Ferritin H deficiency deteriorates cellular iron handling and worsens Salmonella typhimurium infection by triggering hyperinflammation.

Iron is an essential nutrient for mammals as well as for pathogens. Inflammation-driven changes in systemic and cellular iron homeostasis are central for host-mediated antimicrobial strategies. Here, we studied the role of the iron storage protein ferritin H (FTH) for the control of infections with the intracellular pathogen Salmonella enterica serovar Typhimurium by macrophages. Mice lacking FTH in the myeloid lineage (LysM-Cre+/+Fthfl/fl mice) displayed impaired iron storage capacities in the tissue leukocyte compartment, increased levels of labile iron in macrophages, and an accelerated macrophage-mediated iron turnover. While under steady-state conditions, LysM-Cre+/+Fth+/+ and LysM-Cre+/+Fthfl/fl animals showed comparable susceptibility to Salmonella infection, i.v. iron supplementation drastically shortened survival of LysM-Cre+/+Fthfl/fl mice. Mechanistically, these animals displayed increased bacterial burden, which contributed to uncontrolled triggering of NF-κB and inflammasome signaling and development of cytokine storm and death. Importantly, pharmacologic inhibition of the inflammasome and IL-1ß pathways reduced cytokine levels and mortality and partly restored infection control in iron-treated ferritin-deficient mice. These findings uncover incompletely characterized roles of ferritin and cellular iron turnover in myeloid cells in controlling bacterial spread and for modulating NF-κB and inflammasome-mediated cytokine activation, which may be of vital importance in iron-overloaded individuals suffering from severe infections and sepsis.

The Role of Nutrition in COVID-19 Susceptibility and Severity of Disease: A Systematic Review.

BACKGROUND: Many nutrients have powerful immunomodulatory actions with the potential to alter susceptibility to coronavirus disease 2019 (COVID-19) infection, progression to symptoms, likelihood of severe disease, and survival. OBJECTIVE: The aim was to review the latest evidence on how malnutrition across all its forms (under- and overnutrition and micronutrient status) may influence both susceptibility to, and progression of, COVID-19. METHODS: We synthesized information on 13 nutrition-related components and their potential interactions with COVID-19: overweight, obesity, and diabetes; protein-energy malnutrition; anemia; vitamins A, C, D, and E; PUFAs; iron; selenium; zinc; antioxidants; and nutritional support. For each section we provide: 1) a landscape review of pertinent material; 2) a systematic search of the literature in PubMed and EMBASE databases, including a wide range of preprint servers; and 3) a screen of 6 clinical trial registries. All original research was considered, without restriction to study design, and included if it covered: 1) severe acute respiratory syndrome coronavirus (CoV) 2 (SARS-CoV-2), Middle East respiratory syndrome CoV (MERS-CoV), or SARS-CoV viruses and 2) disease susceptibility or 3) disease progression, and 4) the nutritional component of interest. Searches took place between 16 May and 11 August 2020. RESULTS: Across the 13 searches, 2732 articles from PubMed and EMBASE, 4164 articles from the preprint servers, and 433 trials were returned. In the final narrative synthesis, we include 22 published articles, 38 preprint articles, and 79 trials. CONCLUSIONS: Currently there is limited evidence that high-dose supplements of micronutrients will either prevent severe disease or speed up recovery. However, results of clinical trials are eagerly awaited. Given the known impacts of all forms of malnutrition on the immune system, public health strategies to reduce micronutrient deficiencies and undernutrition remain of critical importance. Furthermore, there is strong evidence that prevention of obesity and type 2 diabetes will reduce the risk of serious COVID-19 outcomes. This review is registered at PROSPERO as CRD42020186194.

Flipside of the Coin: Iron Deficiency and Colorectal Cancer.

