Impaired iron recycling from erythrocytes is an early hallmark of aging

Slusarczyk, Patryk; Mandal, Pratik Kumar; Zurawska, Gabriela; Niklewicz, Marta; Chouhan, Komal; Mahadeva, Raghunandan; Jończy, Aneta; Macias, Matylda; Szybińska, Aleksandra; Cybulska, Magdalena; Krawczyk, Olga; Herman, Sylwia; Mikula, Michał; Serwa, Remigiusz A.; Lenartowicz, Małgorzata; Pokrzywa, Wojciech; Mleczko-Sanecka, Katarzyna

doi:10.7554/elife.79196

Cited by 18 publications

(15 citation statements)

References 96 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, little is known about Bmp6 regulation in the context of non‐pathological states. Aging is characterized by tissue iron deposition, 14 but interestingly also hallmarked by a decline in NRF2‐mediated signaling 19 . To investigate the regulation of Bmp6 mRNA expression under such conditions, we compared 8‐ to 10‐week‐old young females with 10–11‐month‐old mice.…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Iron‐triggered signaling via ETS1 and the p38/JNK MAPK pathway regulates Bmp6 expression

Zurawska,

Jończy,

Niklewicz

et al. 2024

American J Hematol

Self Cite

View full text Add to dashboard Cite

BMP6 is an iron‐sensing cytokine whose transcription in liver sinusoidal endothelial cells (LSECs) is enhanced by high iron levels, a step that precedes the induction of the iron‐regulatory hormone hepcidin. While several reports suggested a cell‐autonomous induction of Bmp6 by iron‐triggered signals, likely via sensing of oxidative stress by the transcription factor NRF2, other studies proposed the dominant role of a paracrine yet unidentified signal released by iron‐loaded hepatocytes. To further explore the mechanisms of Bmp6 transcriptional regulation, we used female mice aged 10–11 months, which are characterized by hepatocytic but not LSEC iron accumulation, and no evidence of systemic iron overload. We found that LSECs of aged mice exhibit increased Bmp6 mRNA levels as compared to young controls, but do not show a transcriptional signature characteristic of activated NFR2‐mediated signaling in FACS‐sorted LSECs. We further observed that primary murine LSECs derived from both wild‐type and NRF2 knock‐out mice induce Bmp6 expression in response to iron exposure. By analyzing transcriptomic data of FACS‐sorted LSECs from aged versus young mice, as well as early after iron citrate injections, we identified ETS1 as a candidate transcription factor involved in Bmp6 transcriptional regulation. By performing siRNA‐mediated knockdown, small‐molecule treatments, and chromatin immunoprecipitation in primary LSECs, we show that Bmp6 transcription is regulated by iron via ETS1 and p38/JNK MAP kinase‐mediated signaling, at least in part independently of NRF2. Thereby, these findings identify the new components of LSEC iron sensing machinery broadly associated with cellular stress responses.

show abstract

Section: Resultsmentioning

confidence: 99%

“…The aging experiments were conducted using female WT C57BL/6J mice, as reported previously 14 or NRF2 KO (B6.129X1‐ Nfe2l2 tm1Ywk /J) female and male mice. Aged‐matched male WT C57BL/6J and NRF2 KO mice or C57BL/6J WT females (8–12 weeks old) were used for the generation of primary liver cell cultures.…”

Section: Methodsmentioning

confidence: 99%

Iron‐triggered signaling via ETS1 and the p38/JNK MAPK pathway regulates Bmp6 expression

Zurawska,

Jończy,

Niklewicz

et al. 2024

American J Hematol

Self Cite

View full text Add to dashboard Cite

show abstract

“…Isolation of non-parenchymal liver cells (NPCs) for primary cell cultures together with cell treatments and immunofluorescence are described in the Supplementary Methods. Isolation of cells from the spleen, bone marrow, and aorta, flow cytometry, FACS-sorting, liver tissue immunofluorescence, heme/iron measurements, preparation of conjugated mouse Hb, stressed RBCs, and RBC ghosts, and real-time quantitative PCR (RT-qPCR) were performed as previously reported, 25 or/and described in detail in Supplementary Methods.…”

Section: Cell-based and Biochemical Assaysmentioning

confidence: 99%

Liver sinusoidal endothelial cells constitute a major route for hemoglobin clearance

