Human Classical Monocytes Control the Intracellular Stage of Leishmania braziliensis by Reactive Oxygen Species

Novais, Fernanda O.; Nguyen, Ba Tiep; Beiting, Daniel P.; Carvalho, Lucas P.; Glennie, Nelson D.; Passos, Sônia Regina Lambert; Carvalho, Edgar M.; Scott, Phillip

doi:10.1093/infdis/jiu013

Cited by 95 publications

(104 citation statements)

References 44 publications

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“…As expected, the classical monocytes made up the majority of the total monocytes-about 85 to 95%, with the intermediate and nonclassical monocytes ranging anywhere from 1.5 to 8% of the cells depending on the donors sorted (Fig. 1A, and data not shown), with findings very similar to those of other published prior studies (1,18). After sorting, we assessed the ability of the three subsets to produce and secrete cytokines that have been used to define inflammatory (TNF-␣), regulatory (IL-10), or alternative activation (CCL22) in human cells (Fig.…”

Section: Resultssupporting

confidence: 90%

“…While several studies have investigated the role of monocyte subsets in bacterial, viral, and parasitic infections (17,18; reviewed in reference 1), their roles in infection with extracellular parasites (such as filariae) have not been fully elucidated. In fact, monocyte dysfunction in filarial infection is one of several mechanisms proposed to explain parasite antigen-specific T cell hyporesponsiveness seen with patent lymphatic filariasis (19).…”

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confidence: 99%

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Human Monocyte Subsets at Homeostasis and Their Perturbation in Numbers and Function in Filarial Infection

et al. 2014

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To characterize the function and plasticity of the major human circulating monocyte populations and to explore their role in systemic helminth infection, highly purified (by flow-based sorting) human monocyte subsets [nonclassical]) were examined at homeostasis and after activation. Among these three subsets the classical and intermediate subsets were found to be the major sources of inflammatory and regulatory cytokines, as well as cytokines/chemokines associated with alternative activation, whereas the nonclassical and classical populations demonstrated an ability to transmigrate through endothelial monolayers. Moreover, it was primarily the classical subset that was the most efficient in promoting autologous T cell proliferation. The distribution of these subsets changed in the context of a systemic helminth (Wuchereria bancrofti) infection such that patent infection altered the frequency and distribution of these monocyte subsets with the nonclassical monocytes being expanded (almost 2-fold) in filarial infection. To understand further the filarial/monocyte interface, in vitro modeling demonstrated that the classical subset internalized filarial antigens more efficiently than the other two subsets but that the parasite-driven regulatory cytokine interleukin-10 was exclusively coming from the intermediate subset. Our data suggest that monocyte subsets have a differential function at homeostasis and in response to helminth parasites.

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Section: Resultssupporting

confidence: 90%

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confidence: 99%

Human Monocyte Subsets at Homeostasis and Their Perturbation in Numbers and Function in Filarial Infection

et al. 2014

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“…3B). Next, we investigated the ability of AhR-deficient macrophages to produce NO and ROS since the members of this group of molecules are major cytotoxic mediators involved in clearance of intracellular pathogens by macrophages (33,34,36). We did not observe any differences in the amounts of NO released by T. cruziinfected macrophages from the two groups of mice (data not shown).…”

Section: Deficiency Of Ahr Results In a Reduction Of In Vitro Ros Promentioning

confidence: 93%

“…These cells are equipped with cytotoxic mechanisms responsible for parasite death (34,35). Therefore, we wanted to explore if the absence of AhR in these cells contributed to the reduced parasitemia observed in vivo in the T. cruzi-infected AhR KO mice.…”

Section: Deficiency Of Ahr Results In a Reduction Of In Vitro Ros Promentioning

confidence: 99%

The Aryl Hydrocarbon Receptor Modulates Production of Cytokines and Reactive Oxygen Species and Development of Myocarditis during Trypanosoma cruzi Infection

