IL-10 Indirectly Regulates Corneal Lymphangiogenesis and Resolution of Inflammation via Macrophages

B7 EMINGpublicationsHos D, Bucher F, Regenfuss B, Dreisow ML, Bock F, Heindl LM, Eming SA, Cursiefen C; Am J Pathol. 2015 Nov 19. pii: S0002-9440(15)00574-X. doi: 10.1016/j.ajpath.2015.09.012. [Epub ahead of print]


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 on 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 affect lymphatic endothelial cells. The expression of proinflammatory cytokine and the numbers of infiltrating macrophage 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 deficiency in mice mimicked conditional deletion of Stat3 in myeloid cells (lysozyme M Cre mice Stat3fl/fl), 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 mice Stat3fl/fl 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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