The Neurotrophic Receptor Ntrk2 Directs Lymphoid Tissue Neovascularization during Leishmania donovani Infection

Dalton, Jane E.; Glover, Amy; Hoodless, Laura J.; Lim, Eng Kiat; Beattie, Lynette; Kirby, Alun C.; Kaye, Paul M.

doi:10.1371/journal.ppat.1004681

Cited by 21 publications

(20 citation statements)

References 55 publications

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“…donovani -infected mice lacking Blimp-1 or IL-10 expression by T cells was dramatic splenomegaly. Angiogenesis is a dominant feature of splenomegaly during experimental VL [ 44 ], driven by inflammation-induced expression of neurotropic receptor on vascular endothelium and interactions with ligands produced by mononuclear phagocytes [ 43 ]. TNF produced by macrophages can promote angiogenesis [ 74 , 75 ], and chronic inflammation and vascular remodelling are intimately linked in autoimmune disease settings [ 76 ].…”

Section: Discussionmentioning

confidence: 99%

Blimp-1-Dependent IL-10 Production by Tr1 Cells Regulates TNF-Mediated Tissue Pathology

et al. 2016

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Tumor necrosis factor (TNF) is critical for controlling many intracellular infections, but can also contribute to inflammation. It can promote the destruction of important cell populations and trigger dramatic tissue remodeling following establishment of chronic disease. Therefore, a better understanding of TNF regulation is needed to allow pathogen control without causing or exacerbating disease. IL-10 is an important regulatory cytokine with broad activities, including the suppression of inflammation. IL-10 is produced by different immune cells; however, its regulation and function appears to be cell-specific and context-dependent. Recently, IL-10 produced by Th1 (Tr1) cells was shown to protect host tissues from inflammation induced following infection. Here, we identify a novel pathway of TNF regulation by IL-10 from Tr1 cells during parasitic infection. We report elevated Blimp-1 mRNA levels in CD4+ T cells from visceral leishmaniasis (VL) patients, and demonstrate IL-12 was essential for Blimp-1 expression and Tr1 cell development in experimental VL. Critically, we show Blimp-1-dependent IL-10 production by Tr1 cells prevents tissue damage caused by IFNγ-dependent TNF production. Therefore, we identify Blimp-1-dependent IL-10 produced by Tr1 cells as a key regulator of TNF-mediated pathology and identify Tr1 cells as potential therapeutic tools to control inflammation.

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Section: Discussionmentioning

confidence: 99%

Blimp-1-Dependent IL-10 Production by Tr1 Cells Regulates TNF-Mediated Tissue Pathology

et al. 2016

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“…The splenic architecture plays a crucial role in orchestrating and directing the trafficking of lymphocytes [ 70 ]. During VL, the breakdown of the splenic architecture is mediated by IFNγ and TNF [ 12 , 39 ], and comprises compartment-specific remodelling [ 71 ], as well as neovascularisation mediated by Ntkr2 [ 72 ]. Consistent with these findings [ 12 ], we showed glycolysis blockade in Il27ra -/- mice rescued splenic architecture by preserving marginal zone macrophages, reducing IFNγ and TNF levels and retaining T and B cells in the spleen.…”

Section: Discussionmentioning

confidence: 99%

IL-27 signalling regulates glycolysis in Th1 cells to limit immunopathology during infection

Rivera

Winterford

et al. 2020

PLoS Pathog

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Inflammation is critical for controlling pathogens, but also responsible for symptoms of infectious diseases. IL-27 is an important regulator of inflammation and can limit development of IFNγ-producing Tbet + CD4 + T (Th1) cells. IL-27 is thought to do this by stimulating IL-10 production by CD4 + T cells, but the underlying mechanisms of these immunoregulatory pathways are not clear. Here we studied the role of IL-27 signalling in experimental visceral leishmaniasis (VL) caused by infection of C57BL/6 mice with the human pathogen Leishmania donovani . We found IL-27 signalling was critical for the development of IL-10-producing Th1 (Tr1) cells during infection. Furthermore, in the absence of IL-27 signalling, there was improved control of parasite growth, but accelerated splenic pathology characterised by the loss of marginal zone macrophages. Critically, we discovered that IL-27 signalling limited glycolysis in Th1 cells during infection that in turn attenuated inflammation. Furthermore, the modulation of glycolysis in the absence of IL-27 signalling restricted tissue pathology without compromising anti-parasitic immunity. Together, these findings identify a novel mechanism by which IL-27 mediates immune regulation during disease by regulating cellular metabolism.

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“…Splenomegaly in experimental VL is associated with compartment specific remodelling of the red and white pulp, mediated through the action of TNF, inflammatory monocytes and loss of stromal cell integrity 32, [49][50][51][52] . Analysis of the splenic response at R x +7 provided evidence for diminution of the cellular responses though not to the same extent as seen in the liver.…”

Section: Discussionmentioning

confidence: 99%

Tissue-specific transcriptomic changes associated with AmBisome® treatment of BALB/c mice with experimental visceral leishmaniasis

Forrester¹,

Siefert²,

Ashwin³

et al. 2019

Wellcome Open Res

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Background: Liposomal amphotericin B (AmBisome®) as a treatment modality for visceral leishmaniasis (VL) has had significant impact on patient care in some but not all regions where VL is endemic. As the mode of action of AmBisome® in vivo is poorly understood, we compared the tissue-specific transcriptome in drug-treated vs untreated mice with experimental VL. Methods: BALB/c mice infected with L. donovani were treated with 8mg/kg AmBisome®, resulting in parasite elimination from liver and spleen over a 7-day period. At day 1 and day 7 post treatment (Rx+1 and Rx+7), transcriptomic profiling was performed on spleen and liver tissue from treated and untreated mice and uninfected mice. BALB/c mice infected with M. bovis BCG (an organism resistant to amphotericin B) were analysed to distinguish between direct effects of AmBisome® and those secondary to parasite death. Results: AmBisome® treatment lead to rapid parasitological clearance. At Rx+1, spleen and liver displayed only 46 and 88 differentially expressed (DE) genes (P<0.05; 2-fold change) respectively. In liver, significant enrichment was seen for pathways associated with TNF, fatty acids and sterol biosynthesis. At Rx+7, the number of DE genes was increased (spleen, 113; liver 400). In spleen, these included many immune related genes known to be involved in anti-leishmanial immunity. In liver, changes in transcriptome were largely accounted for by loss of granulomas. PCA analysis indicated that treatment only partially restored homeostasis. Analysis of BCG-infected mice treated with AmBisome® revealed a pattern of immune modulation mainly targeting macrophage function. Conclusions: Our data indicate that the tissue response to AmBisome® treatment varies between target organs and that full restoration of homeostasis is not achieved at parasitological cure. The pathways required to restore homeostasis deserve fuller attention, to understand mechanisms associated with treatment failure and relapse and to promote more rapid restoration of immune competence.

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The Neurotrophic Receptor Ntrk2 Directs Lymphoid Tissue Neovascularization during Leishmania donovani Infection

Cited by 21 publications

References 55 publications

Blimp-1-Dependent IL-10 Production by Tr1 Cells Regulates TNF-Mediated Tissue Pathology

Blimp-1-Dependent IL-10 Production by Tr1 Cells Regulates TNF-Mediated Tissue Pathology

IL-27 signalling regulates glycolysis in Th1 cells to limit immunopathology during infection

Tissue-specific transcriptomic changes associated with AmBisome® treatment of BALB/c mice with experimental visceral leishmaniasis

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