RESUMO
Ferritin, which was only discovered in the last century, has stirred a formidable debate. Ferritin has long been appreciated as a non-specific acute-phase reactant. Several years ago, we hypothesized the contributory role of ferritin as a pathogenic molecule rather than being a product of inflammation. The latest emerging evidence provides support to this notion. Such revelation provides a step forward towards the understanding of disease conditions associated with hyperferritinaemia, and hence provide new targets for treatment modalities.
Assuntos
Proteínas de Fase Aguda/metabolismo , Ferritinas/metabolismo , Inflamação/imunologia , Distúrbios do Metabolismo do Ferro/imunologia , Macrófagos/imunologia , Animais , Humanos , Imunomodulação , Ativação de Macrófagos , Terapia de Alvo MolecularRESUMO
UNLABELLED: Expression of the cytoprotective enzyme heme oxygenase-1 (HO-1) is significantly reduced in the brain prefrontal cortex of HIV-positive individuals with HIV-associated neurocognitive disorders (HAND). Furthermore, this HO-1 deficiency correlates with brain viral load, markers of macrophage activation, and type I interferon responses. In vitro, HIV replication in monocyte-derived macrophages (MDM) selectively reduces HO-1 protein and RNA expression and induces production of neurotoxic levels of glutamate; correction of this HO-1 deficiency reduces neurotoxic glutamate production without an effect on HIV replication. We now demonstrate that macrophage HO-1 deficiency, and the associated neurotoxin production, is a conserved feature of infection with macrophage-tropic HIV-1 strains that correlates closely with the extent of replication, and this feature extends to HIV-2 infection. We further demonstrate that this HO-1 deficiency does not depend specifically upon the HIV-1 accessory genes nef, vpr, or vpu but rather on HIV replication, even when markedly limited. Finally, antiretroviral therapy (ART) applied to MDM after HIV infection is established does not prevent HO-1 loss or the associated neurotoxin production. This work defines a predictable relationship between HIV replication, HO-1 loss, and neurotoxin production in MDM that likely reflects processes in place in the HIV-infected brains of individuals receiving ART. It further suggests that correcting this HO-1 deficiency in HIV-infected MDM could provide neuroprotection above that provided by current ART or proposed antiviral therapies directed at limiting Nef, Vpr, or Vpu functions. The ability of HIV-2 to reduce HO-1 expression suggests that this is a conserved phenotype among macrophage-tropic human immunodeficiency viruses that could contribute to neuropathogenesis. IMPORTANCE: The continued prevalence of HIV-associated neurocognitive disorders (HAND) underscores the need for adjunctive therapy that targets the neuropathological processes that persist in antiretroviral therapy (ART)-treated HIV-infected individuals. To this end, we previously identified one such possible process, a deficiency of the antioxidative and anti-inflammatory enzyme heme oxygenase-1 (HO-1) in the brains of individuals with HAND. In the present study, our findings suggest that the HO-1 deficiency associated with excess glutamate production and neurotoxicity in HIV-infected macrophages is a highly conserved phenotype of macrophage-tropic HIV strains and that this phenotype can persist in the macrophage compartment in the presence of ART. This suggests a plausible mechanism by which HIV infection of brain macrophages in ART-treated individuals could exacerbate oxidative stress and glutamate-induced neuronal injury, each of which is associated with neurocognitive dysfunction in infected individuals. Thus, therapies that rescue the HO-1 deficiency in HIV-infected individuals could provide additional neuroprotection to ART.
