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Phase-specific functions of macrophages determine injury-mediated corneal hem- and lymphangiogenesis.

ABSTRACT: Macrophages are critical mediators of injury-associated corneal hemangiogenesis (HA) and lymphangiogenesis (LA). Yet, molecular regulators of the hem- and lymphangiogenic potential of corneal wound macrophages are poorly understood. Using two different mouse models of acute (perforating corneal incision injury) and chronic (corneal suture placement model) corneal injury, here we identified distinct functions of early- versus late-phase corneal wound macrophages in corneal HA and LA. Whereas early-phase wound macrophages are essential for initiation and progression of injury-mediated corneal HA and LA, late-phase wound macrophages control maintenance of established corneal lymphatic vessels, but not blood vessels. Furthermore, our findings reveal that the hem- and lymphangiogenic potential of corneal wound macrophages is controlled by the type of the corneal damage. Whereas perforating corneal incision injury induced primarily wound macrophages with lymphangiogenic potential, corneal suture placement provoked wound macrophages with both hem- and lymphangiogenic potential. Our findings highlight a previously unrecognized injury-context dependent role of early- versus late-phase corneal wound macrophages with potential clinical impact on therapy development for sight-threatening corneal neovascular diseases.

SUBMITTER: Kiesewetter A

PROVIDER: S-EPMC6343005 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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Phase-specific functions of macrophages determine injury-mediated corneal hem- and lymphangiogenesis.

Kiesewetter A A Cursiefen C C Eming S A SA Hos D D

Scientific reports 20190122 1

Macrophages are critical mediators of injury-associated corneal hemangiogenesis (HA) and lymphangiogenesis (LA). Yet, molecular regulators of the hem- and lymphangiogenic potential of corneal wound macrophages are poorly understood. Using two different mouse models of acute (perforating corneal incision injury) and chronic (corneal suture placement model) corneal injury, here we identified distinct functions of early- versus late-phase corneal wound macrophages in corneal HA and LA. Whereas earl ...[more]

PMID: 30670724

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Project description:Lymphangiogenesis is one of the major causes of corneal graft rejection. Among the lymphangiogenic factors, vascular endothelial growth factor (VEGF)-C and -D are considered to be the most potent. Both bind to VEGF receptor 3 (VEGFR3) to activate Prospero homeobox 1 (Prox1), a transcription factor essential for the development and maintenance of lymphatic vasculature. MicroRNAs (miRNAs) bind to the 3' untranslated regions (3' UTRs) of target genes in a sequence-specific manner and suppress gene expression. In the current study, we searched for miRNAs that target the pro-lymphangiogenic factor Prox1.Among the miRNAs predicted by the bioinformatic analysis to seed match with the 3' UTR of Prox-1, we chose 3 (miR-466, miR-4305, and miR-4795-5p) for further investigation. Both the miR-466 and miR-4305 mimics, but not the miR-4795-5p mimic, significantly reduced the luciferase activity of the Prox-1 3' UTR reporter vector. In primary lymphatic endothelial cells (HDLEC), miR-466 mimic transfection suppressed Prox1 mRNA and protein expression, while miR-4305 mimic transfection did not. Experiments using mutated reporter constructs of the two possible seed match sites on the 3' UTR of Prox1 suggested that the target site 2 directly bound miR-466. HDLEC transfected with the miR-466 mimic suppressed tube formation as compared to the scrambled control. Furthermore, HDLEC transfected with a miR-466 inhibitor showed enhanced tube formation as compared to control inhibitor transfected cells, and this inhibitory effect was counteracted by Prox1 siRNA. The miR-466 mimic reduced angiogenesis and lymphangiogenesis resulting in clearer corneas in an cornea injury rat model compared to the scrambled control.Our data suggest that miR-446 may have a protective effect on transplanted corneas by suppressing Prox1 expression at the post-transcriptional level. The results of the current study may provide insights into the mechanisms of lymphangiogenesis resulting from corneal graft rejection and alkali-burn injuries, as well as into the development of new treatments for lymphangiogenic eye diseases.

Dataset Information

Phase-specific functions of macrophages determine injury-mediated corneal hem- and lymphangiogenesis.

Publications

Phase-specific functions of macrophages determine injury-mediated corneal hem- and lymphangiogenesis.

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