Iron deficiency, with or without anemia, is the most frequent hematological manifestation in individuals with cancer, and is especially common in patients with colorectal cancer. Iron is a vital micronutrient that plays an essential role in many biological functions, in the context of which it has been found to be intimately linked to cancer biology. To date, however, whereas a large number of studies have comprehensively investigated and reviewed the effects of excess iron on cancer initiation and progression, potential interrelations of iron deficiency with cancer have been largely neglected and are not well-defined. Emerging evidence indicates that reduced iron intake and low systemic iron levels are associated with the pathogenesis of colorectal cancer, suggesting that optimal iron intake must be carefully balanced to avoid both iron deficiency and iron excess. Since iron is vital in the maintenance of immunological functions, insufficient iron availability may enhance oncogenicity by impairing immunosurveillance for neoplastic changes and potentially altering the tumor immune microenvironment. Data from clinical studies support these concepts, showing that iron deficiency is associated with inferior outcomes and reduced response to therapy in patients with colorectal cancer. Here, we elucidate cancer-related effects of iron deficiency, examine preclinical and clinical evidence of its role in tumorigenesis, cancer progression and treatment response. and highlight the importance of adequate iron supplementation to limit these outcomes.

Pathological mechanism of joint destruction in haemophilic arthropathy.

Haemophilic arthropathy (HA), caused by intra-articular haemorrhage, is one of the most common complications in patients with haemophilia. Factor replacement therapy provides missing coagulation factors to prevent children with haemophilia from joint bleeding and decreases their risk for HA. However, haemophilia patients in developing countries are still suffering from HA due to insufficient replacement therapy. Symptoms such as pain and activity limitations caused by HA seriously affect the functional abilities and quality of life of patients with HA, causing a high disability rate in the haemophilia cohort. The pathological mechanism of HA is complicated because the whole pathological mainly involves hypertrophic synovitis, osteopenia, cartilage and bone destruction, and these pathological changes occur in parallel and interact with each other. Inflammation plays an important role in the whole complex pathological process, and iron, cytokines, growth factors and other factors are involved. This review summarizes the pathological mechanism of HA to provide background for clinical and basic research.

Cutting Edge: Activation-Induced Iron Flux Controls CD4 T Cell Proliferation by Promoting Proper IL-2R Signaling and Mitochondrial Function.

Iron has long been established as a critical mediator of T cell development and proliferation. However, the mechanisms by which iron controls CD4 T cell activation and expansion remain poorly understood. In this study, we show that stimulation of CD4 T cells from C57BL/6 mice not only decreases total and labile iron levels but also leads to changes in the expression of iron homeostatic machinery. Additionally, restraining iron availability in vitro severely inhibited CD4 T cell proliferation and cell cycle progression. Although modulating cellular iron levels increased IL-2 production by activated T lymphocytes, CD25 expression and pSTAT5 levels were decreased, indicating that iron is necessary for IL-2R-mediated signaling. We also found that iron deprivation during T cell stimulation negatively impacts mitochondrial function, which can be reversed by iron supplementation. In all, we show that iron contributes to activation-induced T cell expansion by positively regulating IL-2R signaling and mitochondrial function.

Comparison of Oral and Parenteral Iron Administration on Iron Homeostasis, Oxidative and Immune Status in Anemic Neonatal Pigs.

The present study was to evaluate the consequences of iron status across oral and parenteral iron administrations in prevention of iron deficiency anemia. A total of 24 one-day-old male neonatal piglets were allocated into three groups given non-iron supplementation (NON), intramuscular iron dextran injection (FeDex), and oral administration of ferrous glycine chelate (FeGly), respectively. At day 8, no significant differences in final body weight, average weight gain, and tissue coefficients were observed among three groups (P > 0.05). Both oral FeGly and FeDex injection significantly increased serum iron, ferritin, hemoglobin, and tissue iron deposition (P < 0.05). However, FeDex-injected supplementation resulted in rapidly rising hepcidin levels and hepatic iron deposition (P < 0.05). In addition, compared to parenteral iron supplementation, greater serum IgA level, SOD, and GSH-Px activities, lower expressions of IL-1ß and TNF-α in the liver, and lower expressions of IL-6 and TNF-α in the spleen were found in oral iron piglets (P < 0.05). According to our results, oral administration of ferrous glycine chelate improved iron homeostasis, and oxidative and immune status in anemic neonatal pigs.

