title: The neurotrophic receptor Ntrk2 directs lymphoid tissue neovascularization during Leishmania donovani infection.
abstract: The neurotrophic tyrosine kinase receptor type 2 (Ntrk2, also known as TrkB) and its ligands brain derived neurotrophic factor (Bdnf), neurotrophin-4 (NT-4/5), and neurotrophin-3 (NT-3) are known primarily for their multiple effects on neuronal differentiation and survival. Here, we provide evidence that Ntrk2 plays a role in the pathologic remodeling of the spleen that accompanies chronic infection. We show that in Leishmania donovani-infected mice, Ntrk2 is aberrantly expressed on splenic endothelial cells and that new maturing blood vessels within the white pulp are intimately associated with F4/80(hi)CD11b(lo)CD11c(+) macrophages that express Bdnf and NT-4/5 and have pro-angiogenic potential in vitro. Furthermore, administration of the small molecule Ntrk2 antagonist ANA-12 to infected mice significantly inhibited white pulp neovascularization but had no effect on red pulp vascular remodeling. We believe this to be the first evidence of the Ntrk2/neurotrophin pathway driving pathogen-induced vascular remodeling in lymphoid tissue. These studies highlight the therapeutic potential of modulating this pathway to inhibit pathological angiogenesis.
authors.affiliation: Centre for Immunology and Infection, Department of Biology and Hull York Medical School, University of York, York, United Kingdom.
authors.forename: Jane E
authors.initials: JE
authors.lastname: Dalton
authors.affiliation: Jack Birch Unit, Department of Biology, University of York, York, United Kingdom.
authors.forename: Amy C
authors.initials: AC
authors.lastname: Glover
authors.affiliation: Centre for Immunology and Infection, Department of Biology and Hull York Medical School, University of York, York, United Kingdom.
authors.forename: Laura
authors.initials: L
authors.lastname: Hoodless
authors.affiliation: Centre for Immunology and Infection, Department of Biology and Hull York Medical School, University of York, York, United Kingdom.
authors.forename: Eng-Kiat
authors.initials: EK
authors.lastname: Lim
authors.affiliation: Centre for Immunology and Infection, Department of Biology and Hull York Medical School, University of York, York, United Kingdom.
authors.forename: Lynette
authors.initials: L
authors.lastname: Beattie
authors.affiliation: Centre for Immunology and Infection, Department of Biology and Hull York Medical School, University of York, York, United Kingdom.
authors.forename: Alun
authors.initials: A
authors.lastname: Kirby
authors.affiliation: Centre for Immunology and Infection, Department of Biology and Hull York Medical School, University of York, York, United Kingdom.
authors.forename: Paul M
authors.initials: PM
authors.lastname: Kaye
mesh_terms: D000818:Animals; D001381:Azepines / Q000494:pharmacology; D001549:Benzamides / Q000494:pharmacology; D019208:Brain-Derived Neurotrophic Factor / Q000096:biosynthesis; D002460:Cell Line; D042783:Endothelial Cells / Q000378:metabolism; D005260:Female; D007893:Leishmania donovani / Q000472:pathogenicity*; D007898:Leishmaniasis, Visceral / Q000469:parasitology / Q000473:pathology*; D008264:Macrophages / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D018919:Neovascularization, Physiologic / Q000502:physiology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D017475:Receptors, Nerve Growth Factor / Q000096:biosynthesis; D015398:Signal Transduction / Q000502:physiology; D013154:Spleen / Q000098:blood supply* / Q000378:metabolism; D013163:Splenomegaly / Q000469:parasitology / Q000473:pathology; D020813:Receptor, trkB
chemical_list: D001381:Azepines; D001549:Benzamides; D019208:Brain-Derived Neurotrophic Factor; D008562:Membrane Glycoproteins; D011505:Protein-Tyrosine Kinases; D017475:Receptors, Nerve Growth Factor; C559317:ANA 12 compound; C089191:neurotrophin 4(5) receptor; C064371:Ntrk2 protein, mouse; D020813:Receptor, trkB