Science sub-issue: Cracking the mystery of iron deficiency affecting immunity! Two independent research institutions have found that iron deficiency impairs the production and function of neutrophils and affects the discovery of innate immunoscience

*For medical professionals only

The human body consumes approximately 25 mg of iron per day for the production of red blood cells[1].

Iron deficiency anemia is prevalent
in the population.
Iron is an essential component of heme, and iron deficiency affects the synthesis of hemoglobin in red blood cells, reducing the number of red blood cells in plasma
.

But how does iron deficiency affect white blood cells?

Recently, the team of Hal Drakesmith from the University of Oxford and the team of Bruno Galy of the German Cancer Research Center published important research results in the journal Science Advances [2-3].

They used hepcidin-induced and iron-regulatory protein (IRP) 1/2 gene deficient mice to conduct research and found that hepcidin-mediated hypohemoferemia leads to a large decrease in neutrophils and affects the effector function
of neutrophils.
Similarly, IRP1/2 deletion leads to neutropenia and affects neutrophil development and differentiation
.
However, monocytes are not sensitive
to changes in blood iron concentration.

Together, these two studies revealed that iron deficiency may regulate the innate immune system
by affecting the production and function of neutrophils.

Screenshot of the first page of the paper

Iron is involved in many cellular biochemical processes, including oxidative metabolism, DNA synthesis, and epigenetic
remodeling.
Hepcidin is an important hormone that regulates iron homeostasis and intestinal iron absorption, and it can reduce iron concentration in serum by blocking iron circulation and iron absorption [4].

The expression of hepcidin in the body is affected by the level of inflammation: when inflammation or infection occurs, the level of hepcidin in the body rises
.
At methepcidin levels, iron is confined to macrophages, resulting in lower plasma iron levels, which can cause hypoferrosis
.

This response may be a strategic defense
for the host to restrict iron acquisition by pathogenic microorganisms.
However, persistent iron deficiency may impair the effector function of lymphocytes, making the body ineffective in suppressing pathogenic infection
.
Previous studies have shown that iron deficiency inhibits T cell activation and the production
of reactive oxygen species (ROS) in neutrophils.

From this, we can find that blood iron concentration is not only regulated by the body's immunity, but also can in turn affect the body's immune function
.
So, how do plasma iron and extracellular iron affect cellular innate immunity?

Hal Drakesmith and his colleagues first used existing proteome data to predict iron levels in human peripheral blood leukocytes and found that iron levels in neutrophils were significantly higher than in other types of leukocytes
.
By estimating the number of white blood cells produced per day, the researchers expected that neutrophils consumed more than a hundred times more iron during neutrophilgenesis than B cells and T cells, and neutrophils may be more sensitive to
changes in blood iron concentrations.

Proteome predictions indicate that neutrophils require more iron for production

To confirm this conjecture, the researchers injected the experimental group mice with a hepcidin analogue (mHep RP73, 100 nM, 100 μL/pc) for 4 consecutive days to obtain hypoferferosis phenotypic mice
.
The results showed that compared with the control group, the number of neutrophils and eosinophils in the blood and spleen of mice in the experimental group was significantly reduced, and the number of monocytes did not change
.

Neutrophils and eosinophils were significantly reduced in the hepcidin-treated mice

Next, the researchers examined the expression levels
of the transferrin receptor (CD71) in the targeted group cells.
CD71 mediates the entry of iron into cells
via transferrin through endocytosis.
The researchers found that in control mice, blast CD71 expression was significantly higher than directed monocytes progenitor cells
.
This result confirms previous predictions that neutrophil production requires iron more
.
In addition, the proportion of blastomyelocytes in the S-phase was significantly increased in mice in the hepcidin-treated group, which may be associated with
decreased neutrophil production.

IRP1 and IRP2 interact to jointly regulate iron homeostasis
in cells.
Bruno Galy's team used conditional Irp alleles to interfere with the expression of IRP1 and IRP2 throughout the mouse body to obtain both IRP1 and IRP2 deficiency mice (P1/2-KO).

The content of hepcidin in P1/2-KO mice was significantly increased, while the number of neutrophils in the bone marrow was significantly reduced
.

Further experimental results suggest that a decrease in cell count may be associated with
increased glycolysis and autophagy activity.
By interfering with the expression of key iron homeostasis genes, this study revealed the important role of iron in granulocyte development and differentiation, and also suggested a link
between iron metabolism and the innate immune system.

Hepcidin expression decreased in IRP1/2-deficient mice

IRP1/2 deletion inhibits neutrophil production

Both studies have shown that iron metabolism can affect neutrophil production
.

Next, Hal Drakesmith's team explored whether iron deficiency in the body affects neutrophil effector function
.
The researchers treated neutrophils isolated from hypoferferoxate mice and control mice with phorboester (PMA), and the results showed that hypoferferemia reduced PMA-induced ROS
.

The researchers added fluorescent E.
coli to the neutrophil culture medium and then used flow cytometry to determine the phagocytic function
of neutrophils.
The results of the study suggest that hypoferritosis impairs the phagocytic function
of neutrophils.

Yeast glycans are a fungal surface ligand that promotes the production
of cellular inflammatory factors by binding to cell surface receptors.
After adding yeast glycan stimulation to the cell culture medium, the expression of CCL2 and TNF-α was detected with ELISA, and the results showed that hypoferricosis inhibited the production
of chemokines and inflammatory factors.
The above results suggest that hypoferropathy can specifically alter the effector function of neutrophils and disrupt immunity
.

Hypoferemia affects effector function of neutrophils

Decreased blood iron concentration and elevated hepcidin levels are usually seen in inflammatory states
.
Hal Drakesmith's team further proposed that antagonizing endogenous hepcidin during inflammation enhance neutrophil production? Transcription of hepatic hepcidin relies on the BMP6 signaling pathway
.
The researchers injected mice with BMP6 antibodies to reduce endogenous hepcidin production
.
The results showed that in the inflammatory state, injection of BMP6 antibody into mice could significantly increase blood iron concentration and significantly promote neutrophil production
.
This suggests that antagonizing endogenous hepcidin during acute inflammatory responses enhances neutrophil production
.

Antagonizing endogenous hepcidin in inflammatory states enhances neutrophil production

Overall, the above studies show that appropriate blood iron concentration is critical
for maintaining neutrophil production and their effector function.
These findings provide new insights
into how iron metabolism affects the innate immune system.
At the same time, it also provides a basis
for the clinical application of granulogenesis mobilizers in patients with infection and iron deficiency.

References:

[1].
Muckenthaler MU, Rivella S, Hentze MW, Galy B.
A Red Carpet for Iron Metabolism.
Cell.
2017; 168(3):344-361.
doi:10.
1016/j.
cell.
2016.
12.
034

[2].
Frost JN, Wideman SK, Preston AE, et al.
Plasma iron controls neutrophil production and function.
Sci Adv.
2022; 8(40):eabq5384.
doi:10.
1126/sciadv.
abq5384

[3].
Bonadonna M, Altamura S, Tybl E, et al.
Iron regulatory protein (IRP)-mediated iron homeostasis is critical for neutrophil development and differentiation in the bone marrow.
Sci Adv.
2022; 8(40):eabq4469.
doi:10.
1126/sciadv.
abq4469

[4].
Drakesmith H, Nemeth E, Ganz T.
Ironing out Ferroportin.
Cell Metab.
2015; 22(5):777-787.
doi:10.
1016/j.
cmet.
2015.
09.
006

Responsible editorWang Xuening