Indoleamine 2,3-dioxygenase and iron are required for Mycobacterium leprae survival

Barbosa, Mayara Garcia de Mattos; Prata, Rhana Berto da Silva; Andrade, Priscila Ribeiro; Ferreira, Helen; Silva, Bruno Jorge de Andrade; Oliveira, Jéssica Araújo da Paixão de; Assis, Tayná Quintella; Toledo-Pinto, Thiago Gomes de; Bezerra, Ohanna Cavalcanti de Lima; Nery, José Augusto da Costa; Rosa, Patrícia Sammarco; Bozza, Marcelo T.; Lara, Flávio Alves; Moraes, Milton Ozório; Schmitz, Verônica; Sarno, Euzenir Nunes; Pinheiro, Roberta Olmo

doi:10.1016/j.micinf.2017.06.006

Cited by 24 publications

(29 citation statements)

References 32 publications

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“…It was hypothesized that previous contact with M. leprae might limit the functional capacity of monocytes, reducing the ability to mount an effective immune response in a secondary contact [50]. Together, these data support the idea that an anti-inflammatory regenerative environment restrictive of microbicidal response is promoted in lepromatous patient's skin lesions, leading to differentiation of a heterogeneous subset of highly phagocytic iron and lipid-loaded foamy macrophages that create an ideal environment for survival and vast propagation of the M. leprae infection and consequently the increase in the number of skin lesion in this pole of the disease [16,22,37,[42][43][44]48].…”

Section: Introductionsupporting

confidence: 60%

“…Several studies demonstrated the predominance of M2 markers like CD68, CD209, CD163, SRA-I, HO-1, arginase-1, IL-10, IL-13, TGF-β, and basic fibroblast growth factor in multibacillary lepromatous patients' skin lesion macrophages [16,22,37,[42][43][44]. In the same way, CD163, the hemoglobin (Hb) scavenger receptor, might contribute to the polarization of multibacillary lepromatous macrophages to an anti-inflammatory profile by increasing the expression of indoleamine 2,3-dioxygenase (IDO) and IL-10, in addition to increasing the internalization of M. leprae and iron, contributing to the mycobacterial persistence [16,45].…”

Section: Introductionmentioning

confidence: 99%

“…The increase in the internalization of Hb-haptoglobin (Hp) complex by CD163 contributes to the activation of the enzyme HO-1 via IL-10 [46]. de Mattos Barbosa and colleagues [42] proposed that M. leprae-infected skin macrophages would increase the acquisition of iron both by transferrin and heme-bound, via transferrin receptor 1 and CD163, activating the enzyme HO-1 that catalyzes heme into carbon monoxide, biliverdin, and free iron, increasing the intracellular iron pool and the iron storage in the protein ferritin (Ft), due to a reduction in expression of the sole iron exporter, ferroportin 1 (Fpn-1) [42] (Figure 2). Iron retention via Ft and reduced secretion of iron by Fpn-1 are classical traits of microbicidal inflammatory M1 macrophages, while tissue repair-associated M2 are characterized by enhanced HO-1-mediated heme catalysis and increased iron exportation via Fpn-1 [46].…”

Section: Introductionmentioning

confidence: 99%

“…Iron retention via Ft and reduced secretion of iron by Fpn-1 are classical traits of microbicidal inflammatory M1 macrophages, while tissue repair-associated M2 are characterized by enhanced HO-1-mediated heme catalysis and increased iron exportation via Fpn-1 [46]. Even though there is a prevalence of M1 or M2 markers in the polar clinical forms of leprosy, skin lesion macrophages present themselves in a spectrum of heterogeneous phenotypes sharing characteristics of both subtypes, and more than one specific population can be present at the same time [38,42,47].…”

Section: Introductionmentioning

confidence: 99%

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Macrophages in the Pathogenesis of Leprosy

Prata¹,

Barbosa²,

Silva³

et al. 2020

Macrophage Activation - Biology and Disease

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Leprosy is a chronic infectious disease caused by the intracellular pathogen Mycobacterium leprae. The disease may present different clinical forms depending on the immunological status of the host. M. leprae may infect macrophages and Schwann cells, and recent studies have demonstrated that macrophages are fundamental cells for determining the outcome of the disease. Skin lesions from patients with the paucibacillary form of the disease present a predominance of macrophages with a pro-inflammatory phenotype (M1), whereas skin lesions of multibacillary patients present a predominance of anti-inflammatory macrophages (M2). More recently, it was shown that autophagy is responsible for the control of bacillary load in paucibacillary macrophages and that the blockade of autophagy is involved in the onset of acute inflammatory reactional episodes in multibacillary cells. So, strategies that aim to induce autophagy in infected macrophages are promising not only to improve the efficacy of multidrug therapy (MDT) but also to avoid the occurrence of reactional episodes that are responsible for the disabilities observed in leprosy patients.2 production of nitric oxide, thus causing peripheral nerve damage characteristic of patients with leprosy [10]. Other studies have shown the ability of M. leprae to induce the production of oxidative mediators and their products, peroxynitrite and nitrotyrosine [11][12][13][14].Studies have demonstrated the ability of M. leprae to interact with a range of scavenger receptors of macrophages culminating in a tolerogenic response profile. The scavenger receptors are membrane receptors whose main function is the removal of molecules and cellular debris from the body, binding through a variety of polyanions, leading to phagocytosis of the target, being found in several cell types such as macrophages [15]. The ability of M. leprae to interact with the CD163 receptor, a scavenger receptor, which, during this interaction, can act as a co-receptor for M. leprae entry in macrophages, has been described [16]. It is known that activation of this receptor is related to the activation of the transcription factor nuclear factor erythroid 2-related factor 2 (NRF2), leading to the synthesis and increase of the activity of the enzyme heme oxygenase-1 (HO-1), which, through anti-inflammatory and antioxidant pathways, releases interleukin (IL)-10 and generates carbon monoxide, contributing to the polarization of these cells [17][18][19]. Bonilla and colleagues [20] demonstrated that autophagy, a mechanism of metabolic control, regulates the expression of scavenger receptors macrophage receptor with collagenous structure (MARCO) and scavenger receptor type A (SRA-I) that increase phagocytosis and NRF2 activity during Bacillus Calmette-Guérin (BCG) or M. tuberculosis (H37Rv) infection.M. leprae is able to induce macrophage SRA-I and CD36 expression [6] that contributes to the uptake of lipids, culminating in an increase in the uptake and accumulation of oxidized lipids within the macrophages, leading to a fo...

