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: Deniz Hos, Franziska Bucher, Birgit Regenfuss, Marie-Luise Dreisow, Felix Bock, Ludwig M Heindl, Sabine A Eming, Claus Cursiefen
• Journal: The American journal of pathology (Am J Pathol) Vol. 186 Issue 1 Pg. 159-71 (Jan 2016) ISSN: 1525-2191 [Electronic] United States
• PMID: 26608451 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2016 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

Chemical References

• Vascular Endothelial Growth Factor C
• Interleukin-10

Topics

• Animals
• Corneal Neovascularization (immunology, pathology)
• Disease Models, Animal
• Enzyme-Linked Immunosorbent Assay
• Humans
• Immunohistochemistry
• Inflammation (immunology, pathology)
• Interleukin-10 (genetics, immunology, pharmacology)
• Keratitis (immunology, pathology)
• Lymphangiogenesis
• Macrophages (immunology)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Real-Time Polymerase Chain Reaction
• Vascular Endothelial Growth Factor C (biosynthesis)