Publications by authors named "Miguel P Soares"

82 Publications

Donor-Derived Myeloid Heme Oxygenase-1 Controls the Development of Graft-Versus-Host Disease.

Front Immunol 2020 18;11:579151. Epub 2021 Jan 18.

Institute for Medical Immunology, Université Libre de Bruxelles, Gosselies, Belgium.

Graft-versus-host disease (GVHD) remains a major clinical drawback of allogeneic hematopoietic stem cell transplantation (HSCT). Here, we investigated how the stress responsive heme catabolizing enzyme heme oxygenase-1 (HO-1, encoded by ) regulates GVHD in response to allogeneic hematopoietic stem cell transplantation in mice and humans. We found that deletion of the allele, specifically in the myeloid compartment of mouse donor bone marrow, promotes the development of aggressive GVHD after allogeneic transplantation. The mechanism driving GVHD in mice transplanted with allogeneic bone marrow lacking HO-1 expression in the myeloid compartment involves enhanced T cell alloreactivity. The clinical relevance of these observations was validated in two independent cohorts of HSCT patients. Individuals transplanted with hematopoietic stem cells from donors carrying a long homozygous (GT) repeat polymorphism (L/L) in the promoter, which is associated with lower HO-1 expression, were at higher risk of developing severe acute GVHD as compared to donors carrying a short (GT) repeat (S/L or S/S) polymorphism associated with higher HO-1 expression. In this study, we showed the unique importance of donor-derived myeloid HO-1 in the prevention of lethal experimental GVHD and we corroborated this observation by demonstrating the association between human (GT) microsatellite polymorphisms and the incidence of severe acute GVHD in two independent HSCT patient cohorts. Donor-derived myeloid HO-1 constitutes a potential therapeutic target for HSCT patients and large-scale prospective studies in HSCT patients are necessary to validate the HO-1 L/L genotype as an independent risk factor for developing severe acute GVHD.
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http://dx.doi.org/10.3389/fimmu.2020.579151DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7849683PMC
January 2021

Loss of α-gal during primate evolution enhanced antibody-effector function and resistance to bacterial sepsis.

Cell Host Microbe 2021 03 25;29(3):347-361.e12. Epub 2021 Jan 25.

Instituto Gulbenkian de Ciência, 2780-156 Oeiras, Portugal. Electronic address:

Most mammals express a functional GGTA1 gene encoding the N-acetyllactosaminide α-1,3-galactosyltransferase enzyme, which synthesizes Gal-α1-3Gal-β1-4GlcNAc (α-gal) and are thus tolerant to this self-expressed glycan. Old World primates including humans, however, carry loss-of-function mutations in GGTA1 and lack α-gal. Presumably, fixation of such mutations was propelled by natural selection, favoring the emergence of α-gal-specific immunity, conferring resistance to α-gal-expressing pathogens. Here, we show that loss of Ggta1 function in mice enhances resistance to bacterial sepsis, irrespectively of α-Gal-specific immunity. Rather, the absence of α-gal from IgG-associated glycans increases IgG effector function via a mechanism associated with enhanced IgG-Fc gamma receptor (FcγR) binding. The ensuing survival advantage against sepsis comes alongside a cost of accelerated reproductive senescence in Ggta1-deleted mice. Mathematical modeling of this trade-off suggests that high exposure to virulent pathogens exerts sufficient selective pressure to fix GGTA1 loss-of-function mutations, as likely occurred during the evolution of primates toward humans.
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http://dx.doi.org/10.1016/j.chom.2020.12.017DOI Listing
March 2021

M. tuberculosis Reprograms Hematopoietic Stem Cells to Limit Myelopoiesis and Impair Trained Immunity.

Cell 2020 Oct;183(3):752-770.e22

Meakins-Christie Laboratories, Department of Medicine, Department of Microbiology and Immunology, Department of Pathology, McGill University, Montreal, QC, Canada; McGill International TB Centre, McGill University Health Centre, Montreal, QC, Canada. Electronic address:

A greater understanding of hematopoietic stem cell (HSC) regulation is required for dissecting protective versus detrimental immunity to pathogens that cause chronic infections such as Mycobacterium tuberculosis (Mtb). We have shown that systemic administration of Bacille Calmette-Guérin (BCG) or β-glucan reprograms HSCs in the bone marrow (BM) via a type II interferon (IFN-II) or interleukin-1 (IL1) response, respectively, which confers protective trained immunity against Mtb. Here, we demonstrate that, unlike BCG or β-glucan, Mtb reprograms HSCs via an IFN-I response that suppresses myelopoiesis and impairs development of protective trained immunity to Mtb. Mechanistically, IFN-I signaling dysregulates iron metabolism, depolarizes mitochondrial membrane potential, and induces cell death specifically in myeloid progenitors. Additionally, activation of the IFN-I/iron axis in HSCs impairs trained immunity to Mtb infection. These results identify an unanticipated immune evasion strategy of Mtb in the BM that controls the magnitude and intrinsic anti-microbial capacity of innate immunity to infection.
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http://dx.doi.org/10.1016/j.cell.2020.09.062DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7599081PMC
October 2020

Heme Oxygenase-1 Induction by Blood-Feeding Arthropods Controls Skin Inflammation and Promotes Disease Tolerance.

