defense against bacterial pathogens,” says Bruno Gali. Interestingly, on the other hand, iron deficiency is one of the body’s defense strategies against bacterial infections: many pathogens depend on iron. To slow their reproduction, the body accumulates the metal in certain cells, which serve as a storage chamber, so that it is more difficult for pathogenic microorganisms to gain access to this valuable resource.

Another publication in the same issue of the magazine Achievements of sciencein which Galli also participates, demonstrates that iron deficiency in blood serum, as it usually does in infections, leads to a decrease in the number of neutrophils in the mice and limits the ability of these immune cells to fight the bacteria. “Iron deficiency appears to modulate the innate immune system. It suppresses the maturation of neutrophils and also reduces their defensive power,” says Bruno Galli. “Limiting available iron appears to be a double-edged sword: on the one hand, the body thus prevents the spread of bacteria. On the other hand, the function of an important arm of the innate immune system suffers.”

Not only infections, but also inflammation often lead to iron deficiency and thus anemia. Cancer patients, whose disease is accompanied by chronic inflammatory diseases, therefore often suffer from anemia, which can seriously limit their quality of life. “Next, we want to investigate whether iron deficiency in chronic inflammation worsens immune function,” says Gali.

Anemia is not the only health problem associated with iron deficiency

Additional information:
Michael Bonadonna et al. Iron homeostasis, mediated by the iron regulatory protein (IRP), is critical for the development and differentiation of neutrophils in the bone marrow, Achievements of science (2022). DOI: 10.1126/sciadv.abq4469

Joe N. Frost et al. Plasma iron controls the production and function of neutrophils, Achievements of science (2022). DOI: 10.1126/sciadv.abq5384

Citation: Iron deficiency suppresses important part of innate immune system (2022, October 7) Retrieved October 7, 2022 from

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