期刊
AMERICAN JOURNAL OF PATHOLOGY
卷 186, 期 1, 页码 159-171出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.ajpath.2015.09.012
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资金
- German Research Foundation (Deutsche Forschungsgemeinschaft, DFG) [FOR2240, DFG HO 5556/1-1, DFG Cu 47/4-2, DFG Cu 47/6-1, DFG Cu 47/10-1]
- EU [COST BM1302]
- GEROK Program, University of Cologne
- Bayer Graduate School of Pharmacology, University of Cologne
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 Stat(fL/fL) mice), corroborating the critical rote 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.
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