Cell Rep 2020 10;33(4):108317

Vector Molecular Biology Section, Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20852, USA. Electronic address:

Hematophagous vectors lacerate host skin and capillaries to acquire a blood meal, resulting in leakage of red blood cells (RBCs) and inflammation. Here, we show that heme oxygenase-1 (HO-1), a pleiotropic cytoprotective isoenzyme that mitigates heme-mediated tissue damage, is induced after bites of sand flies, mosquitoes, and ticks. Further, we demonstrate that erythrophagocytosis by macrophages, including a skin-residing CD163CD91 professional iron-recycling subpopulation, produces HO-1 after bites. Importantly, we establish that global deletion or transient inhibition of HO-1 in mice increases inflammation and pathology following Leishmania-infected sand fly bites without affecting parasite number, whereas CO, an end product of the HO-1 enzymatic reaction, suppresses skin inflammation. This indicates that HO-1 induction by blood-feeding sand flies promotes tolerance to Leishmania infection. Collectively, our data demonstrate that HO-1 induction through erythrophagocytosis is a universal mechanism that regulates skin inflammation following blood feeding by arthropods, thus promoting early-stage disease tolerance to vector-borne pathogens.
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http://dx.doi.org/10.1016/j.celrep.2020.108317DOI Listing
October 2020

Interleukin-1 promotes autoimmune neuroinflammation by suppressing endothelial heme oxygenase-1 at the blood-brain barrier.

Acta Neuropathol 2020 10 11;140(4):549-567. Epub 2020 Jul 11.

Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany.

The proinflammatory cytokine interleukin 1 (IL-1) is crucially involved in the pathogenesis of multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis (EAE). Herein, we studied the role of IL-1 signaling in blood-brain barrier (BBB) endothelial cells (ECs), astrocytes and microglia for EAE development, using mice with the conditional deletion of its signaling receptor IL-1R1. We found that IL-1 signaling in microglia and astrocytes is redundant for the development of EAE, whereas the IL-1R1 deletion in BBB-ECs markedly ameliorated disease severity. IL-1 signaling in BBB-ECs upregulated the expression of the adhesion molecules Vcam-1, Icam-1 and the chemokine receptor Darc, all of which have been previously shown to promote CNS-specific inflammation. In contrast, IL-1R1 signaling suppressed the expression of the stress-responsive heme catabolizing enzyme heme oxygenase-1 (HO-1) in BBB-ECs, promoting disease progression via a mechanism associated with deregulated expression of the IL-1-responsive genes Vcam1, Icam1 and Ackr1 (Darc). Mechanistically, our data emphasize a functional crosstalk of BBB-EC IL-1 signaling and HO-1, controlling the transcription of downstream proinflammatory genes promoting the pathogenesis of autoimmune neuroinflammation.
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http://dx.doi.org/10.1007/s00401-020-02187-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7498485PMC
October 2020

Labile heme impairs hepatic microcirculation and promotes hepatic injury.

Arch Biochem Biophys 2019 09 11;672:108075. Epub 2019 Aug 11.

Department of Anesthesiology and Intensive Care Medicine, Jena University Hospital, Germany; Center for Sepsis Control and Care, Jena University Hospital, Germany; Institute for Infectious Disease and Infection Control, Jena University Hospital, Germany. Electronic address:

Sepsis is a life-threatening clinical syndrome defined as a deregulated host response to infection associated with organ dysfunction. Mechanisms underlying the pathophysiology of septic liver dysfunction are incompletely understood. Among others, the iron containing tetrapyrrole heme inflicts hepatic damage when released into the circulation during systemic inflammation and sepsis. Accordingly, hemolysis and decreased concentrations of heme-scavenging proteins coincide with an unfavorable outcome of critically ill patients. As the liver is a key organ in heme metabolism and host response to infection, we investigated the impact of labile heme on sinusoidal microcirculation and hepatocellular integrity. We here provide experimental evidence that heme increases portal pressure via a mechanism that involves hepatic stellate cell-mediated sinusoidal constriction, a hallmark of microcirculatory failure under stress conditions. Moreover, heme exerts direct cytotoxicity in vitro and aggravates tissue damage in a model of polymicrobial sepsis. Heme binding by albumin, a low-affinity but high-capacity heme scavenger, attenuates heme-mediated vasoconstriction in vivo and prevents heme-mediated cytotoxicity in vitro. We demonstrate that fractions of serum albumin-bound labile heme are increased in septic patients. We propose that heme scavenging might be used therapeutically to maintain hepatic microcirculation and organ function in sepsis.
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http://dx.doi.org/10.1016/j.abb.2019.108075DOI Listing
September 2019

Ferritin regulates organismal energy balance and thermogenesis.

Mol Metab 2019 06 21;24:64-79. Epub 2019 Mar 21.

Instituto Gulbenkian de Ciência, Oeiras, Portugal. Electronic address:

Objective: The ferritin heavy/heart chain (FTH) gene encodes the ferroxidase component of the iron (Fe) sequestering ferritin complex, which plays a central role in the regulation of cellular Fe metabolism. Here we tested the hypothesis that ferritin regulates organismal Fe metabolism in a manner that impacts energy balance and thermal homeostasis.

