title: IL-10 Indirectly Regulates Corneal Lymphangiogenesis and Resolution of Inflammation via Macrophages.
abstract: The role of IL-10, a primarily anti-inflammatory cytokine, in the regulation of inflammatory lymphangiogenesis is undetermined. Herein, we show that IL-10 modulates corneal lymphangiogenesis and resolution of inflammation. IL-10 was not expressed in healthy corneas but was up-regulated in inflamed corneas by infiltrating macrophages. Macrophages up-regulated the expression of prolymphangiogenic vascular endothelial growth factor-C upon stimulation with IL-10. Consistently, corneal inflammation resulted in reduced expression of vascular endothelial growth factor-C and decreased corneal lymphangiogenesis in IL-10-deficient mice (IL-10(-/-)). The effect of IL-10 on lymphangiogenesis was indirect via macrophages, because IL-10 did not directly affect lymphatic endothelial cells. The expression of proinflammatory cytokines and the numbers of infiltrating macrophages increased and remained elevated in inflamed corneas of IL-10(-/-) mice, indicating that IL-10 deficiency led to more severe and prolonged inflammation. The corneal phenotype of IL-10 deficient mice was mimicked in mice with conditional deletion of Stat3 in myeloid cells (lysozyme M Cre mice Stat3(fl/fl) mice), corroborating the critical role of macrophages in the regulation of lymphangiogenesis. Furthermore, local treatment with IL-10 promoted lymphangiogenesis and faster egress of macrophages from inflamed corneas. Taken together, we demonstrate that IL-10 indirectly regulates inflammatory corneal lymphangiogenesis via macrophages. Reduced lymphangiogenesis in IL-10(-/-) and lysozyme M Cre Stat3(fl/fl) mice is associated with more severe inflammatory responses, whereas IL-10 treatment results in faster resolution of inflammation. IL-10 might be used therapeutically to terminate pathological inflammation.
authors.affiliation: Department of Ophthalmology, University of Cologne, Cologne, Germany. Electronic address: deniz.hos@uk-koeln.de.
authors.forename: Deniz
authors.initials: D
authors.lastname: Hos
authors.affiliation: Department of Ophthalmology, University of Cologne, Cologne, Germany.
authors.forename: Franziska
authors.initials: F
authors.lastname: Bucher
authors.affiliation: Department of Ophthalmology, University of Cologne, Cologne, Germany.
authors.forename: Birgit
authors.initials: B
authors.lastname: Regenfuss
authors.affiliation: Department of Ophthalmology, University of Cologne, Cologne, Germany.
authors.forename: Marie-Luise
authors.initials: ML
authors.lastname: Dreisow
authors.affiliation: Department of Ophthalmology, University of Cologne, Cologne, Germany.
authors.forename: Felix
authors.initials: F
authors.lastname: Bock
authors.affiliation: Department of Ophthalmology, University of Cologne, Cologne, Germany.
authors.forename: Ludwig M
authors.initials: LM
authors.lastname: Heindl
authors.affiliation: Department of Dermatology, University of Cologne, Cologne, Germany; Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany; Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, Cologne, Germany.
authors.forename: Sabine A
authors.initials: SA
authors.lastname: Eming
authors.affiliation: Department of Ophthalmology, University of Cologne, Cologne, Germany.
authors.forename: Claus
authors.initials: C
authors.lastname: Cursiefen
mesh_terms: D000818:Animals; D016510:Corneal Neovascularization / Q000276:immunology* / Q000473:pathology; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D007150:Immunohistochemistry; D007249:Inflammation / Q000276:immunology / Q000473:pathology; D016753:Interleukin-10 / Q000235:genetics / Q000276:immunology* / Q000494:pharmacology; D007634:Keratitis / Q000276:immunology* / Q000473:pathology*; D042583:Lymphangiogenesis; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D060888:Real-Time Polymerase Chain Reaction; D042582:Vascular Endothelial Growth Factor C / Q000096:biosynthesis
chemical_list: D042582:Vascular Endothelial Growth Factor C; D016753:Interleukin-10