Leishmania-Infected Macrophages Are Targets of NK Cell-Derived Cytokines but Not of NK Cell Cytotoxicity

Prajeeth, Chittappen Kandiyil; Haeberlein, Simone; Sebald, Heidi; Schleicher, Ulrike; Bogdan, Christian

doi:10.1128/iai.00079-11

Cited by 38 publications

(32 citation statements)

References 79 publications

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“…BMDC and BMM were generated from bone marrow cells (Prajeeth et al, 2011) and used at day 7 or 8 to 10 of culture, respectively. rmIL-4 (0.5-10 ng/ml) and rmTNF (10 or 50 ng/ml) (R&D Systems) were added as stimulant(s).…”

Section: Methodsmentioning

confidence: 99%

TNF-Mediated Restriction of Arginase 1 Expression in Myeloid Cells Triggers Type 2 NO Synthase Activity at the Site of Infection

et al. 2016

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Neutralization or deletion of tumor necrosis factor (TNF) causes loss of control of intracellular pathogens in mice and humans, but the underlying mechanisms are incompletely understood. Here, we found that TNF antagonized alternative activation of macrophages and dendritic cells by IL-4. TNF inhibited IL-4-induced arginase (Arg) 1 expression by decreasing histone acetylation, without affecting STAT6 phosphorylation and nuclear translocation. In Leishmania major-infected C57BL/6 wild-type mice, type 2 nitric oxide (NO) synthase (NOS2) was detected in inflammatory dendritic cells/macrophages, some of which coexpressed Arg1. In TNF-deficient mice Arg1 was hyperexpressed causing an impaired production of NO in situ. A similar phenotype was seen in L. major-infected BALB/c mice. Arg1 deletion in hematopoietic cells protected these mice from an otherwise lethal disease, although their disease-mediating T cell response (Th2, Treg) was maintained. Thus, deletion or TNF-mediated restriction of Arg1 unleashes the production of NO by NOS2 which is critical for pathogen control.

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Section: Methodsmentioning

confidence: 99%

TNF-Mediated Restriction of Arginase 1 Expression in Myeloid Cells Triggers Type 2 NO Synthase Activity at the Site of Infection

et al. 2016

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“…Resident dermal DC as well as newly immigrated DC will sense and endocytose Leishmania , transport them to the draining lymph node and elicit a protective natural killer (NK) cell and type 1 T helper cell (Th1) response in an interleukin (IL)-12-dependent fashion 39–45. Interferon γ (IFNγ), which is secreted by these cells, is essential for activating macrophages (and presumably also DC) to kill intracellular Leishmania amastigotes 46. IFNγ induces and/or promotes the release of ROI, the expression of inducible or type 2 nitric oxide synthase (iNOS, NOS2), the indoleamine-2, 3-dioxygenase-mediated depletion of tryptophan, the secretion of TNF and of antimicrobial peptides (figure 1).…”

Section: Infection Cycle Pathogenesis and Immunologymentioning

confidence: 99%

Leishmaniasis in rheumatology, haematology and oncology: epidemiological, immunological and clinical aspects and caveats: Figure 1

Bogdan

2012

Ann Rheum Dis

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Leishmaniasis is an intracellular protozoan infection that can lead to cutaneous, mucocutaneous, visceral or systemic manifestations depending on the parasite species and virulence and on the host immune response. It is endemic in countries of Europe (Mediterranean basin), Asia, Africa, Central and South America, but autochthonous cases begin to emerge outside classical disease areas. CD4+ T helper cells, interferon γ, dendritic cells and macrophages are the key components of antileishmanial defence. Leishmaniasis is an important differential diagnosis in patients with chronic lesions of the skin or mucous membranes or with fever, hepatosplenomegaly, lymphadenopathy, pancytopenia, histocytosis, haemophagocytic syndrome or glomerulonephritis. Organ transplant recipients and patients with autoimmune syndromes are at particular risk of developing visceral leishmaniasis following immunosuppressive therapy (eg, with steroids, methotrexate, ciclosporin or tumour necrosis factor-neutralising biological agents). Diagnosis and adequate treatment of leishmaniasis requires the combined use of culture, microscopic and nucleic acid amplication methods and species identification by sequencing and other molecular techniques. Standard regimens for the treatment of visceral leishmaniasis are intravenous liposomal amphotericin B (3 mg/kg body weight for 10 days) or oral miltefosine (150 mg/day for 28 days).

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“…The DCs will then secrete cytokines such as IL-12 or type I IFN that promote the polarization of naive T cells into Th1 effector lymphocytes [18,19]. Natural killer (NK) cells also participate in the innate immune response and control of the parasites, as an early source of IFN-g and contribute to the development of Th1 cells that produce high levels of IFN-g and TNF-a [20]. Whereas IFN-g and TNF-a activate macrophages to generate toxic molecules, radical nitrogen intermediates (RNI) or radical oxygen intermediates (ROI) that destroy Leishmania parasites inside macrophages [21].…”

Section: Biology and Life Cycle Of Leishmania Parasitesmentioning

confidence: 99%

Making an anti-amastigote vaccine for visceral leishmaniasis: rational, update and perspectives

Fernandes

Coelho

Machado-Coelho

et al. 2012

Current Opinion in Microbiology

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Leishmania-Infected Macrophages Are Targets of NK Cell-Derived Cytokines but Not of NK Cell Cytotoxicity

Cited by 38 publications

References 79 publications

TNF-Mediated Restriction of Arginase 1 Expression in Myeloid Cells Triggers Type 2 NO Synthase Activity at the Site of Infection

TNF-Mediated Restriction of Arginase 1 Expression in Myeloid Cells Triggers Type 2 NO Synthase Activity at the Site of Infection

Leishmaniasis in rheumatology, haematology and oncology: epidemiological, immunological and clinical aspects and caveats: Figure 1

Making an anti-amastigote vaccine for visceral leishmaniasis: rational, update and perspectives

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