Universität zu Köln

Hos, Deniz (2016). The Contribution of Macrophages to Inflammatory Corneal Lymphangiogenesis. PhD thesis, Universität zu Köln.

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Abstract

The cornea is physiologically devoid of blood and lymphatic vessels. However, severe inflammation can result in a secondary ingrowth of both vessel types, a process termed “corneal neovascularization”. Macrophages seem to play an important role in this process, although the underlying mechanisms are not well defined. Corneal blood vessels lead to reduced visual acuity when they grow into the optical center, and lymphatic vessels contribute to corneal transplant rejection, dry eye disease, or ocular allergy. In this regard, lymphatic vessels facilitate antigen presenting cell trafficking to the lymph nodes, where accelerated sensitization against allo- or autoantigens occurs. Thus, persistent corneal neovascularization is considered as harmful, and anti(lymph)angiogenic therapy has recently emerged as a novel approach in the treatment of several inflammatory corneal diseases. One aim of this work was to identify targets for anti(lymph)angiogenic therapy at the cornea and to identify effective anti(lymph)angiogenic compounds, which might be used to treat corneal neovascular diseases. Using a mouse model of sterile corneal inflammation, we found that glucocorticosteroids are strong Inhibitors of corneal (lymph)angiogenesis. Glucocorticosteroids suppressed macrophage infiltration into the cornea and inhibited pro-inflammatory cytokine expression in macrophages. Furthermore, we identified insulin receptor substrate-1 (IRS-1) as a mediator of inflammatory corneal (lymph)angiogenesis. IRS-1 was expressed by corneal macrophages, and inhibition of IRS-1 reduced vascular endothelial growth factor (VEGF)-A, VEGF-C and VEGF-D expression in these cells. Consistently, treatment of inflamed corneas with GS-101, an antisense oligonucleotide directed against IRS-1, strongly inhibited inflammatory corneal (lymph)angiogenesis. Another aim of this study was to analyze whether corneal lymphangiogenesis might also have beneficial functions, as studies in extraocular tissues had demonstrated that lymphatic vessels are also important to terminate inflammatory responses. However, studies showing similar functions for corneal lymphatic vessels were missing and the mediators of this putative anti-inflammatory process were unknown. Here, we analyzed the role of Interleukin-10 (IL-10), a primarily antiinflammatory cytokine, in the regulation of inflammatory corneal lymphangiogenesis. IL-10 was expressed in inflamed corneas by infiltrating macrophages. Furthermore, macrophages treated with IL-10 upregulated pro-lymphangiogenic VEGF-C expression, which is known to induce lymphatic vessel growth. IL-10 deficiency or conditional ablation of IL-10 signaling specifically in myeloid cells lead to reduced inflammatory corneal lymphangiogenesis and prolonged corneal Inflammation, whereas treatment with IL-10 promoted lymphangiogenesis and faster egress of macrophages from inflamed corneas. These results collectively indicate that IL-10 indirectly regulates corneal lymphangiogenesis and resolution of corneal inflammation via macrophages, which is the first report of a beneficial function of corneal lymphangiogenesis in (sterile) corneal inflammation. Taken together, we have identified novel anti(lymph)angiogenic compounds, which mainly affect the contribution of macrophages to inflammatory corneal lymphangiogenesis. Furthermore, we have described a novel anti-inflammatory role for corneal lymphangiogenesis, which is mediated by macrophages. Our work highlights the importance of macrophages for corneal lymphangiogenesis, and might contribute to future immunomodulatory therapeutic strategies promoting corneal repair or preventing disease.

Item Type:	Thesis (PhD thesis)
Creators:	Creators Email ORCID ORCID Put Code Hos, Deniz deniz.hos@uk-koeln.de UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-74004
Date:	2016
Language:	English
Faculty:	Faculty of Mathematics and Natural Sciences
Divisions:	Zentrum für Molekulare Medizin
Subjects:	Medical sciences Medicine
Uncontrolled Keywords:	Keywords Language Macrophages UNSPECIFIED Cornea UNSPECIFIED lymphangiogenesis UNSPECIFIED
Date of oral exam:	20 December 2016
Referee:	Name Academic Title Kashkar, Hamid Prof. Dr. Hammerschmidt, Matthias Prof. Dr.
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/7400