Methods: We developed a mouse strain, referred herein as Fth, expressing a tamoxifen-inducible Cre recombinase under the control of the Rosa26 (R26) promoter and carrying two LoxP (fl) sites: one at the 5'end of the Fth promoter and another the 3' end of the first Fth exon. Tamoxifen administration induces global deletion of Fth in adult Fth mice, testing whether FTH is required for maintenance of organismal homeostasis.

Results: Under standard nutritional Fe supply, Fth deletion in adult Fth mice led to a profound deregulation of organismal Fe metabolism, oxidative stress, inflammation, and multi-organ damage, culminating in death. Unexpectedly, Fth deletion was also associated with a profound atrophy of white and brown adipose tissue as well as with collapse of energy expenditure and thermogenesis. This was attributed mechanistically to mitochondrial dysfunction, as assessed in the liver and in adipose tissue.

Conclusion: The FTH component of ferritin acts as a master regulator of organismal Fe homeostasis, coupling nutritional Fe supply to organismal redox homeostasis, energy expenditure and thermoregulation.
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http://dx.doi.org/10.1016/j.molmet.2019.03.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6531837PMC
June 2019

Renal control of disease tolerance to malaria.

Proc Natl Acad Sci U S A 2019 03 4;116(12):5681-5686. Epub 2019 Mar 4.

Instituto Gulbenkian de Ciência, 2780-156 Oeiras, Portugal;

Malaria, the disease caused by spp. infection, remains a major global cause of morbidity and mortality. Host protection from malaria relies on immune-driven resistance mechanisms that kill However, these mechanisms are not sufficient per se to avoid the development of severe forms of disease. This is accomplished instead via the establishment of disease tolerance to malaria, a defense strategy that does not target directly. Here we demonstrate that the establishment of disease tolerance to malaria relies on a tissue damage-control mechanism that operates specifically in renal proximal tubule epithelial cells (RPTEC). This protective response relies on the induction of heme oxygenase-1 (; HO-1) and ferritin H chain () via a mechanism that involves the transcription-factor nuclear-factor E2-related factor-2 (). As it accumulates in plasma and urine during the blood stage of infection, labile heme is detoxified in RPTEC by HO-1 and FTH, preventing the development of acute kidney injury, a clinical hallmark of severe malaria.
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http://dx.doi.org/10.1073/pnas.1822024116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6431151PMC
March 2019

Disease Tolerance as an Inherent Component of Immunity.

Annu Rev Immunol 2019 04 23;37:405-437. Epub 2019 Jan 23.

Instituto Gulbenkian de Ciência, 2780-156 Oeiras, Portugal; email:

Pathogenic organisms exert a negative impact on host health, revealed by the clinical signs of infectious diseases. Immunity limits the severity of infectious diseases through resistance mechanisms that sense and target pathogens for containment, killing, or expulsion. These resistance mechanisms are viewed as the prevailing function of immunity. Under pathophysiologic conditions, however, immunity arises in response to infections that carry health and fitness costs to the host. Therefore, additional defense mechanisms are required to limit these costs, before immunity becomes operational as well as thereafter to avoid immunopathology. These are tissue damage control mechanisms that adjust the metabolic output of host tissues to different forms of stress and damage associated with infection. Disease tolerance is the term used to define this defense strategy, which does not exert a direct impact on pathogens but is essential to limit the health and fitness costs of infection. Under this argument, we propose that disease tolerance is an inherent component of immunity.
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http://dx.doi.org/10.1146/annurev-immunol-042718-041739DOI Listing
April 2019

Cross-Talk Between Iron and Glucose Metabolism in the Establishment of Disease Tolerance.

Front Immunol 2018 30;9:2498. Epub 2018 Oct 30.

Instituto Gulbenkian de Ciência, Oeiras, Portugal.

Infectious diseases are associated with disruption of host homeostasis. This can be triggered directly by pathogens or indirectly by host immune-driven resistance mechanisms. Disease tolerance is a defense strategy against infection that sustains host homeostasis, without exerting a direct negative impact on pathogens. The mechanisms governing disease tolerance encompass host metabolic responses that maintain vital homeostatic parameters within a range compatible with survival. Central to this defense strategy is the host's ability to sense and adapt to variations in nutrients, such as iron and glucose. Here we address how host responses regulating iron and glucose metabolism interact to establish disease tolerance and possibly modulate resistance to infection.
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http://dx.doi.org/10.3389/fimmu.2018.02498DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6218924PMC
September 2019

Innate Nutritional Immunity.

J Immunol 2018 07;201(1):11-18

Instituto Gulbenkian de Ciência, 2780-156 Oeiras, Portugal.

Iron (Fe) is an essential micronutrient for both microbes and their hosts. The biologic importance of Fe derives from its inherent ability to act as a universal redox catalyst, co-opted in a variety of biochemical processes critical to maintain life. Animals evolved several mechanisms to retain and limit Fe availability to pathogenic microbes, a resistance mechanism termed "nutritional immunity." Likewise, pathogenic microbes coevolved to deploy diverse and efficient mechanisms to acquire Fe from their hosts and in doing so overcome nutritional immunity. In this review, we discuss how the innate immune system regulates Fe metabolism to withhold Fe from pathogenic microbes and how strategies used by pathogens to acquire Fe circumvent these resistance mechanisms.
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http://dx.doi.org/10.4049/jimmunol.1800325DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6028930PMC
July 2018

Ferritin H Deficiency in Myeloid Compartments Dysregulates Host Energy Metabolism and Increases Susceptibility to Infection.