Assuntos
Anemia Hemolítica/virologia , Ácido Glutâmico/toxicidade , Transtornos do Crescimento/virologia , HIV-1/patogenicidade , HIV-2/patogenicidade , Heme Oxigenase-1/deficiência , Distúrbios do Metabolismo do Ferro/virologia , Macrófagos/virologia , Anemia Hemolítica/genética , Anemia Hemolítica/imunologia , Animais , Fármacos Anti-HIV/farmacologia , Farmacorresistência Viral/genética , Farmacorresistência Viral/imunologia , Expressão Gênica , Ácido Glutâmico/biossíntese , Transtornos do Crescimento/genética , Transtornos do Crescimento/imunologia , HIV-1/imunologia , HIV-2/imunologia , Heme Oxigenase-1/genética , Heme Oxigenase-1/imunologia , Proteínas do Vírus da Imunodeficiência Humana/genética , Proteínas do Vírus da Imunodeficiência Humana/imunologia , Humanos , Distúrbios do Metabolismo do Ferro/genética , Distúrbios do Metabolismo do Ferro/imunologia , Ativação de Macrófagos/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Neuroglia/efeitos dos fármacos , Neuroglia/imunologia , Neuroglia/virologia , Fenótipo , Cultura Primária de Células , Ratos , Ratos Sprague-Dawley , Proteínas Virais Reguladoras e Acessórias/genética , Proteínas Virais Reguladoras e Acessórias/imunologia , Replicação Viral/efeitos dos fármacos , Produtos do Gene nef do Vírus da Imunodeficiência Humana/genética , Produtos do Gene nef do Vírus da Imunodeficiência Humana/imunologia , Produtos do Gene vpr do Vírus da Imunodeficiência Humana/genética , Produtos do Gene vpr do Vírus da Imunodeficiência Humana/imunologiaRESUMO
OBJECTIVE: Increased body iron stores and hepcidin have been hypothesized to promote atherosclerosis by inducing macrophage iron accumulation and release of cytokines, but direct demonstration in human cells is lacking. The aim of this study was to evaluate the effect of iron on cytokine release in monocytes ex vivo and the correlation with vascular damage and to evaluate the relationship among serum levels of hepcidin, cytokines, and vascular damage in patients with metabolic syndrome alterations. METHODS AND RESULTS: Manipulation of iron status with ferric ammonium citrate and hepcidin-25 induced monocyte chemoattractant protein (MCP)-1 and interleukin-6 in human differentiating monocytes of patients with hyperferritinemia associated with the metabolic syndrome (n=11), but not in subjects with hemochromatosis or HFE mutations impairing iron accumulation (n=15), and the degree of induction correlated with the presence of carotid plaques, detected by echocolor-Doppler. In monocytes of healthy subjects (n=7), iron and hepcidin increased the mRNA levels and release of MCP-1, but not of interleukin-6. In 130 patients with metabolic alterations, MCP-1 levels, as detected by ELISA, were correlated with hepcidin-25 measured by time-of-flight mass spectrometry (P=0.005) and were an independent predictor of the presence of carotid plaques (P=0.05). CONCLUSIONS: Hepcidin and macrophage iron correlate with MCP-1 release and vascular damage in high-risk individuals with metabolic alterations.
Assuntos
Peptídeos Catiônicos Antimicrobianos/sangue , Doenças das Artérias Carótidas/etiologia , Quimiocina CCL2/metabolismo , Mediadores da Inflamação/metabolismo , Distúrbios do Metabolismo do Ferro/complicações , Ferro/metabolismo , Macrófagos/metabolismo , Síndrome Metabólica/complicações , Adulto , Idoso , Doenças das Artérias Carótidas/sangue , Doenças das Artérias Carótidas/diagnóstico por imagem , Doenças das Artérias Carótidas/imunologia , Células Cultivadas , Quimiocina CCL2/genética , Distribuição de Qui-Quadrado , Ensaio de Imunoadsorção Enzimática , Feminino , Compostos Férricos/farmacologia , Ferritinas/sangue , Hepcidinas , Humanos , Interleucina-6/metabolismo , Distúrbios do Metabolismo do Ferro/sangue , Distúrbios do Metabolismo do Ferro/imunologia , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Masculino , Espectrometria de Massas , Síndrome Metabólica/sangue , Síndrome Metabólica/imunologia , Pessoa de Meia-Idade , Estresse Oxidativo , Compostos de Amônio Quaternário/farmacologia , RNA Mensageiro/metabolismo , Índice de Gravidade de Doença , Ultrassonografia Doppler em CoresAssuntos
Bactérias/metabolismo , Infecções Bacterianas/metabolismo , Evolução Biológica , Hepcidinas/metabolismo , Distúrbios do Metabolismo do Ferro/metabolismo , Ferro/metabolismo , Inanição/metabolismo , Adaptação Fisiológica , Animais , Bactérias/imunologia , Bactérias/patogenicidade , Infecções Bacterianas/genética , Infecções Bacterianas/imunologia , Infecções Bacterianas/microbiologia , Genótipo , Hepcidinas/imunologia , Homeostase , Interações Hospedeiro-Patógeno , Humanos , Imunidade Inata , Distúrbios do Metabolismo do Ferro/genética , Distúrbios do Metabolismo do Ferro/imunologia , Fenótipo , Inanição/genética , Inanição/imunologiaRESUMO
The coronavirus disease 2019 (COVID-19), an acute respiratory disease caused by severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2), has been declared as a worldwide public health emergency. Interestingly, severe COVID-19 is characterized by fever, hyperferritinemia, and a hyper-inflammatory process with a massive release of pro-inflammatory cytokines, which may be responsible for the high rate of mortality. These findings may advocate for a similarity between severe COVID-19 and some challenging rheumatic diseases, such as adult onset Still's disease, secondary hemophagocytic lymphohistiocytosis, and catastrophic anti-phospholipid syndrome, which have been included in the "hyperferritinemic syndrome" category. Furthermore, as performed in these hyper-inflammatory states, severe COVID-19 may benefit from immunomodulatory therapies.
