title: Lymphangiogenesis is induced by mycobacterial granulomas via vascular endothelial growth factor receptor-3 and supports systemic T-cell responses against mycobacterial antigen.
abstract: Granulomatous inflammation is characteristic of many autoimmune and infectious diseases. The lymphatic drainage of these inflammatory sites remains poorly understood, despite an expanding understanding of lymphatic role in inflammation and disease. Here, we show that the lymph vessel growth factor Vegf-c is up-regulated in Bacillus Calmette-Guerin- and Mycobacterium tuberculosis-induced granulomas, and that infection results in lymph vessel sprouting and increased lymphatic area in granulomatous tissue. The observed lymphangiogenesis during infection was reduced by inhibition of vascular endothelial growth factor receptor 3. By using a model of chronic granulomatous infection, we also show that lymphatic remodeling of tissue persists despite resolution of acute infection and a 10- to 100-fold reduction in the number of bacteria and tissue-infiltrating leukocytes. Inhibition of vascular endothelial growth factor receptor 3 decreased the growth of new vessels, but also reduced the proliferation of antigen-specific T cells. Together, our data show that granuloma-up-regulated factors increase granuloma access to secondary lymph organs by lymphangiogenesis, and that this process facilitates the generation of systemic T-cell responses to granuloma-contained antigens.
authors.affiliation: Department of Pathology and Laboratory Medicine, School of Medicine and Public Health, University of Wisconsin Madison, Madison, Wisconsin; Cellular and Molecular Pathology Training Program, University of Wisconsin Madison, Madison, Wisconsin.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Harding
authors.affiliation: Department of Pathology and Laboratory Medicine, School of Medicine and Public Health, University of Wisconsin Madison, Madison, Wisconsin.
authors.forename: Anna
authors.initials: A
authors.lastname: Ritter
authors.affiliation: Neuroscience Training Program, University of Wisconsin Madison, Madison, Wisconsin.
authors.forename: Aditya
authors.initials: A
authors.lastname: Rayasam
authors.affiliation: Department of Pathology and Laboratory Medicine, School of Medicine and Public Health, University of Wisconsin Madison, Madison, Wisconsin; Cellular and Molecular Pathology Training Program, University of Wisconsin Madison, Madison, Wisconsin.
authors.forename: Zsuzsanna
authors.initials: Z
authors.lastname: Fabry
authors.affiliation: Department of Pathology and Laboratory Medicine, School of Medicine and Public Health, University of Wisconsin Madison, Madison, Wisconsin; Cellular and Molecular Pathology Training Program, University of Wisconsin Madison, Madison, Wisconsin. Electronic address: msandor@wisc.edu.
authors.forename: Matyas
authors.initials: M
authors.lastname: Sandor
mesh_terms: D000818:Animals; D006099:Granuloma / Q000276:immunology* / Q000382:microbiology / Q000473:pathology / Q000662:veterinary; D007111:Immunity, Cellular; D042583:Lymphangiogenesis / Q000276:immunology*; D051379:Mice; D009163:Mycobacterium bovis / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D014376:Tuberculosis / Q000276:immunology* / Q000473:pathology / Q000662:veterinary; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000276:immunology*
chemical_list: D040321:Vascular Endothelial Growth Factor Receptor-3