Zurawska,

Sas,

Jończy

et al. 2023

Preprint

Self Cite

View full text Add to dashboard Cite

Mild hemolysis of senescent erythrocytes occurs physiologically in the spleen, resulting in hemoglobin (Hb) release, whereas pathologic erythrocyte rupture characterizes several diseases. Iron recycling from Hb and Hb detoxification have been attributed to the sequestration of Hb-haptoglobin complexes by macrophages. However, we found the existence of additional efficient Hb clearance routes in mice. We identified liver sinusoidal endothelial cells (LSECs) as the primary cells responsible for Hb sequestration, a process that involves macropinocytosis and operates independently of the Hb-haptoglobin receptor CD163. LSECs expressed heme oxygenase 1 and hepcidin-controlled ferroportin and were the most efficient cellular scavengers of Hb at doses below and above the haptoglobin binding capacity. Erythrocyte transfusion assays further demonstrated that while splenic red pulp macrophages are adept at erytrophagocytosis, liver Kupffer cells and LSECs mainly clear erythrocyte ghosts and Hb, respectively, transported from the spleen via the portal circulation. High-dose Hb injections in mice resulted in transient hepatic iron retention and early activation of the gene encoding heme oxygenase 1 (Hmox1) in LSECs. This response was associated with the transcriptional induction of the iron-sensing angiokineBmp6, culminating in hepcidin-mediated transient serum hypoferremia. Injection of Hb and iron citrate elicited distinct transcriptional signatures in LSECs, and theBmp6induction was phenocopied by erythrocyte lysis upon phenylhydrazine. Collectively, we propose that LSECs provide a key mechanism for Hb clearance, a function that establishes the spleen-liver axis for physiological iron recycling from Hb and contributes to heme detoxification during hemolysis, coupled with the induction of the BMP6-hepcidin axis, ultimately restoring iron homeostasis.Key points-LSECs engage macropinocytosis to efficiently scavenge free hemoglobin-LSEC-mediated hemoglobin clearance participates in iron recycling from spleen-derived hemoglobin and contributes to its detoxification during hemolysis

show abstract

“…23.533972 doi: bioRxiv preprint spleen are the major scavengers that remove unhealthy, old, and malformed RBCs from the circulation to recover iron [7]. In brief, RPMs recognize the RBCs to be removed through the signal on their cell surface and trigger RBC endocytosis and digestion into heme in lysosomes [8]. Subsequently, the heme is decomposed by heme oxygenase-1 (HO-1) into biliverdin, carbon monoxide and iron [9].…”

Section: Introductionmentioning

confidence: 99%

“…Particularly, red pulp macrophages (RPMs) within the spleen, serving as primary phagocytes, are responsible for clearing senescent, damaged, and abnormal erythrocytes from circulation to recycle iron [9]. RPMs initiate the process of RBCs endocytosis and lysosomal digestion into heme, following the recognition of the RBCs earmarked for removal via their cell surface signals [10, 11]. Subsequently, heme oxygenase-1 (HO-1) decomposes the heme into biliverdin, carbon monoxide, and iron [12].…”

Section: Introductionmentioning

confidence: 99%

High-altitude hypoxia exposure inhibits erythrophagocytosis by inducing macrophage ferroptosis in the spleen

Yang

Ding

et al. 2023

Preprint

View full text Add to dashboard Cite

High-altitude polycythemia (HAPC) occurs in high-altitude (HA) environments and involves an imbalance between erythropoiesis and eryptosis. Spleen/splenic macrophages are an important primary tissue/cell of eryptosis and iron recycling. However, the role of the spleen in the pathogenesis of HAPC and the effect of hypobaric hypoxia (HH) on the biology of the spleen and splenic macrophages are still unclear. We used a mouse hypobaric hypoxia (HH) exposure model to simulate an in vivo study of 6000 m HA exposure. For in vitro studies, we used a primary splenic macrophage model treated with 1% hypoxia. We found that the HH-treated mouse model promoted erythropoiesis and led to erythrocytosis. In addition, HH exposure resulted in marked splenic contraction followed by splenomegaly for up to 14 days. HH exposure impaired the red blood cell (RBC) handling capacity of the spleen, which was caused by a decrease in splenic macrophages in the red pulp. Moreover, HH treatment for 7 and 14 days promoted iron mobilization and ferroptosis in the spleen, as reflected by the expression of metabolism-related proteins and ferroptosis-related proteins. All of the protein expression levels were similar to the gene expression levels in human peripheral blood mononuclear cells. Single-cell sequencing of the spleen further demonstrated a significant decrease in macrophages in the spleen 7 days after HH exposure. In in vitro studies, we confirmed that primary splenic macrophages decreased and induced ferroptosis following hypoxic treatment, which was reversed by pre-treatment with the ferroptosis inhibitor ferrostatin-1. Taken together, HH exposure induces splenic ferroptosis, especially in red pulp macrophages, which further inhibits the clearance of RBCs from the spleen. As such, it promotes the retention of RBCs in the spleen and causes splenomegaly, which may further lead to the persistent production of RBCs and ultimately to the development of HAPC.

show abstract

Impaired iron recycling from erythrocytes is an early hallmark of aging

Cited by 18 publications

References 96 publications

Iron‐triggered signaling via ETS1 and the p38/JNK MAPK pathway regulates Bmp6 expression

Iron‐triggered signaling via ETS1 and the p38/JNK MAPK pathway regulates Bmp6 expression

Liver sinusoidal endothelial cells constitute a major route for hemoglobin clearance

High-altitude hypoxia exposure inhibits erythrophagocytosis by inducing macrophage ferroptosis in the spleen

Contact Info

Product

Resources

About