Assuntos
Infecções por Coronavirus/imunologia , Imunoterapia , Distúrbios do Metabolismo do Ferro/imunologia , Pneumonia Viral/imunologia , COVID-19 , Infecções por Coronavirus/fisiopatologia , Infecções por Coronavirus/terapia , Citocinas/imunologia , Ferritinas/sangue , Febre , Humanos , Inflamação , Pulmão/metabolismo , Pulmão/fisiopatologia , Pandemias , Pneumonia Viral/fisiopatologia , Pneumonia Viral/terapia , SíndromeAssuntos
Ferritinas , Distúrbios do Metabolismo do Ferro/imunologia , Ativação de Macrófagos/imunologia , Macrófagos/fisiologia , Doença de Still de Início Tardio/imunologia , Autoanticorpos , Autoimunidade , Ferritinas/sangue , Ferritinas/imunologia , Humanos , Tolerância Imunológica , Inflamação/imunologia , Mediadores da Inflamação/sangue , Distúrbios do Metabolismo do Ferro/fisiopatologia , SíndromeAssuntos
Antígenos CD/metabolismo , Antígenos de Diferenciação Mielomonocítica/metabolismo , Síndrome Antifosfolipídica/imunologia , Ferritinas , Distúrbios do Metabolismo do Ferro/imunologia , Ativação de Macrófagos/imunologia , Macrófagos/fisiologia , Receptores de Superfície Celular/metabolismo , Doença de Still de Início Tardio/imunologia , Antígenos de Diferenciação/metabolismo , Ferritinas/biossíntese , Ferritinas/sangue , Ferritinas/imunologia , Humanos , Inflamação/imunologia , Distúrbios do Metabolismo do Ferro/fisiopatologia , SíndromeAssuntos
Catarata/congênito , Dermatomiosite/sangue , Distúrbios do Metabolismo do Ferro/congênito , Doenças Pulmonares Intersticiais/sangue , Ativação de Macrófagos , Macrófagos/imunologia , Catarata/sangue , Catarata/diagnóstico , Catarata/imunologia , Dermatomiosite/complicações , Dermatomiosite/diagnóstico , Diagnóstico Diferencial , Evolução Fatal , Seguimentos , Humanos , Distúrbios do Metabolismo do Ferro/sangue , Distúrbios do Metabolismo do Ferro/diagnóstico , Distúrbios do Metabolismo do Ferro/imunologia , Doenças Pulmonares Intersticiais/complicações , Doenças Pulmonares Intersticiais/diagnóstico , Macrófagos/patologia , Masculino , Pessoa de Meia-IdadeAssuntos
Distúrbios do Metabolismo do Ferro/veterinária , Ferro/metabolismo , Perissodáctilos , Animais , Animais de Zoológico , Infecções Bacterianas/complicações , Infecções Bacterianas/veterinária , Eritrócitos , Eritropoese , Regulação da Expressão Gênica , Ferro/sangue , Distúrbios do Metabolismo do Ferro/genética , Distúrbios do Metabolismo do Ferro/imunologia , Proteínas Reguladoras de Ferro/genética , Proteínas Reguladoras de Ferro/metabolismo , Macrófagos/química , Macrófagos/fisiologia , Perissodáctilos/classificação , Perissodáctilos/genética , Fagocitose , Especificidade da EspécieRESUMO
Withdrawal of iron from serum (hypoferraemia) is a conserved innate immune antimicrobial strategy that can withhold this critical nutrient from invading pathogens, impairing their growth. Hepcidin (Hamp1) is the master regulator of iron and its expression is induced by inflammation. Mice lacking Hamp1 from birth rapidly accumulate iron and are susceptible to infection by blood-dwelling siderophilic bacteria such as Vibrio vulnificus. In order to study the innate immune role of hepcidin against a background of normal iron status, we developed a transgenic mouse model of tamoxifen-sensitive conditional Hamp1 deletion (termed iHamp1-KO mice). These mice attain adulthood with an iron status indistinguishable from littermate controls. Hamp1 disruption and the consequent decline of serum hepcidin concentrations occurred within hours of a single tamoxifen dose. We found that the TLR ligands LPS and Pam3CSK4 and heat-killed Brucella abortus caused an equivalent induction of inflammation in control and iHamp1-KO mice. Pam3CSK4 and B. abortus only caused a drop in serum iron in control mice, while hypoferraemia due to LPS was evident but substantially blunted in iHamp1-KO mice. Our results characterise a powerful new model of rapidly inducible hepcidin disruption, and demonstrate the critical contribution of hepcidin to the hypoferraemia of inflammation.