Front Immunol 2018 3;9:860. Epub 2018 May 3.

Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL, United States.

Iron is an essential factor for the growth and virulence of (. However, little is known about the mechanisms by which the host controls iron availability during infection. Since ferritin heavy chain (FtH) is a major intracellular source of reserve iron in the host, we hypothesized that the lack of FtH would cause dysregulated iron homeostasis to exacerbate TB disease. Therefore, we used knockout mice lacking FtH in myeloid-derived cell populations to study disease progression. We found that FtH plays a critical role in protecting mice against , as evidenced by increased organ burden, extrapulmonary dissemination, and decreased survival in mice. Flow cytometry analysis showed that reduced levels of FtH contribute to an excessive inflammatory response to exacerbate disease. Extracellular flux analysis showed that FtH is essential for maintaining bioenergetic homeostasis through oxidative phosphorylation. In support of these findings, RNAseq and mass spectrometry analyses demonstrated an essential role for FtH in mitochondrial function and maintenance of central intermediary metabolism . Further, we show that FtH deficiency leads to iron dysregulation through the hepcidin-ferroportin axis during infection. To assess the clinical significance of our animal studies, we performed a clinicopathological analysis of iron distribution within human TB lung tissue and showed that severely disrupts iron homeostasis in distinct microanatomic locations of the human lung. We identified hemorrhage as a major source of metabolically inert iron deposition. Importantly, we observed increased iron levels in human TB lung tissue compared to healthy tissue. Overall, these findings advance our understanding of the link between iron-dependent energy metabolism and immunity and provide new insight into iron distribution within the spectrum of human pulmonary TB. These metabolic mechanisms could serve as the foundation for novel host-directed strategies.
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http://dx.doi.org/10.3389/fimmu.2018.00860DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5943674PMC
July 2019

Electrophilic properties of itaconate and derivatives regulate the IκBζ-ATF3 inflammatory axis.

Nature 2018 04 18;556(7702):501-504. Epub 2018 Apr 18.

Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA.

Metabolic regulation has been recognized as a powerful principle guiding immune responses. Inflammatory macrophages undergo extensive metabolic rewiring marked by the production of substantial amounts of itaconate, which has recently been described as an immunoregulatory metabolite . Itaconate and its membrane-permeable derivative dimethyl itaconate (DI) selectively inhibit a subset of cytokines , including IL-6 and IL-12 but not TNF. The major effects of itaconate on cellular metabolism during macrophage activation have been attributed to the inhibition of succinate dehydrogenase, yet this inhibition alone is not sufficient to account for the pronounced immunoregulatory effects observed in the case of DI. Furthermore, the regulatory pathway responsible for such selective effects of itaconate and DI on the inflammatory program has not been defined. Here we show that itaconate and DI induce electrophilic stress, react with glutathione and subsequently induce both Nrf2 (also known as NFE2L2)-dependent and -independent responses. We find that electrophilic stress can selectively regulate secondary, but not primary, transcriptional responses to toll-like receptor stimulation via inhibition of IκBζ protein induction. The regulation of IκBζ is independent of Nrf2, and we identify ATF3 as its key mediator. The inhibitory effect is conserved across species and cell types, and the in vivo administration of DI can ameliorate IL-17-IκBζ-driven skin pathology in a mouse model of psoriasis, highlighting the therapeutic potential of this regulatory pathway. Our results demonstrate that targeting the DI-IκBζ regulatory axis could be an important new strategy for the treatment of IL-17-IκBζ-mediated autoimmune diseases.
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http://dx.doi.org/10.1038/s41586-018-0052-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6037913PMC
April 2018

Cross-Regulation of Iron and Glucose Metabolism in Response to Infection.

Biochemistry 2017 10 20;56(43):5713-5714. Epub 2017 Oct 20.

Instituto Gulbenkian de Ciência , Oeiras, Portugal.

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http://dx.doi.org/10.1021/acs.biochem.7b00728DOI Listing
October 2017

Characterization of plasma labile heme in hemolytic conditions.

FEBS J 2017 10 11;284(19):3278-3301. Epub 2017 Sep 11.

Instituto Gulbenkian da Ciência, Oeiras, Portugal.

Extracellular hemoglobin, a byproduct of hemolysis, can release its prosthetic heme groups upon oxidation. This produces metabolically active heme that is exchangeable between acceptor proteins, macromolecules and low molecular weight ligands, termed here labile heme. As it accumulates in plasma labile heme acts in a pro-oxidant manner and regulates cellular metabolism while exerting pro-inflammatory and cytotoxic effects that foster the pathogenesis of hemolytic diseases. Here, we developed and characterized a panel of heme-specific single domain antibodies (sdAbs) that together with a cellular-based heme reporter assay, allow for quantification and characterization of labile heme in plasma during hemolytic conditions. Using these approaches, we demonstrate that when generated during hemolytic conditions labile heme is bound to plasma molecules with an affinity higher than 10 m and that 2-8% (~ 2-5 μm) of the total amount of heme detected in plasma can be internalized by bystander cells, termed here bioavailable heme. Acute, but not chronic, hemolysis is associated with transient reduction of plasma heme-binding capacity, that is, the ability of plasma molecules to bind labile heme with an affinity higher than 10 m. The heme-specific sdAbs neutralize the pro-oxidant activity of soluble heme in vitro, suggesting that these maybe used to counter the pathologic effects of labile heme during hemolytic conditions. Finally, we show that heme-specific sdAbs can be used to visualize cellular heme. In conclusion, we describe a panel of heme-specific sdAbs that when used with other approaches provide novel insights to the pathophysiology of heme.
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http://dx.doi.org/10.1111/febs.14192DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5978748PMC
October 2017

Involvement of the p62/NRF2 signal transduction pathway on erythrophagocytosis.

