Study suggests iron accumulation plays a central role in senescence and fibrosis

In a recent study published in Nature Metabolism, researchers investigated the association between cellular damage, iron buildup, senescence, and fibrosis.

Study: Iron accumulation drives fibrosis, senescence and the senescence-associated secretory phenotype. Image Credit: Sadovnikova Olga/Shutterstock.com
Study: Iron accumulation drives fibrosis, senescence and the senescence-associated secretory phenotype. Image Credit: Sadovnikova Olga/Shutterstock.com

Background

Fibrogenesis is a defensive reaction to tissue damage that results in life-threatening disorders. Senescent cells, also known as the senescent-associated secretory phenotype (SASP), are the primary cause of fibrosis. Fibrosis causes organ damage and the development of cardiovascular, interstitial lung, and renal disorders by replacing healthy tissues with collagen-rich scar tissue. Profibrogenic factors such as tumor growth factor beta (TGF-β) and interleukin-11 (IL-11) may cause senescent cells to become fibrogenic.

About the study

In the present study, researchers identified iron accumulation as a therapeutically exploitable cause of pathological senescence and fibrosis.

The study investigated the function of iron buildup in fibrotic tissues, especially in mice with lung fibrosis and people with idiopathic pulmonary fibrosis (IPF). Perl's Prussian blue staining was used to examine mouse kidneys and kidney samples from diabetic kidney disease patients. They also investigated the gene signatures of iron transporter and storage genes in the lung transcriptomes of healthy individuals and IPF patients. The team examined iron kinetics during fibrogenesis in tissues obtained from acute respiratory distress syndrome (ARDS) patients.

Mice were administered intratracheal bleomycin or intraperitoneal (i.p.) folic acid (FA) to assess the impact of iron buildup in injured tissues. They also investigated whether iron buildup was a bystander effect or a causal factor in fibrogenesis.

The researchers additionally examined whether intratracheal iron may cause senescence since vascular or hemolytic injuries can release iron from damaged red blood cells (RBCs), contributing to inflammation, senescence, and fibrosis. They developed a mouse model (Tie2-Cre-ERT2; Rosa26-iDTR) in which tamoxifen and diphtheria toxin injections may ablate a percentage of endothelium cells, resulting in microhemorrhages, primarily in the lungs, allowing animal survival.

To investigate the function of iron in FA-induced renal fibrosis, the researchers administered FA to mice in the presence or absence of the iron chelator deferiprone (DP). They investigated the effects of iron on in vitro-grown cells to improve mechanistic understanding of the relationship between iron and aging. In addition, the researchers assessed injury-stimulated iron release and accumulation in vitro.

The team used single-cell ribonucleic acid sequencing (scRNA-seq) of murine lungs two and six days after iron exposure to improve understanding of the cellular types underpinning these two stages of iron response. They also examined a scRNA-seq meta-analysis of IPF patients for the enrichment of the interstitial fibrosis and tubular atrophy (IFTA score) and a Magnetic resonance imaging (MRI) study of 13 renal allograft recipients for the R2* signal in the kidney cortex and the fibrosis level evaluated on biopsies.

Results

Iron buildup was associated with cell senescence and different fibrotic disorders in murine animals and humans. Hemolytic and vascular damage can cause iron deposition, inducing senescence and promoting fibrosis. Even after the extracellular iron upsurge had subsided, senescent cells continued to collect iron.

Cells subjected to various senescence-eliciting insults accumulated excessive ferritin-bound forms of iron, predominantly inside lysosomes with labile iron in large quantities, which fed the formation of SASP and reactive oxygen species (ROS). Iron detection by MRI could enable non-invasive evaluation of fibrotic load in the renal tissues of humans and mice with fibrosis.

The snRNA sequencing analysis findings revealed that iron stimulated transient neutrophil recruitment, persistent monocyte, macrophage, and dendritic cellular growth, and the gradual suppression of the relatively abundant bronchial artery cells. The intratracheal iron injection was sufficient to induce the hallmarks of fibrogenesis, including collagen deposition, senescence, vascular rarefaction, inflammation, and innate immune infiltration.

The team noted Iron buildup in murine fibrotic cardiac tissues with transgenic adrenoceptor beta 1 (Adrb1) overexpression or ischemic cardiac disease resulting from coronary arterial ligation. Similar findings were obtained in murine renal fibrosis caused by an i.p. FA injection or ureteral blockage on one side. IPF patients revealed a significant enhancement of the iron transport signature in both datasets, demonstrating that changed gene expression of iron absorption and storage genes is a distinguishing hallmark of IPF.  

The researchers found a transitory rise in the number of fibroblasts and goblet cells in the non-immune compartment, with the most notable alterations being the stimulation of plasminogen activator molecules, tissue inhibitor of metalloproteinase 1 (TIMP1), and the repression of angiogenic molecules, vascular endothelial growth factor A (VEGF A) and angiopoietin 1 (Angpt1). IPF lung tissues were enriched for iron accumulation signature (IAS) genes in bulk lung tissue and numerous cell types.

The study findings showed that iron buildup contributes to senescence and fibrosis, and iron metabolism may be a therapeutic target for senescence-related disorders. Iron buildup in fibrosis occurs early after tissue damage and evolves as a distinguishing hallmark of certain fibrotic diseases. Iron excess can trigger fibrogenesis and senescence.

The researchers distinguished between 'excessive extracellular iron' as a putative senescence trigger and 'excessive intracellular iron' as a driver of senescent cell pathogenic consequences.

Journal reference:
Pooja Toshniwal Paharia

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Pooja Toshniwal Paharia

Dr. based clinical-radiological diagnosis and management of oral lesions and conditions and associated maxillofacial disorders.

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