• Biomarkers
• Iron metabolism
• Liver injury
• Sepsis
• Serum iron
• Total iron-binding capacity

• Humans
• Male
• Female
• Sepsis/complications
• Sepsis/blood
• Prospective Studies
• Biomarkers/blood
• Middle Aged
• Iron/blood
• Iron/metabolism
• Transferrin/metabolism
• Transferrin/analysis
• Aged
• Risk Factors
• ROC Curve
• Ferritins/blood
• Iron Metabolism Disorders/blood
• Iron Metabolism Disorders/diagnosis
• Iron Metabolism Disorders/complications
• Liver Diseases/etiology
• Liver Diseases/blood
• Liver Diseases/diagnosis
• Liver/pathology
• Adult
• Predictive Value of Tests

• Alveolar epithelial cells
• Ferroptosis
• Fibroblast
• Iron metabolism
• Macrophage
• Pulmonary fibrosis

• Humans
• Pulmonary Fibrosis/drug therapy
• Lipid Peroxidation
• Oxidative Stress
• Alveolar Epithelial Cells
• Iron

• Dmt1
• Microbiota
• ferritin
• iron parameters
• lung
• splanchnic area

• Animals
• Mice
• Gastrointestinal Microbiome/physiology
• Iron, Dietary/metabolism
• Iron, Dietary/administration & dosage
• Cation Transport Proteins/metabolism
• Cation Transport Proteins/genetics
• Liver/metabolism
• Liver/microbiology
• Duodenum/metabolism
• Duodenum/microbiology
• Hepcidins/metabolism
• Ferritins/metabolism
• Germ-Free Life
• Host Microbial Interactions
• Lung/microbiology
• Lung/metabolism
• Iron/metabolism
• Basic Helix-Loop-Helix Transcription Factors/metabolism
• Basic Helix-Loop-Helix Transcription Factors/genetics
• Bacteria/classification
• Bacteria/metabolism
• Bacteria/genetics
• Bacteria/isolation & purification
• Mice, Inbred C57BL
• Hemoglobins/metabolism
• Male

• Heavy metals
• Hypertension
• Mineral homeostasis
• Mitochondrial dysfunction
• Non-essential metals
• Pulmonary artery hypertension
• Pulmonary hypoxia
• Right ventricle dysfunction
• Trace elements

• Animals
• Humans
• Hypertension, Pulmonary/metabolism
• Pulmonary Artery/metabolism
• Pulmonary Artery/pathology
• Lung/metabolism
• Hypertension
• Inflammation/metabolism
• Ventricular Remodeling

• P30 ES030283 NIEHS NIH HHS
• P20 GM113226 NIGMS NIH HHS
• R01 AI172873 NIAID NIH HHS
• R21 ES031510 NIEHS NIH HHS
• R01 ES032189 NIEHS NIH HHS
• U18 TR003787 NCATS NIH HHS
• R01 HL158779 NHLBI NIH HHS
• R35 ES028373 NIEHS NIH HHS
• P42 ES023716 NIEHS NIH HHS

Iron is essential to the virulence of Aspergillus species, and restricting iron availability is a critical mechanism of antimicrobial host defense. Macrophages recruited to the site of infection are at the crux of this process, employing multiple intersecting mechanisms to orchestrate iron sequestration from pathogens. To gain an integrated understanding of how this is achieved in aspergillosis, we generated a transcriptomic time series of the response of human monocyte-derived macrophages to Aspergillus and used this and the available literature to construct a mechanistic computational model of iron handling of macrophages during this infection. We found an overwhelming macrophage response beginning 2 to 4 h after exposure to the fungus, which included upregulated transcription of iron import proteins transferrin receptor-1, divalent metal transporter-1, and ZIP family transporters, and downregulated transcription of the iron exporter ferroportin. The computational model, based on a discrete dynamical systems framework, consisted of 21 3-state nodes, and was validated with additional experimental data that were not used in model generation. The model accurately captures the steady state and the trajectories of most of the quantitatively measured nodes. In the experimental data, we surprisingly found that transferrin receptor-1 upregulation preceded the induction of inflammatory cytokines, a feature that deviated from model predictions. Model simulations suggested that direct induction of transferrin receptor-1 (TfR1) after fungal recognition, independent of the iron regulatory protein-labile iron pool (IRP-LIP) system, explains this finding. We anticipate that this model will contribute to a quantitative understanding of iron regulation as a fundamental host defense mechanism during aspergillosis.

IMPORTANCE Invasive pulmonary aspergillosis is a major cause of death among immunosuppressed individuals despite the best available therapy. Depriving the pathogen of iron is an essential component of host defense in this infection, but the mechanisms by which the host achieves this are complex. To understand how recruited macrophages mediate iron deprivation during the infection, we developed and validated a mechanistic computational model that integrates the available information in the field. The insights provided by this approach can help in designing iron modulation therapies as anti-fungal treatments.