Sci Rep 2017 07 19;7(1):5812. Epub 2017 Jul 19.

CEDOC, NOVA Medical School|Faculdade de Ciências Médicas, Universidade NOVA de Lisboa, 1169-056, Lisboa, Portugal.

Erythrophagocytosis, the phagocytic removal of damaged red blood cells (RBC), and subsequent phagolysosome biogenesis are important processes in iron/heme metabolism and homeostasis. Phagolysosome biogenesis implies the interaction of nascent phagosomes with endocytic compartments and also autophagy effectors. Here, we report that besides recruitment of microtubule-associated protein-1-light chain 3 (LC3), additional autophagy machinery such as sequestosome 1 (p62) is also acquired by single-membrane phagosomes at very early stages of the phagocytic process and that its acquisition is very important to the outcome of the process. In bone marrow-derived macrophages (BMDM) silenced for p62, RBC degradation is inhibited. P62, is also required for nuclear translocation and activation of the transcription factor Nuclear factor E2-related Factor 2 (NRF2) during erythrophagocytosis. Deletion of the Nrf2 allele reduces p62 expression and compromises RBC degradation. In conclusion, we reveal that erythrophagocytosis relies on an interplay between p62 and NRF2, potentially acting as protective mechanism to maintain reactive oxygen species at basal levels and preserve macrophage homeostasis.
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http://dx.doi.org/10.1038/s41598-017-05687-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5517431PMC
July 2017

Metabolic Adaptation Establishes Disease Tolerance to Sepsis.

Cell 2017 Jun;169(7):1263-1275.e14

Instituto Gulbenkian de Ciência, 2780-156 Oeiras, Portugal. Electronic address:

Sepsis is an often lethal syndrome resulting from maladaptive immune and metabolic responses to infection, compromising host homeostasis. Disease tolerance is a defense strategy against infection that preserves host homeostasis without exerting a direct negative impact on pathogens. Here, we demonstrate that induction of the iron-sequestering ferritin H chain (FTH) in response to polymicrobial infections is critical to establish disease tolerance to sepsis. The protective effect of FTH is exerted via a mechanism that counters iron-driven oxidative inhibition of the liver glucose-6-phosphatase (G6Pase), and in doing so, sustains endogenous glucose production via liver gluconeogenesis. This is required to prevent the development of hypoglycemia that otherwise compromises disease tolerance to sepsis. FTH overexpression or ferritin administration establish disease tolerance therapeutically. In conclusion, disease tolerance to sepsis relies on a crosstalk between adaptive responses controlling iron and glucose metabolism, required to maintain blood glucose within a physiologic range compatible with host survival.
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http://dx.doi.org/10.1016/j.cell.2017.05.031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5480394PMC
June 2017

Specific expression of heme oxygenase-1 by myeloid cells modulates renal ischemia-reperfusion injury.

Sci Rep 2017 03 15;7(1):197. Epub 2017 Mar 15.

Institute for Medical Immunology (IMI), Université Libre de Bruxelles, Gosselies, Belgium.

Renal ischemia-reperfusion injury (IRI) is a major risk factor for delayed graft function in renal transplantation. Compelling evidence exists that the stress-responsive enzyme, heme oxygenase-1 (HO-1) mediates protection against IRI. However, the role of myeloid HO-1 during IRI remains poorly characterized. Mice with myeloid-restricted deletion of HO-1 (HO-1), littermate (LT), and wild-type (WT) mice were subjected to renal IRI or sham procedures and sacrificed after 24 hours or 7 days. In comparison to LT, HO-1 exhibited significant renal histological damage, pro-inflammatory responses and oxidative stress 24 hours after reperfusion. HO-1 mice also displayed impaired tubular repair and increased renal fibrosis 7 days after IRI. In WT mice, HO-1 induction with hemin specifically upregulated HO-1 within the CD11b F4/80 subset of the renal myeloid cells. Prior administration of hemin to renal IRI was associated with significant increase of the renal HO-1 CD11b F4/80 myeloid cells in comparison to control mice. In contrast, this hemin-mediated protection was abolished in HO-1 mice. In conclusion, myeloid HO-1 appears as a critical protective pathway against renal IRI and could be an interesting therapeutic target in renal transplantation.
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http://dx.doi.org/10.1038/s41598-017-00220-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5428056PMC
March 2017

IL-22 Controls Iron-Dependent Nutritional Immunity Against Systemic Bacterial Infections.

Sci Immunol 2017 Feb 3;2(8). Epub 2017 Feb 3.

Department of Pathology and Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, MI 48109, USA.