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Section: Introductionsupporting

confidence: 60%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Macrophages in the Pathogenesis of Leprosy

Prata¹,

Barbosa²,

Silva³

et al. 2020

Macrophage Activation - Biology and Disease

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“…Whilst the genes primarily up-regulated in LL vs. BT or LL vs. Control are involved with endocytosis [41], phagocytosis, lysosomes, lipid transport and metabolism [42][43][44], secretory granules, immune response, iron transport and ferric iron binding [45], neutrophil activation and degranulation [46,47], for which some work has been conducted by other leprosy researchers.…”

Section: Discussionmentioning

confidence: 99%

Reanalysis And Integration Of Public Microarray Datasets Reveals Novel Host Genes Modulated In Leprosy

Leal-Calvo

Moraes

2019

Preprint

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Background:Leprosy is an insidious disease caused primarily by mycobacteria. The difficulties in culturing this slow-growing bacteria together with the chronic progression of the disease have hampered the development of accurate methods for diagnosis. Host gene expression profiling is an important tool to assess overall tissue activity, whether in health or disease conditions. High-throughput gene expression experiments have become popular over the last decade or so, and public databases have been created to easily store and retrieve these data. This has enabled researchers to reuse and reanalyze existing datasets with the aim of generating novel and or more robust information. In this work, after a systematic search, nine microarray datasets evaluating host gene expression in leprosy were reanalyzed and the information was integrated to strengthen evidence of differential expression for several genes. Results: Reanalysis of individual datasets revealed several differentially expressed genes (DEGs). Then, five integration methods were tested, both at the P-value and effect size level. In the end, random effects model (REM) and ratio association (sdef) were selected as the main methods to pinpoint DEGs. Overall, some classic gene/pathways were found corroborating previous findings and validating this approach for analysis. Also, various original DEGs related to poorly understood processes in leprosy were described. Nevertheless, some of the novel genes have already been associated with leprosy pathogenesis by genetic or functional studies, whilst others are, as yet, unrelated or poorly studied in these contexts. Conclusions:This study reinforces evidences of differential expression of several genes and presents novel genes and pathways associated with leprosy pathogenesis. Altogether, these data are useful in better understanding host responses to the disease and, at the same time, provide a list of potential host biomarkers that could be useful in complementing leprosy diagnosis based on transcriptional levels.

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Mycobacterium lepraeinduces a tolerogenic profile in monocyte-derived dendritic cells via TLR2 induction of IDO

Oliveira

Gandini

Sales

et al. 2020

Journal of Leukocyte Biology

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The enzyme IDO-1 is involved in the first stage of tryptophan catabolism and has been described in both microbicidal and tolerogenic microenvironments. Previous data from our group have shown that IDO-1 is differentially regulated in the distinctive clinical forms of leprosy. The present study aims to investigate the mechanisms associated with IDO-1 expression and activity in human monocyte-derived dendritic cells (mDCs) after stimulation with irradiated Mycobacterium leprae and its fractions. M. leprae and its fractions induced the expression and activity of IDO-1 in human mDCs. Among the stimuli studied, irradiated M. leprae and its membrane fraction (MLMA) induced the production of proinflammatory cytokines TNF and IL-6 whereas irradiated M. leprae and its cytosol fraction (MLSA) induced an increase in IL-10. We investigated if TLR2 activation was necessary for IDO-1 induction in mDCs. We observed that in cultures treated with a neutralizing anti-TLR2 antibody, there was a decrease in IDO-1 activity and expression induced by M. leprae and MLMA. The same effect was observed when we used a MyD88 inhibitor. Our data demonstrate that coculture of mDCs with autologous lymphocytes induced an increase in regulatory T (Treg) cell frequency in MLSA-stimulated cultures, showing that M. leprae constituents may play opposite roles that may possibly be related to the dubious effect of IDO-1 in the different clinical forms of disease. Our data show that M. leprae and its fractions are able to differentially modulate the activity and functionality of IDO-1 in mDCs by a pathway that involves TLR2, suggesting that this enzyme may play an important role in leprosy immunopathogenesis.

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Indoleamine 2,3-dioxygenase and iron are required for Mycobacterium leprae survival

Cited by 24 publications

References 32 publications

Macrophages in the Pathogenesis of Leprosy

Macrophages in the Pathogenesis of Leprosy

Reanalysis And Integration Of Public Microarray Datasets Reveals Novel Host Genes Modulated In Leprosy

Mycobacterium lepraeinduces a tolerogenic profile in monocyte-derived dendritic cells via TLR2 induction of IDO

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