Iron progressively accumulates with age and can be further exacerbated by dietary iron intake, genetic factors, and repeated blood transfusions. While iron plays a vital role in various physiological processes within the human body, its accumulation contributes to cellular aging in several species. In its free form, iron can initiate the formation of free radicals at a cellular level and contribute to systemic disorders. This is most evident in high iron conditions such as hereditary hemochromatosis, when accumulation of iron contributes to the development of arthritis, cirrhosis, or cardiomyopathy. A growing body of research has further identified iron’s contributory effects in neurodegenerative diseases, ocular disorders, cancer, diabetes, endocrine dysfunction, and cardiovascular diseases. Reducing iron levels by repeated phlebotomy, iron chelation, and dietary restriction are the common therapeutic considerations to prevent iron toxicity. Chelators such as deferoxamine, deferiprone, and deferasirox have become the standard of care in managing iron overload conditions with other potential applications in cancer and cardiotoxicity. In certain animal models, drugs with iron chelating ability have been found to promote health and even extend lifespan. As we further explore the role of iron in the aging process, iron chelators will likely play an increasingly important role in our health.

• aging
• chronic diseases
• iron
• iron chelator
• oxidative stress

Excess pulmonary iron has been implicated in the pathogenesis of lung disease, including asthma and COPD. An association between higher iron content in sputum macrophages and infective exacerbations of COPD has previously been demonstrated.

To assess the mechanisms of pulmonary macrophage iron sequestration, test the effect of macrophage iron-loading on cellular immune function, and prospectively determine if sputum hemosiderin index can predict infectious exacerbations of COPD.

Intra- and extracellular iron was measured in cell-line-derived and in freshly isolated sputum macrophages under various experimental conditions including treatment with exogenous IL-6 and hepcidin. Bacterial uptake and killing were compared in the presence or absence of iron-loading. A prospective cohort of COPD patients with defined sputum hemosiderin indices were monitored to determine the annual rate of severe infectious exacerbations.

Gene expression studies suggest that airway macrophages have the requisite apparatus of the hepcidin-ferroportin axis. IL-6 and hepcidin play roles in pulmonary iron sequestration, though IL-6 appears to exert its effect via a hepcidin-independent mechanism. Iron-loaded macrophages had reduced uptake of COPD-relevant organisms and were associated with higher growth rates. Infectious exacerbations were predicted by sputum hemosiderin index (β = 0.035, p = 0.035).

We demonstrate in-vitro and population-level evidence that excess iron in pulmonary macrophages may contribute to recurrent airway infection in COPD. Specifically, IL-6-dependent iron sequestration by sputum macrophages may result in immune cell dysfunction and ultimately lead to increased frequency of infective exacerbation.

The online version contains supplementary material available at 10.1186/s12931-022-01929-7.

• COPD
• Exacerbation
• Infection
• Iron
• Sputum

• Apoptosis
• Idiopathic pulmonary fibrosis
• Iron
• Mitochondria
• Oxidative stress

• Anaemia of chronic disease
• Hepcidin
• diagnosis
• meta-analysis

• Anemia/blood
• Anemia/diagnosis
• Chromatography, Liquid/methods
• Chronic Disease
• Enzyme-Linked Immunosorbent Assay/methods
• Hepcidins/blood
• Humans
• Mass Spectrometry/methods
• ROC Curve

Hepcidin (HAMP) is synthesized in the liver. It is a key iron-regulatory hormone that controls systemic iron homeostasis. Cereblon (CRBN) and Kruppel-like factor 15 (KLF15) are known to regulate diverse physiological functions. In this study, we investigated the role of CRBN on hepatic hepcidin gene expression and production under gluconeogenic stimuli. Fasted mice as well as forskolin (FSK)- and glucagon (GLU)-treated mice had reduced serum iron levels but increased expression levels of hepatic Crbn and Klf15 and hepcidin secretion. MicroRNA (miRNA) expression analysis of fasted and Ad-Crbn-infected mice revealed significant reduction of microRNA-639 (miR-639). Hepatic overexpression of Crbn elevated hepcidin expression and production along with Klf15 gene expression, whereas knockdown of Crbn and Klf15 markedly decreased FSK- and fasting-mediated induction of hepcidin gene expression and its biosynthesis in mouse livers and primary hepatocytes. Moreover, expression of KLF15 significantly increased the activity of hepcidin reporter gene. It was exclusively dependent on the KLF15-binding site identified within the hepcidin gene promoter. Overall, this study demonstrates that CRBN and KLF15 are novel mediators of gluconeogenic signal-induced hepcidin gene expression and production. Thus, CRBN and KLF15 might be novel potential therapeutic targets to intervene metabolic dysfunction.