Host immunity limits iron availability to pathogenic bacteria, but whether immunity limits pathogenic bacteria from accessing host heme, the major source of iron in the body, remains unclear. Using , a mouse enteric pathogen and , a major cause of sepsis in humans as models, we find that interleukin-22, a cytokine best known for its ability to promote epithelial barrier function, also suppresses the systemic growth of bacteria by limiting iron availability to the pathogen. Using an unbiased proteomic approach to understand the mechanistic basis of IL-22 dependent iron retention in the host, we have identified that IL-22 induces the production of the plasma hemoglobin scavenger haptoglobin and heme scavenger hemopexin. Moreover, the anti-microbial effect of IL-22 depends on the induction of hemopexin expression, while haptogloblin is dispensable. Impaired pathogen clearance in infected mice was restored by hemopexin administration and hemopexin-deficient mice had increased pathogen loads after infection. These studies reveal a previously unrecognized host defense mechanism regulated by IL-22 that relies on the induction of hemopexin to limit heme availability to bacteria leading to suppression of bacterial growth during systemic infections.
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http://dx.doi.org/10.1126/sciimmunol.aai8371DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5345941PMC
February 2017

Disease tolerance and immunity in host protection against infection.

Nat Rev Immunol 2017 02 3;17(2):83-96. Epub 2017 Jan 3.

Instituto Gulbenkian de Ciência, Rua da Quinta Grande, 6, 2780-156 Oeiras, Portugal.

The immune system probably evolved to limit the negative effects exerted by pathogens on host homeostasis. This defence strategy relies on the concerted action of innate and adaptive components of the immune system, which sense and target pathogens for containment, destruction or expulsion. Resistance to infection refers to these immune functions, which reduce the pathogen load of an infected host as the means to preserve homeostasis. Immune-driven resistance to infection is coupled to an additional, and arguably as important, defence strategy that limits the extent of dysfunction imposed on host parenchymal tissues during infection, without exerting a direct negative effect on pathogens. This defence strategy, known as disease tolerance, relies on tissue damage control mechanisms that prevent the deleterious effects of pathogens and that uncouples immune-driven resistance mechanisms from immunopathology and disease. In this Review, we provide a unifying view of resistance and disease tolerance in the framework of immunity to infection.
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http://dx.doi.org/10.1038/nri.2016.136DOI Listing
February 2017

Identification of cyclins A1, E1 and vimentin as downstream targets of heme oxygenase-1 in vascular endothelial growth factor-mediated angiogenesis.

Sci Rep 2016 07 8;6:29417. Epub 2016 Jul 8.

Vascular Sciences, Imperial Centre for Translational and Experimental Medicine, National Heart and Lung Institute, Imperial College London, Hammersmith Hospital, London, UK.

Angiogenesis is an essential physiological process and an important factor in disease pathogenesis. However, its exploitation as a clinical target has achieved limited success and novel molecular targets are required. Although heme oxygenase-1 (HO-1) acts downstream of vascular endothelial growth factor (VEGF) to modulate angiogenesis, knowledge of the mechanisms involved remains limited. We set out identify novel HO-1 targets involved in angiogenesis. HO-1 depletion attenuated VEGF-induced human endothelial cell (EC) proliferation and tube formation. The latter response suggested a role for HO-1 in EC migration, and indeed HO-1 siRNA negatively affected directional migration of EC towards VEGF; a phenotype reversed by HO-1 over-expression. EC from Hmox1(-/-) mice behaved similarly. Microarray analysis of HO-1-depleted and control EC exposed to VEGF identified cyclins A1 and E1 as HO-1 targets. Migrating HO-1-deficient EC showed increased p27, reduced cyclin A1 and attenuated cyclin-dependent kinase 2 activity. In vivo, cyclin A1 siRNA inhibited VEGF-driven angiogenesis, a response reversed by Ad-HO-1. Proteomics identified structural protein vimentin as an additional VEGF-HO-1 target. HO-1 depletion inhibited VEGF-induced calpain activity and vimentin cleavage, while vimentin silencing attenuated HO-1-driven proliferation. Thus, vimentin and cyclins A1 and E1 represent VEGF-activated HO-1-dependent targets important for VEGF-driven angiogenesis.
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http://dx.doi.org/10.1038/srep29417DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4937390PMC
July 2016

Beyond killing: Can we find new ways to manage infection?

Evol Med Public Health 2016 18;2016(1):148-57. Epub 2016 Apr 18.

Department of Plant and Microbial Biology, University of Zürich, Switzerland.

The antibiotic pipeline is running dry and infectious disease remains a major threat to public health. An efficient strategy to stay ahead of rapidly adapting pathogens should include approaches that replace, complement or enhance the effect of both current and novel antimicrobial compounds. In recent years, a number of innovative approaches to manage disease without the aid of traditional antibiotics and without eliminating the pathogens directly have emerged. These include disabling pathogen virulence-factors, increasing host tissue damage control or altering the microbiota to provide colonization resistance, immune resistance or disease tolerance against pathogens. We discuss the therapeutic potential of these approaches and examine their possible consequences for pathogen evolution. To guarantee a longer half-life of these alternatives to directly killing pathogens, and to gain a full understanding of their population-level consequences, we encourage future work to incorporate evolutionary perspectives into the development of these treatments.
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http://dx.doi.org/10.1093/emph/eow012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4834974PMC
April 2016

Macrophages and Iron Metabolism.