Assuntos
Brucella abortus/imunologia , Hepcidinas/metabolismo , Inflamação/imunologia , Distúrbios do Metabolismo do Ferro/imunologia , Animais , Antígenos de Bactérias/imunologia , Genótipo , Hepcidinas/genética , Humanos , Inflamação/microbiologia , Distúrbios do Metabolismo do Ferro/microbiologia , Lipopeptídeos/imunologia , Lipopolissacarídeos/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Modelos Animais , Receptores Toll-Like/metabolismoRESUMO
The defensin-like circulatory peptide hepcidin is the iron-regulatory hormone that links innate immunity and iron metabolism. In response to inflammatory stimuli, the liver produces hepcidin: this antimicrobial peptide then limits the iron that is vital to invading pathogens, by decreasing iron release/transfer from enterocytes and macrophages and causing secondary hypoferremia. This may lead, however, to reduced iron availability for erythropoiesis and therefore to anemia (and anemia of chronic disease). When iron is scarce, the rate at which it is released into the bloodstream must be enhanced: indeed, iron starvation and hypoxia readily abrogate hepcidin expression. Conversely, if excess iron enters the circulation, hepcidin transcription is turned on and iron release from the intestine and macrophages abrogated. Circumstantial evidence indicates that the effect of circulatory iron on hepcidin requires functional HFE and hemojuvelin, two proteins of unknown function that have recently been linked to human hereditary hemochromatosis. In this disease it is likely that inadequate levels of circulating hepcidin lead to the uncontrolled release of iron from the intestine and macrophages, followed by tissue iron overload and organ damage. Given its role as the iron-regulatory hormone, the modulation of hepcidin activity using agonists or antagonists might offer new treatment opportunities in different human iron-dependent disorders.
Assuntos
Peptídeos Catiônicos Antimicrobianos/fisiologia , Hemocromatose/metabolismo , Ferro/metabolismo , Peptídeos Catiônicos Antimicrobianos/imunologia , Hemocromatose/imunologia , Hemocromatose/fisiopatologia , Hepcidinas , Homeostase , Humanos , Ferro/imunologia , Distúrbios do Metabolismo do Ferro/imunologia , Distúrbios do Metabolismo do Ferro/metabolismo , Distúrbios do Metabolismo do Ferro/fisiopatologiaRESUMO
Experimental evidence in the last decades show that iron is a fundamental element for normal development of the immune system. Its deficiency affects the capacity to have an adequate immune response. The role of iron in immunity is necessary for immune cells proliferation and maturation, particularly lymphocytes, associated with the generation of a specific response to infection. The body has the capacity to reduce the iron availability to be consumed by infectious elements by proteins such as transferrin and lactoferrin. Also, iron is essential for the proliferation of bacteria, parasites, and neoplastic cells. Thus excess iron could potentially facilitate the development of infections and the invasion of tumoral cells. The immune system has bacteriostatic mechanisms that reduce the availability of the metal, interfering with bacterial growth. Additionally the system uses iron as the intermediary in the production of bacteriostatic cells.
Assuntos
Infecções/imunologia , Ferro/fisiologia , Animais , Formação de Anticorpos/fisiologia , Humanos , Imunidade Celular/fisiologia , Ferro/metabolismo , Deficiências de Ferro , Distúrbios do Metabolismo do Ferro/imunologiaRESUMO
Neonatal hemochromatosis is a rare disease that causes fetal loss and neonatal death in the 1st weeks of life and is one of the most common causes of liver failure in the neonate. The diagnosis is mostly made retrospectively, based on histopathologic features of severe liver fibrosis associated with hepatic and extrahepatic siderosis. Several etiologies may underlie this phenotype, including a recently hypothesized gestational alloimmune disease. Fifty-one cases of liver failure with intrahepatic siderosis in fetuses and neonates were analyzed retrospectively. Maternal and infant data were collected from hospitalization and autopsy reports. All available slides were reviewed independently by 3 pathologists. Immunologic studies were performed on maternal sera collected immediately after delivery. The diagnosis of neonatal haemochromatosis was retained in 33 cases, including 1 case with Down syndrome and 1 case with myofibromas. Liver siderosis was inversely proportional to fibrosis progression. In fetuses, iron storage was more frequent in the thyroid than in the pancreas. Perls staining in labial salivary glands was positive in 1 of 5 cases. Abnormal low signal intensity by magnetic resonance imaging was detected in the pancreas in 2 of 7 cases. Renal tubular dysgenesis was observed in 7 of 23 autopsy cases. Chronic villitis was seen in 7 of 15 placentas. Half of the mothers presented with an autoimmune background and/or autoantibodies in their sera. Our work highlights the importance of autopsy in cases of neonatal hemochromatosis and marshals additional data in support of the hypothesis that neonatal hemochromatosis could reflect maternal immune system dysregulation.