• Ferroptosis
• Inflammation
• Iron chelator
• Iron retention
• Oxidative stress

• Ferroptosis
• Homeostasis
• Humans
• Iron
• Sepsis
• Trace Elements

• alveolar macrophages
• ferroportin
• inflammation
• iron
• lung
• neutrophils

• ARDS
• acute lung injury
• inflammation
• iron overload

• Acute Lung Injury/metabolism
• Acute Lung Injury/pathology
• Animals
• Disease Models, Animal
• Female
• Hepcidins/genetics
• Hepcidins/metabolism
• Inflammation/metabolism
• Inflammation/pathology
• Iron Overload/metabolism
• Iron Overload/pathology
• Lipopolysaccharides/administration & dosage
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout

• K08 HL127293 NHLBI NIH HHS
• R01 DK107309 NIDDK NIH HHS
• R01 HD096863 NICHD NIH HHS
• National Heart, Lung, and Blood Institute

Hepcidin is the hyposideremic hormone regulating iron metabolism. It is a defensin-like disulfide-bonded peptide with antimicrobial activity. The main site of hepcidin production is the liver where its synthesis is modulated by iron, inflammation and erythropoietic signaling. However, hepcidin locally produced in several peripheral organs seems to be an important actor for the maintenance of iron homeostasis in these organs. This review highlights the presence of peripheral hepcidin and its potential functions. Understanding the role of extrahepatic hepcidin could be of great physiological and therapeutic importance for several specific pathologies.

• Hepcidin
• Extrahepatic hepcidin
• Iron metabolism
• Bacterial infection
• Inflammation

The human response to Mycobacterium tuberculosis (Mtb) infection is affected by the availability of iron (Fe), which is necessary for proper immune cell function and is essential for the growth and virulence of bacteria. Increase in host Fe levels promotes Mtb growth and tuberculosis (TB) pathogenesis, while Fe-supplementation to latently infected, asymptomatic individuals is a significant risk factor for disease reactivation. However, the effect of Fe-supplementation on the host immunity during latent Mtb infection remains unclear, due partly to the paucity in availability of animal models that recapitulate key pathophysiological features seen in humans. We have demonstrated that rabbits can develop non-progressive latency similar to infected humans. In this study, using this model we have evaluated the effect of Fe-supplementation on the bacterial growth, disease pathology, and immune response. Systemic and lung Fe parameters, gene expression profile, lung bacterial burden, and disease pathology were determined in the Mtb-infected/Fe- or placebo-supplemented rabbits. Results show that Fe-supplementation to Mtb-infected rabbits did not significantly change the hematocrit and Hb levels, although it elevated total Fe in the lungs. Expression of selected host iron- and immune-response genes in the blood and lungs was perturbed in Mtb-infected/Fe-supplemented rabbits. Iron-supplementation during acute or chronic stages of Mtb infection did not significantly affect the bacterial burden or disease pathology in the lungs. Data presented in this study is of significant relevance for current public health policies on Fe-supplementation therapy given to anemic patients with latent Mtb infection.

• Mycobacterium tuberculosis
• Perls’ stain
• gene expression
• immune response
• iron supplementation
• latent infection
• pathology
• pulmonary
• rabbit
• tuberculosis

The lung presents a unique challenge for iron homeostasis. The entire airway is in direct contact with the environment and its iron particulate matter and iron-utilizing microbes. However, the homeostatic and adaptive mechanisms of pulmonary iron regulation are poorly understood. This review provides an overview of systemic and local lung iron regulation, as well as the roles of iron in the development of lung infections, airway disease, and lung injury. These mechanisms provide an important foundation for the ongoing development of therapeutic applications.

• COPD
• acute lung injury
• cystic fibrosis
• hepcidin
• iron
• lung
• lung infection

A strong mechanistic link between the regulation of iron homeostasis and oxygen sensing is evident in the lung, where both systems must be properly controlled to maintain lung function. Imbalances in pulmonary iron homeostasis are frequently associated with respiratory diseases, such as chronic obstructive pulmonary disease and with lung cancer. However, the underlying mechanisms causing alterations in iron levels and the involvement of iron in the development of lung disorders are incompletely understood. Here, we review current knowledge about the regulation of pulmonary iron homeostasis, its functional importance, and the link between dysregulated iron levels and lung diseases. Gaining greater knowledge on how iron contributes to the pathogenesis of these diseases holds promise for future iron-related therapeutic strategies.

• hypoxia
• iron homeostasis
• lung diseases
• oxygen sensing

• Cardiomyopathy
• Genetic regulation
• Heart failure
• Hemochromatosis
• Hepcidin
• Iron deficiency
• Iron metabolism
• Iron overload
• Mitochondrial function

• cytokine
• erythrocytosis
• hepcidin
• high altitude
• immune balance
• inflammation
• iron metabolism

• Anemia, Iron-Deficiency/complications
• Animals
• Disease Models, Animal
• Disease Susceptibility
• Female
• Hepcidins/deficiency
• Hepcidins/genetics
• Homeostasis
• Iron/metabolism
• Mice
• Mice, Inbred BALB C
• Mice, Inbred C57BL
• Mice, Knockout
• Mycobacterium tuberculosis/pathogenicity
• Tuberculosis/complications
• Tuberculosis/pathology

• Wellcome Trust
• MC_UU_00008/10 Medical Research Council
• MC_UU_12010/10 Medical Research Council
• Wellcome Trust (GB)