Immunity 2016 Mar;44(3):492-504

Department of Animal & Avian Sciences and Department of Cell Biology & Molecular Genetics, University of Maryland, College Park, MD 20742, USA.

Iron is a transition metal that due to its inherent ability to exchange electrons with a variety of molecules is essential to support life. In mammals, iron exists mostly in the form of heme, enclosed within an organic protoporphyrin ring and functioning primarily as a prosthetic group in proteins. Paradoxically, free iron also has the potential to become cytotoxic when electron exchange with oxygen is unrestricted and catalyzes the production of reactive oxygen species. These biological properties demand that iron metabolism is tightly regulated such that iron is available for core biological functions while preventing its cytotoxic effects. Macrophages play a central role in establishing this delicate balance. Here, we review the impact of macrophages on heme-iron metabolism and, reciprocally, how heme-iron modulates macrophage function.
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http://dx.doi.org/10.1016/j.immuni.2016.02.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4794998PMC
March 2016

Heme oxygenase 1 controls early innate immune response of macrophages to Salmonella Typhimurium infection.

Cell Microbiol 2016 10 18;18(10):1374-89. Epub 2016 Mar 18.

Department of Internal Medicine VI, Infectious Diseases, Immunology, Rheumatology, Pneumology, Medical University of Innsbruck, 6020, Innsbruck, Austria.

Macrophages are central for the immune control of intracellular microbes. Heme oxygenase 1 (HO-1, hmox) is the first and rate limiting enzyme in the breakdown of heme originating from degraded senescent erythrocytes and heme-proteins, yielding equal amounts of iron, carbon monoxide and biliverdin. HO-1 is strongly up-regulated in macrophages in response to inflammatory signals, including bacterial endotoxin. In view of the essential role of iron for the growth and proliferation of intracellular bacteria along with known effects of the metal on innate immune function, we examined whether HO-1 plays a role in the control of infection with the intracellular bacterium Salmonella Typhimurium. We studied the course of infection in stably-transfected murine macrophages (RAW264.7) bearing a tetracycline-inducible plasmid producing hmox shRNA and in primary HO-1 knockout macrophages. While uptake of bacteria into macrophages was not affected, a significantly reduced survival of intracellular Salmonella was observed upon hmox knockdown or pharmacological hmox inhibition, which was independent of Nramp1 functionality. This could be traced to limitation of iron availability for intramacrophage bacteria along with enhanced stimulation of innate immune effector pathways, including the formation of reactive oxygen and nitrogen species and increased TNF-α expression. Mechanistically, these latter effects result from intracellular iron limitation with subsequent activation of NF-κB and further inos, tnfa and p47phox transcription along with reduced formation of the anti-inflammatory and radical scavenging molecules, CO and biliverdin as a consequence of HO-1 silencing. Taken together our data provide novel evidence that the infection-driven induction of HO-1 exerts detrimental effects in the early control of Salmonella infection, whereas hmox inhibition can favourably modulate anti-bacterial immune effector pathways of macrophages and promote bacterial elimination.
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http://dx.doi.org/10.1111/cmi.12578DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6557132PMC
October 2016

Microbiota Control of Malaria Transmission.

Trends Parasitol 2016 Feb 13;32(2):120-130. Epub 2016 Jan 13.

Instituto Gulbenkian de Ciência, Rua da Quinta Grande, 6, 2780-156, Oeiras, Portugal; Current address: Maurice Müller Laboratories (DKF), Universitätsklinik für Viszerale Chirurgie und Medizin Inselspital, Murtenstrasse 35, University of Bern, 3010 Bern, Switzerland. Electronic address:

Stable mutualistic interactions between multicellular organisms and microbes are an evolutionarily conserved process with a major impact on host physiology and fitness. Humans establish such interactions with a consortium of microorganisms known as the microbiota. Despite the mutualistic nature of these interactions, some bacterial components of the human microbiota express immunogenic glycans that elicit glycan-specific antibody (Ab) responses. The ensuing circulating Abs are protective against infections by pathogens that express those glycans, as demonstrated for Plasmodium, the causative agent of malaria. Presumably, a similar protective Ab response acts against other vector-borne diseases.
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http://dx.doi.org/10.1016/j.pt.2015.11.004DOI Listing
February 2016

Red alert: labile heme is an alarmin.

Curr Opin Immunol 2016 Feb 29;38:94-100. Epub 2015 Dec 29.

Universidade Federal do Rio de Janeiro, Av. Carlos Chagas Filho 373, Cidade Universitária, 21941-902 Rio de Janeiro, Brazil. Electronic address:

Alarmins are a heterogeneous group of endogenous molecules that signal cellular damage when sensed extracellularly. Heme is an endogenous molecule that acts as a prosthetic group of hemoproteins, such as hemoglobin and myoglobin. When released from damaged red blood cells or muscle cells, oxidized hemoglobin and myoglobin release their prosthetic heme groups, respectively. This generates labile heme, which is sensed by pattern recognition receptors (PRR) expressed by innate immune cells and possibly regulatory T cells (TREG). The ensuing adaptive response, which alerts for the occurrence of red blood cell or muscle cell damage, regulates the pathologic outcome of hemolysis or rhabdomyolysis, respectively. In conclusion, we propose that labile heme is an alarmin.
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http://dx.doi.org/10.1016/j.coi.2015.11.006DOI Listing
February 2016

Microbiota's No Wasting Policy.