Curcumin: hopeful treatment of hemophilic arthropathy via inhibition of inflammation and angiogenesis.

Introduction: Hemophilic arthropathy (HA) is a serious complication among hemophilic patients causing a wide range of morbidity due to the inflammatory reactions followed by repeated episodes of bleeding. This condition has recently been shown to be accompanied by angiogenesis. The cascade starts with iron accumulation leading to an increase in CD68+ and CD11b+ cells responsible for initiating the inflammation.Areas covered: During inflammation, different factors and cytokines such as interleukin 1 (IL-1), IL-6, and tumor necrosis factor α (TNF-α) actively play parts in the pathogenesis of HA and also angiogenesis. It has been demonstrated that different pro-angiogenic and angiogenic factors such as hypoxia-inducible factor 1α (HIF-1α), vascular endothelial growth factor (VEGF), oxidative stress and matrix metalloproteinases (MMPs) are also important in the pathogenesis of HA. Curcumin is known for its strong anti-inflammatory and anti-angiogenic potentials. This agent is able to inhibit the mentioned inflammatory and angiogenic factors such as IL-1, IL-6, TNF-α, VEGF, MMPs, and HIF-1α. Also, as well as anti-angiogenic and anti-inflammatory activity, curcumin has a strong antioxidant potential and can decrease oxidative stress.Expert opinion: It seems that curcumin could be considered as a possible agent for the treatment of HA through inhibition of inflammation, oxidative stress, and angiogenesis.

OsHV-1 infection leads to mollusc tissue lesion and iron redistribution, revealing a strategy of iron limitation against pathogen.

The mass mortality of molluscs caused by OsHV-1 infection has frequently occurred worldwide in recent years. Meanwhile the interaction between OsHV-1 and its host is largely unknown. Innate immunity mainly makes up the mollusc defense system, due to the lack of adaptive immunity in invertebrates. The iron limitation strategy is an indispensable facet of innate immunity across vertebrate and invertebrate species. In this study, an iron limitation strategy was interestingly found to contribute to mollusc innate immune responses against OsHV-1 infection. Firstly, ark clams, Scapharca broughtonii, were experimentally infected with OsHV-1, and serious hyperaemia in hepatopancreases and the erosion of gills were observed post OsHV-1 infection according to a histology assay. Meanwhile, based on quantification and Prussian blue staining, the process of iron efflux from ark clams was described post OsHV-1 infection. Secondly, ferritin, as an important iron storage protein, was characterized in ark clams and showed significant iron binding activity. According to the results of an immunohistochemistry assay, ferritin was supposed to be responsible for the iron translocation in ark clams post OsHV-1 infection. Its expression level was significantly fluctuant in response to OsHV-1 infection. Finally, oxidative stress was assessed by the analyses of H2O2 content, total antioxidant capacity and MDA level post OsHV-1 infection. Supplementary iron was found to promote ROS generation and death of hemocytes in vivo. These results highlighted that microenvironment changes in the essential nutrient iron should be an important aspect of the pathogenesis of OsHV-1 disease.

Multiple nutritional factors and thyroid disease, with particular reference to autoimmune thyroid disease.

Hashimoto's thyroiditis (HT) and Graves' disease (GD) are examples of autoimmune thyroid disease (AITD), the commonest autoimmune condition. Antibodies to thyroid peroxidase (TPO), the enzyme that catalyses thyroid-hormone production and antibodies to the receptor for the thyroid-stimulating hormone, are characteristic of HT and GD, respectively. It is presently accepted that genetic susceptibility, environmental factors, including nutritional factors and immune disorders contribute to the development of AITD. Aiming to investigate the effect of iodine, iron and selenium in the risk, pathogenesis and treatment of thyroid disease, PubMed and the Cochrane Library were searched for relevant publications to provide a narrative review. Iodine: chronic exposure to excess iodine intake induces autoimmune thyroiditis, partly because highly-iodinated thyroglobulin (Tg) is more immunogenic. The recent introduction of universal salt iodisation can have a similar, although transient, effect. Iron: iron deficiency impairs thyroid metabolism. TPO is a haem enzyme that becomes active only after binding haem. AITD patients are frequently iron-deficient since autoimmune gastritis, which reduces iron absorption and coeliac disease which causes iron loss, are frequent co-morbidities. In two-thirds of women with persistent symptoms of hypothyroidism despite appropriate levothyroxine therapy, restoration of serum ferritin above 100 µg/l ameliorated symptoms. Selenium: selenoproteins are essential to thyroid action. In particular, the glutathione peroxidases remove excessive hydrogen peroxide produced there for the iodination of Tg to form thyroid hormones. There is evidence from observational studies and randomised controlled trials that selenium, probably as selenoproteins, can reduce TPO-antibody concentration, hypothyroidism and postpartum thyroiditis. Appropriate status of iodine, iron and selenium is crucial to thyroid health.