et al. 2016

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eThe aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor involved in controlling several aspects of immune responses, including the activation and differentiation of specific T cell subsets and antigen-presenting cells, thought to be relevant in the context of experimental Trypanosoma cruzi infection. The relevance of AhR for the outcome of T. cruzi infection is not known and was investigated here. We infected wild-type (WT) mice and AhR knockout (AhR KO) mice with T. cruzi (Y strain) and determined levels of parasitemia, myocardial inflammation and fibrosis, expression of AhR/cytokines/suppressor of cytokine signaling (SOCS) (spleen/heart), and production of nitric oxide (NO), reactive oxygen species (ROS), and peroxynitrite (ONOO ؊ ) (spleen). AhR expression was increased in the heart of infected WT mice. Infected AhR KO mice displayed significantly reduced parasitemia, inflammation, and fibrosis of the myocardium. This was associated with an anticipated increased immune response characterized by increased levels of inflammatory cytokines and reduced expression of SOCS2 and SOCS3 in the heart. In vitro, AhR deficiency caused impairment in parasite replication and decreased levels of ROS production. In conclusion, AhR influences the development of murine Chagas disease by modulating ROS production and regulating the expression of key physiological regulators of inflammation, SOCS1 to -3, associated with the production of cytokines during experimental T. cruzi infection. The aryl hydrocarbon receptor (AhR) was originally described as a ligand-dependent transcription factor for exogenous ligands such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) capable of activating the aryl hydrocarbon hydroxylase (1, 2). In humans and mice, AhR recognizes several endogenous ligands, such as 6-formylindolo[3,2-b]carbazole (FICZ), kynurenines, indoles (3, 4), and lipoxins (LX) (5). The activation of the AhR signaling pathway controls the genomic expression of diverse target genes, leading to different physiological outcomes (6). More recently, it has been recognized that AhR is involved in the regulation of several immune processes. The major immune mechanisms controlled by AhR are related to the activation and differentiation of specific T cell subsets (T regulatory [Treg] and Th17) and antigenpresenting cells (3). In the context of immunity to infections, it was demonstrated that AhR is an essential protein for murine resistance to Listeria monocytogenes (7) and toxoplasmosis (8).More recently, we found that it was an important factor in controlling parasitemia and inflammation during experimental cerebral malaria (9). Additionally, it is associated with antiviral immunity (10) and is a negative regulator of inflammatory cytokines in response to Leishmania major experimental infection (11). Taken together, the results of these studies strongly suggest that AhR function during immune responses to infections is complex and likely pathogen specific.Trypanosoma cruzi is a flagellated protozoan parasite that...

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“…For example, infection of murine bone marrow-derived dendritic cells (DC) with L. braziliensis amastigotes results in potent upregulation of CD40 and IL-12 release [3], while DC infection with L. amazonensis amastigotes results in poor expression of CD40, CD83, and IL-12 [4]. Similarly, L. braziliensis amastigotes potently trigger human monocyte oxidative burst, resulting in ROS-dependent parasite clearance [5], while monocytes infected with L. amazonensis amastigotes are defective in oxidative burst [6]. To better understand amastigote interactions with other innate immune cells, we recently examined neutrophil activation and microbicidal activity against L. amazonensis amastigotes.…”

Section: Introductionmentioning

confidence: 99%

Interactions between Neutrophils and <b><i>Leishmania braziliensis</i></b> Amastigotes Facilitate Cell Activation and Parasite Clearance

Carlsen¹,

Jie

Liang

et al. 2015

J Innate Immun

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Leishmania braziliensis and Leishmania amazonensis are both causative agents of cutaneous leishmaniasis in South America. However, patient prognosis and the host immune response differ considerably depending on the infecting parasite species. The mechanisms underlying these differences appear to be multifactorial, with both host and parasite components contributing to disease outcome. As neutrophils are a prominent component of the inflammatory infiltrate in chronic cutaneous, diffuse cutaneous and mucocutaneous lesions, we examined neutrophil activation and microbicidal activity against amastigotes of L. amazonensis and L. braziliensis. We found that murine neutrophils internalized L. braziliensis amastigotes with greater efficiency than did L. amazonensis amastigotes. Additionally, L. braziliensis infection was a potent trigger for neutrophil activation, oxidative burst, degranulation and the production of interleukin (IL)-22 and IL-10, while L. amazonensis amastigotes poorly induced these responses. Finally, neutrophils were able to kill L. braziliensis amastigotes, especially when cells were activated with phorbol myristate acetate. L. amazonensis amastigotes, however, were highly resistant to neutrophil microbicidal mechanisms. This study reveals, for the first time, differential neutrophil responsiveness to distinct species of Leishmania amastigotes and highlights the complexity of neutrophil-amastigote interactions during chronic leishmaniasis.

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Human Classical Monocytes Control the Intracellular Stage of Leishmania braziliensis by Reactive Oxygen Species

Cited by 95 publications

References 44 publications

Human Monocyte Subsets at Homeostasis and Their Perturbation in Numbers and Function in Filarial Infection

Human Monocyte Subsets at Homeostasis and Their Perturbation in Numbers and Function in Filarial Infection

The Aryl Hydrocarbon Receptor Modulates Production of Cytokines and Reactive Oxygen Species and Development of Myocarditis during Trypanosoma cruzi Infection

Interactions between Neutrophils and <b><i>Leishmania braziliensis</i></b> Amastigotes Facilitate Cell Activation and Parasite Clearance

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