Authors:
Miguel P Soares

Cell 2015 Nov;163(5):1057-1058

Instituto Gulbenkian de Ciência, Rua da Quinta Grande 6, 2780-156 Oeiras, Portugal. Electronic address:

Schieber et al. demonstrate that a specific gut microbiota bacterial strain induces a host-mediated protection mechanism against inflammation-driven wasting syndrome. This salutary effect confers a net survival advantage against bacterial infection, without interfering with the host's pathogen load, revealing that host-microbiota interactions regulate disease tolerance to infection.
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http://dx.doi.org/10.1016/j.cell.2015.10.077DOI Listing
November 2015

Nrf2 as a master regulator of tissue damage control and disease tolerance to infection.

Biochem Soc Trans 2015 Aug 3;43(4):663-8. Epub 2015 Aug 3.

Instituto Gulbenkian de Ciência, Rua da Quinta Grande, 62, 6, 2780-156 Oeiras, Portugal.

Damage control refers to those actions made towards minimizing damage or loss. Depending on the context, these can range from emergency procedures dealing with the sinking of a ship or to a surgery dealing with severe trauma or even to an imaginary company in Marvel comics, which repairs damaged property arising from conflicts between super heroes and villains. In the context of host microbe interactions, tissue damage control refers to an adaptive response that limits the extent of tissue damage associated with infection. Tissue damage control can limit the severity of infectious diseases without interfering with pathogen burden, conferring disease tolerance to infection. This contrasts with immune-driven resistance mechanisms, which although essential to protect the host from infection, can impose tissue damage to host parenchyma tissues. This damaging effect is countered by stress responses that confer tissue damage control and disease tolerance to infection. Here we discuss how the stress response regulated by the transcription factor nuclear factor-erythroid 2-related factor 2 (Nrf2) acts in such a manner.
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http://dx.doi.org/10.1042/BST20150054DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4613525PMC
August 2015

The Iron age of host-microbe interactions.

EMBO Rep 2015 Nov 16;16(11):1482-500. Epub 2015 Oct 16.

Department of Internal Medicine VI, Infectious Diseases, Immunology, Rheumatology, Pneumology, Medical University, Innsbruck, Austria

Microbes exert a major impact on human health and disease by either promoting or disrupting homeostasis, in the latter instance leading to the development of infectious diseases. Such disparate outcomes are driven by the ever-evolving genetic diversity of microbes and the countervailing host responses that minimize their pathogenic impact. Host defense strategies that limit microbial pathogenicity include resistance mechanisms that exert a negative impact on microbes, and disease tolerance mechanisms that sustain host homeostasis without interfering directly with microbes. While genetically distinct, these host defense strategies are functionally integrated, via mechanisms that remain incompletely defined. Here, we explore the general principles via which host adaptive responses regulating iron (Fe) metabolism impact on resistance and disease tolerance to infection.
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http://dx.doi.org/10.15252/embr.201540558DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4641501PMC
November 2015

Disruption of Parasite hmgb2 Gene Attenuates Plasmodium berghei ANKA Pathogenicity.

Infect Immun 2015 Jul 27;83(7):2771-84. Epub 2015 Apr 27.

Sorbonne Universités, Centre d'Immunologie et des Maladies Infectieuses (CIMI-Paris), Paris, France INSERM, U1135, CIMI-Paris, Paris, France CNRS, ERL 8255, CIMI-Paris, Paris, France

Eukaryotic high-mobility-group-box (HMGB) proteins are nuclear factors involved in chromatin remodeling and transcription regulation. When released into the extracellular milieu, HMGB1 acts as a proinflammatory cytokine that plays a central role in the pathogenesis of several immune-mediated inflammatory diseases. We found that the Plasmodium genome encodes two genuine HMGB factors, Plasmodium HMGB1 and HMGB2, that encompass, like their human counterparts, a proinflammatory domain. Given that these proteins are released from parasitized red blood cells, we then hypothesized that Plasmodium HMGB might contribute to the pathogenesis of experimental cerebral malaria (ECM), a lethal neuroinflammatory syndrome that develops in C57BL/6 (susceptible) mice infected with Plasmodium berghei ANKA and that in many aspects resembles human cerebral malaria elicited by P. falciparum infection. The pathogenesis of experimental cerebral malaria was suppressed in C57BL/6 mice infected with P. berghei ANKA lacking the hmgb2 gene (Δhmgb2 ANKA), an effect associated with a reduction of histological brain lesions and with lower expression levels of several proinflammatory genes. The incidence of ECM in pbhmgb2-deficient mice was restored by the administration of recombinant PbHMGB2. Protection from experimental cerebral malaria in Δhmgb2 ANKA-infected mice was associated with reduced sequestration in the brain of CD4(+) and CD8(+) T cells, including CD8(+) granzyme B(+) and CD8(+) IFN-γ(+) cells, and, to some extent, neutrophils. This was consistent with a reduced parasite sequestration in the brain, lungs, and spleen, though to a lesser extent than in wild-type P. berghei ANKA-infected mice. In summary, Plasmodium HMGB2 acts as an alarmin that contributes to the pathogenesis of cerebral malaria.
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http://dx.doi.org/10.1128/IAI.03129-14DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4468538PMC
July 2015