Role of essential trace elements in tuberculosis infection: A review article.

Malnutrition is one of the risk factors in tuberculosis (TB) infection. Mineral levels perturbation is seen in patients with TB. Moreover there are some strategies to starve pathogens of essential metals. Here we decided to conclude association between some essential elements and TB. Copper, calcium and iron are essential for hosts' immune system although calcium and iron are necessary for Mycobacterium tuberculosis vitality. Changing these elements alongside with anti-TB therapy is suggested for better treatment outcomes.

Iron prevents the development of experimental cerebral malaria by attenuating CXCR3-mediated T cell chemotaxis.

Cerebral malaria is a severe neurological complication of Plasmodium falciparum infection. Previous studies have suggested that iron overload can suppress the generation of a cytotoxic immune response; however, the effect of iron on experimental cerebral malaria (ECM) is yet unknown. Here we determined that the incidence of ECM was markedly reduced in mice treated with iron dextran. Protection was concomitant with a significant decrease in the sequestration of CD4+ and CD8+ T cells within the brain. CD4+ T cells demonstrated markedly decreased CXCR3 expression and had reduced IFNγ-responsiveness, as indicated by mitigated expression of IFNγR2 and T-bet. Additional analysis of the splenic cell populations indicated that parenteral iron supplementation was also associated with a decrease in NK cells and increase in regulatory T cells. Altogether, these results suggest that iron is able to inhibit ECM pathology by attenuating the capacity of T cells to migrate to the brain.

Iron metabolism in transplantation.

Recipient's iron status is an important determinant of clinical outcome in transplantation medicine. This review addresses iron metabolism in solid organ transplantation, where the role of iron as a mediator of ischemia-reperfusion injury, as an immune-modulatory element, and as a determinant of organ and graft function is discussed. Although iron chelators reduce ischemia-reperfusion injury in cell and animal models, these benefits have not yet been implemented into clinical practice. Iron deficiency and iron overload are associated with reduced immune activation, whose molecular mechanisms are reviewed in detail. Furthermore, iron overload and hyperferritinemia are associated with poor prognosis in end-stage organ failure in patients awaiting kidney, or liver transplantation. This negative prognostic impact of iron overload appears to persist after transplantation, which highlights the need for optimizing iron management before and after solid organ transplantation. In contrast, iron deficiency and anemia are also associated with poor prognosis in patients with end-stage heart failure. Intravenous iron supplementation should be managed carefully because parenterally induced iron overload could persist after successful transplantation. In conclusion, current evidence shows that iron overload and iron deficiency are important risk factors before and after solid organ transplantation. Iron status should therefore be actively managed in patients on the waiting list and after transplantation.

Iron administration reduces airway hyperreactivity and eosinophilia in a mouse model of allergic asthma.

The prevalence of allergic diseases has increased dramatically during the last four decades and is paralleled by a striking increase in iron intake by infants in affluent societies. Several studies have suggested a link between increased iron intake and the marked increase in prevalence of allergic diseases. We hypothesized that the increased iron intake by infants offers an explanation for the increased prevalence of allergic disease in industrialized societies during the past four decades. A well-established mouse model of ovalbumin (OVA)-driven allergic asthma was used to test the effects of differences in iron intake and systemic iron levels on the manifestations of allergic asthma. Surprisingly, iron supplementation resulted in a significant decrease in airway eosinophilia, while systemic iron injections lead to a significant suppression of both allergen-induced airway eosinophilia and hyperreactivity compared to placebo. In contrast, mice fed on an iron-deprived diet did not show any difference in developing experimentally induced allergic asthma when compared to those fed on an iron-sufficient control diet. In contrast to our hypothesis, airway manifestations of allergic asthma are suppressed by both increased levels of iron intake and systemic iron administrations in the mouse model.

