Iron homeostasis in a mouse model of thalassemia intermedia is altered between adolescence and adulthood

Sanyear, Chanita; Butthep, Punnee; Eamsaard, Wiraya; Fucharoen, Suthat; Svasti, Saovaros; Masaratana, Patarabutr

doi:10.7717/peerj.8802

Cited by 9 publications

(8 citation statements)

References 82 publications

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“…To the best of our knowledge, RPM loss was not extensively studied in a mouse model of thalassemia. However, interestingly, thalassemic mice display enhanced splenic Perls’-stained deposits that appear to be extracellular and are not amenable to iron chelation therapy ( Sanyear et al, 2020 ; Vadolas et al, 2021 ), possibly resembling those identified by the present study. Of note, genetic disruption of Hrg1 leads to the formation of heme aggregate hemozoin inside enlarged phagolysosomes ( Pek et al, 2019 ).…”

Section: Discussionsupporting

confidence: 69%

Impaired iron recycling from erythrocytes is an early hallmark of aging

Slusarczyk

Mandal

Zurawska

et al. 2023

eLife

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Aging affects iron homeostasis, as evidenced by tissue iron loading and anemia in the elderly. Iron needs in mammals are met primarily by iron recycling from senescent red blood cells (RBCs), a task chiefly accomplished by splenic red pulp macrophages (RPMs) via erythrophagocytosis. Given that RPMs continuously process iron, their cellular functions might be susceptible to age-dependent decline, a possibility that has been unexplored to date. Here, we found that 10-11-month-old female mice exhibit iron loading in RPMs, largely attributable to a drop in iron exporter ferroportin, which diminishes their erythrophagocytosis capacity and lysosomal activity. Furthermore, we identified a loss of RPMs during aging, underlain by the combination of proteotoxic stress and iron-dependent cell death resembling ferroptosis. These impairments lead to the retention of senescent hemolytic RBCs in the spleen, and the formation of undegradable iron- and heme-rich extracellular protein aggregates, likely derived from ferroptotic RPMs. We further found that feeding mice an iron-reduced diet alleviates iron accumulation in RPMs, enhances their ability to clear erythrocytes, and reduces damage. Consequently, this diet ameliorates hemolysis of splenic RBCs and reduces the burden of protein aggregates, mildly increasing serum iron availability in aging mice. Taken together, we identified RPM collapse as an early hallmark of aging and demonstrated that dietary iron reduction improves iron turnover efficacy.

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Section: Discussionsupporting

confidence: 69%

Impaired iron recycling from erythrocytes is an early hallmark of aging

Slusarczyk

Mandal

Zurawska

et al. 2023

eLife

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“…Our results are similar to those from an earlier study that reported BACH1 expression in β-thalassemia/HbE monocytes (Srinoun et al, 2017). The expression of Slc40a1 was consistent with the findings of a study on splenic heterozygous β-globin knockout mice (BKO) (Sanyear et al, 2020). A decrease in Spic, Slc40a1, and HMOX1 expression levels were also observed in a study on BACH1 knockout mice (Haldar et al, 2014), which also found that heme products could induce BACH1 degradation and inhibit target gene expression.…”

Section: Discussionsupporting

confidence: 91%

BACH1 regulates erythrophagocytosis and iron‐recycling in β‐thalassemia

et al. 2023

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Macrophages play essential roles in erythrophagocytosis and iron recycling. β-thalassemia is characterized by a genetic defect in hemoglobin synthesis, which increases the rate of iron recycling. We previously showed that reduced expression of the BTB and CNC homolog 1 (BACH1) gene leads to increased phagocytosis of abnormal RBCs by activated monocytes. However, the mechanisms underlying this abnormal RBC clearance remained unclear. Herein, the spleen and bone marrow cells of β-thalassemic mice were examined for erythrophagocytosis CD markers and iron-recycling genes. Higher expression levels of CD47 and CD163 on RBCs and macrophages, respectively, were observed in β-thalassemic mice than in wild-type cells. The decreased expression of BACH1 caused an increase in Nrf2, Spic, Slc40a1, and HMOX1 expression in splenic red pulp macrophages of thalassemic mice. To investigate BACH1 regulation, a macrophage cell line was transfected with BACH1-siRNA. Decreased BACH1 expression caused an increase in CD163 expression; however, the expression levels were lower when the cells were cultured in media supplemented with β-thalassemia/HbE patient plasma. Additionally, the iron recycling-related genes SPIC, SLC40A1, and HMOX1 were significantly upregulated in BACH1-suppressed macrophages. Our findings provide insights into BACH1 regulation, which plays an important role in erythrophagocytosis and iron recycling in thalassemic macrophages.

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“…To the best of our knowledge, RPM loss was not extensively studied in a mouse model of thalassemia. However, interestingly, thalassemic mice display enhanced splenic Perls’-stained deposits that appear extracellular and are not amenable to iron chelation therapy (Sanyear et al, 2020; Vadolas et al, 2021), possibly resembling those identified by the present study.…”

Section: Discussionsupporting

confidence: 74%

Impaired iron recycling from erythrocytes is an early hallmark of aging

Mandal

Slusarczyk

Zurawska

et al. 2022

Preprint

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Aging affects iron homeostasis and erythropoiesis, as evidenced by tissue iron loading in rodents and common anemia in the elderly. Since red pulp macrophages (RPMs) continuously process iron, their cellular functions might be susceptible to age-dependent decline, affecting organismal iron metabolism and red blood cells (RBCs) parameters. However, little is known about the effects of aging on the functioning of RPMs. To study aging RPMs, we employed 10-11-months-old female mice that show serum iron deficiency and iron overload primarily in spleens compared to young controls. We observed that this is associated with iron loading, oxidative stress, diminished mitochondrial and lysosomal activities, and most relevantly, decreased erythrophagocytosis rate in RPMs. We uncovered that these impairments of RPMs lead to the retention of senescent RBCs in the spleen, their excessive local hemolysis, and the formation of iron- and heme-rich large extracellular protein aggregates, likely derived from damaged RBCs and RPMs. We further found that feeding mice an iron-reduced diet alleviates iron accumulation and reactive oxygen species build-up in RPMs, restores mitochondrial and lysosomal functions, and improves their ability to clear erythrocytes. Consequently, this diet improves splenic RBCs fitness, limits hemolysis and formation of iron-rich aggregates, normalizes splenic iron levels, and tends to increase serum iron availability in aging mice. Mechanistically, using readouts from aged RPMs and in vitro cultures of RPM-like cells, we show that diminished erythrophagocytic activity of RPMs can be attributed to a combination of increased iron levels, reduced expression of heme-catabolizing enzyme heme oxygenase 1 (HO-1), and endoplasmic reticulum stress. Taken together, we identified RPM dysfunction as an early hallmark of physiological aging and demonstrated that dietary iron reduction improves iron turnover efficacy.

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Iron homeostasis in a mouse model of thalassemia intermedia is altered between adolescence and adulthood

Cited by 9 publications

References 82 publications

Impaired iron recycling from erythrocytes is an early hallmark of aging

Impaired iron recycling from erythrocytes is an early hallmark of aging

BACH1 regulates erythrophagocytosis and iron‐recycling in β‐thalassemia

Impaired iron recycling from erythrocytes is an early hallmark of aging

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