Thomas Langmann - assoc. RG

Interferon-beta signaling in microglia as novel therapeutical concept for age-related macular degeneration

Abstract

Age-related macular degeneration (AMD) is a multifactorial disease leading to vision loss in elderly patients. Genome-wide association studies, analyses of human retinal tissue and animal models revealed that AMD pathogenesis involves chronic activation of innate immunity including complement factors and microglia reactivity in the retina. Established therapy for a sub-group of neovascular AMD patients involves intra-vitreal anti-VEGF (vascular epidermal growth factor) medication whereas no treatment exists for non-responders and patients with the atrophic form. We recently proposed that cellular components of the retinal immune system, namely reactive microglia could be novel therapeutic targets. We showed that lack of regulatory interferon-ß signaling in the retina accelerates mononuclear phagocyte reactivity and promotes choroidal neovascularization (CNV) in the murine laser model of neovascular AMD (Fig. 1A). Conversely, systemic interferon-ß (IFN-ß) therapy attenuated microgliosis and significantly reduced CNV (Fig. 1B). In the current project, we aim to 1) identify the underlying molecular mechanisms of how interferon signaling in microglia protects from inflammatory angiogenesis and whether these pathways are connected to the complement system. We also aim to 2) test the protective IFN-ß concept in a murine model for the dry atrophic form of AMD using a light damage paradigm. Deciphering the molecular pathways of IFN-ß signaling in the retina is fundamental for treating inflammatory and neovascular diseases of the retina including both sight-threatening forms of AMD.

Clinical/medical relevance and sustainability in disease understanding

AMD affects nearly 30% of elderly people. There is limited therapy for the neovascular form and no treatment for the atrophic form, which is present in 70% of all AMD patients. Both forms ultimately lead to legal blindness. Elucidating the molecular mechanisms of interferon-? signaling in the retina has a high translational relevance since novel therapeutical concepts are urgently required for the steadily increasing number of elderly AMD patients.


Prof. Dr. rer. nat. Thomas Langmann

Dept. of Ophthalmology

Prof. Dr. rer. nat. Thomas Langmann

Experimental Immunology of the Eye
assoc. CMMC Research Group

thomas.langmann@uk-koeln.de

Work +49 221 478 7324

Building 35 (Anatomy)
Joseph-Stelzmann-Str. 9
50931 Cologne

http://expimmeye.uni-koeln.de

Publications - Thomas Langmann

Link to PubMed

Figure 1

(A) More laser-lesion-associated reactive microglia (green) and choroidal neovascularization (CNV) (red) in Ifnar-deficient microglia and
(B) less microglia-reactivity and CNV in IFN-b treated retinas. Modified from Lückoff et al., EMBO Mol Med 2016.