Molecular cloning, characterization and mRNA expression of selenium-binding protein in abalone (Haliotis discus hannai Ino): Response to dietary selenium, iron and zinc.

Selenium-binding protein (SEBP) is believed to play crucial role in controlling the oxidation/reduction in the physiological processes. In this study, the cDNA of selenium-binding protein from abalone Haliotis discus hannai Ino (HdhSEBP) was cloned by homology cloning and rapid amplification of cDNA ends (RACE) technique. The full length of HdhSEBP cDNA was 2071 bp, consisting of a 5' untranslated region (UTR) of 55 bp, a 3' UTR of 522 bp, and an open reading frame (ORF) of 1494 bp. The deduced protein has 497 amino acid residues with a calculated molecular mass of 55.6 kDa and a predicted isoelectric point of 5.47. BLAST analysis reveals that HdhSEBP shares high identities with other known SEBPs from mammal, bird, fish and mollusk, etc. The mRNA expression patterns of HdhSEBP in hepatopancreas and haemocytes were measured by real-time PCR in abalone fed with nine different diets containing graded levels of selenium (0, 1 and 50 mg kg(-1)), iron (0, 65 and 1300 mg kg(-1)) and zinc (0, 35 and 700 mg kg(-1)) for 20 weeks, respectively. The results showed that the expression of the HdhSEBP mRNA increased and reached the maximum at optimal dietary selenium (1 mg kg(-1)), iron (65 mg kg(-1)) and zinc (35 mg kg(-1)), respectively. Deficient or excessive level of dietary selenium, iron or zinc, respectively, leaded to significant depression of HdhSEBP mRNA. It is concluded that the expression levels of HdhSEBP are affected by dietary selenium, iron or zinc.

Iron homoeostasis in rheumatic disease.

Iron is critical in nearly all cell functions and the ability of a cell, tissue and organism to procure this metal is obligatory for survival. Iron is necessary for normal immune function, and relative iron deficiency is associated with mild immunosuppression. Concentrations of this metal in excess of those required for function can present both an oxidative stress and elevate risks for infection. As a result, the human has evolved to have a complex mechanism of regulating iron and limiting its availability. This homoeostasis can be disrupted. Autoimmune diseases and gout often present with abnormal iron homoeostasis, thus supporting a participation of the metal in these injuries. We review the role of iron in normal immune function and discuss both clinical evidence of altered iron homoeostasis in autoimmune diseases and gout as well as possible implications of both depletion and supplementation of this metal in this patient population. We conclude that altered iron homoeostasis may represent a purposeful response to inflammation that could have theoretical anti-inflammatory benefits. We encourage physicians to avoid routine iron supplementation in those without depleted iron stores.

Iron, copper and immunocompetence.

Microminerals including copper and iron are essential to immunity and health in human beings. The development of powerful tools in analytical cell biology and molecular genetics has facilitated efforts to identify specific cellular and molecular functions of trace elements in the maturation, activation and functions of host defence mechanisms. Selected recent reports about the role of copper and iron nutrition on immune functions are critically analysed here. Effects of trace element supplementation on infectious morbidity are also reviewed. While micromineral deficiencies, in general, may have widespread effects on nearly all components of immune response, these effects can be reversed by supplementation. However, the conflicting effects of iron deficiency and iron supplementation in vitro on the defensive systems reveals the urgent need for further additional information on the in vivo situation. In the elderly, vaccination against respiratory infections is likely to protect only 30-70% of the population. However, it may be possible to modulate immune function and ultimately reduce the severity of infections through micronutrient supplementation. Thus, microminerals contribute to the maintenance of the balance between immunity and health in humans.

Nonhematological benefits of iron.

Iron deficiency anemia is common in people with chronic kidney disease (CKD) and its importance in supporting erythropoiesis is unquestioned especially in those patients treated with erythropoietin. Clinical symptomatology such as fatigability, cold intolerance, failure to concentrate and poor effort intolerance is often attributed to anemia or uremia. That iron deficiency, per se, can cause these symptoms is poorly recognized. Clinical and animal studies that support the benefits of iron supplementation, independent of increasing hemoglobin, such as those on immune function, physical performance, thermoregulation, cognition, and restless leg syndrome and aluminum absorption is the subject of this narrative review.

Testing the feasibility and initial effects of iron and vitamin C to enhance nursing home residents' immune status following an influenza vaccine.

Influenza infections pose a serious threat to residents living in nursing homes and are a major cause of morbidity and mortality in older adults. It is estimated that influenza vaccination is only 30%-40% effective in the frail elderly. This 2-group experimental design study examined the efficacy of giving iron supplements to nursing home residents aged 65 and older to improve immune response following influenza vaccination. Specific aims of the study were to test study procedures and explore initial immune response. A number of barriers were encountered during the recruitment and consent phase limiting subject recruitment. Only serum transferrin was significantly different following the 30-day administration of iron supplementation. It was concluded that to achieve sufficient power to examine the effect of the intervention on immune response and infection rates, aggressive recruiting strategies at multiple sites are necessary.

Mechanisms of nutrient modulation of the immune response.

Lack of adequate macronutrients or selected micronutrients, especially zinc, selenium, iron, and the antioxidant vitamins, can lead to clinically significant immune deficiency and infections in children. Undernutrition in critical periods of gestation and neonatal maturation and during weaning impairs the development and differentiation of a normal immune system. Infections are both more frequent and more often become chronic in the malnourished child. Recent identification of genetic mechanisms is revealing critical pathways in the gastrointestinal immune response. New studies show that the development of tolerance, control of inflammation, and response to normal mucosal flora are interrelated and linked to specific immune mechanisms. Nutrients act as antioxidants and as cofactors at the level of cytokine regulation. Protein calorie malnutrition and zinc deficiency activate the hypothalamic-pituitary-adrenal axis. Increased circulating levels of glucocorticoids cause thymic atrophy and affect hematopoiesis. Chronic undernutrition and micronutrient deficiency compromise cytokine response and affect immune cell trafficking. The combination of chronic undernutrition and infection further weakens the immune response, leading to altered immune cell populations and a generalized increase in inflammatory mediators. Obesity caused by excess nutrition or excess storage of fats relative to energy expenditure is a form of malnutrition that is increasingly seen in children. Leptin is emerging as a cytokine-like immune regulator that has complex effects in both overnutrition and in the inflammatory response in malnutrition. Because the immune system is immature at birth, malnutrition in childhood might have long-term effects on health.

Effects of 4 weeks iron supplementation on haematological and immunological status in elite female soccer players.

The effects of 4 weeks iron supplementation on haematological and immunological status were studied in 25 elite female soccer players aged 20-28 years. The subjects were randomized and assigned to one of the following two groups; subjects given 40 mg/day iron supplementation (S group) or those given placebo (C group). The oral iron supplementation (40 mg elemental iron) was taken in 15 ml solution once a day by the S group, and the C group took a placebo for 4 weeks. Daily energy and protein intakes met the Korean Recommended Dietary Allowances. Blood haemoglobin concentration did not change in the S group, but decreased significantly (P<0.05) in the C group over the 4-week experimental period. Haematocrit, mean cell volume, mean cell haemoglobin and total iron binding capacity decreased significantly, and mean cell haemoglobin concentration increased significantly (P<0.05) in both the S and C groups. Plasma ferritin concentration increased significantly (P<0.05) in the S group, but did not change in the C group. The change of plasma immunological parameters and erythrocyte anti-oxidative enzyme activities were almost the same between the S and C groups. These results suggest that 4 weeks of iron supplementation by elite female soccer players significantly increased body iron stores and inhibited decrease of haemoglobin concentration induced by soccer training.